Epigenetic modulation for upregulation of genes

Abstract

The present disclosure is directed to compositions and methods for increasing expression of target genes in a cell, e.g., using an expression activator that comprises a targeting moiety that binds a target gene and an effector domain comprising an epigenetic activating domain. Systems comprising two or more expression activators are also disclosed.

Description

[0001]Attorney Docket: OGY-02925 EPIGENETIC MODULATION FOR UPREGULATION OF GENES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application Ser. No. 63 / 643,712 filed May 7, 2024, which is incorporated by reference herein in its entirety. BACKGROUND Epigenetic mechanisms mediate DNA sequence and homeostatic gene expression, with dysregulation at this pre-transcriptional interface found at the root of myriad diseases. SUMMARY Therapeutic modulation of the epigenome presents a unique opportunity to leverage endogenous mechanisms for pre-transcriptional control of gene expression, avoiding biological and developmental hurdles inherent with existing modalities. The disclosure provides, inter alia, epigenomic controllers (ECs) that can be mRNA-encoded proteins that target the epigenome with specificity for tunable and durable effect persisting after degradation of the mRNA product – decoupling pharmacokinetics (PK) and pharmacodynamics (PD) for an improved safety profile relative to existing modalities. In some embodiments, ECs consist of one or more protein domains (e.g., one or more activating domains and / or effector domains) selected from a validated library and tethered to custom, site-specific DNA-binding-domains to induce a desired regulatory effect. In some embodiments, this fusion is optimally encoded in an mRNA therapeutic producing one or several effector-DBD fusion proteins, delivered tissue-specifically using custom lipid nanoparticles (LNPs). The disclosure is based, at least in part, on the discovery of expression activators comprising a DNA-targeting moiety and an effector domain comprising epigenetic activating domains encoded by a fragment of a gene described herein. As demonstrated herein, the expression activators increased expression of multiple target genes. Accordingly, in some aspects, the disclosure provides an expression activator for increasing expression of a target gene comprising: (i) a DNA-targeting moiety that binds to a target sequence of 15-20 nucleotides in or near the target gene; and (ii) an effector domain comprising an epigenetic activating domain encoded by a fragment of a gene selected from MYBL1, DUX4, MYB, CEPBPD, ATF4, NCOA2, TP53, 1FH12877464.1 Attorney Docket: OGY-02925 FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2 and STB3. In some aspects, the disclosure provides an expression activator for increasing expression of a target gene comprising: (i) a DNA-targeting moiety that binds to a target sequence of 15-20 nucleotides in or near the target gene; and (ii) an effector domain comprising an epigenetic activating domain encoded by a fragment of a gene selected from MYBL1, DUX4, MYB, CEPBPD, ATF4, NCOA2, TP53, FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2, PA.v1b and STB3. In some embodiments, the DNA-targeting moiety comprises a zinc finger (ZF) domain. In some embodiments, the DNA-targeting moiety comprises a transcription activator-like effector (TALE) domain. In some embodiments, the DNA-targeting moiety comprises a nuclease inactive polypeptide and a gRNA comprising a sequence complementary to the target sequence. In some embodiments, the nuclease inactive polypeptide is a nuclease inactive Cas (dCas) polypeptide. In some embodiments, the nuclease inactive polypeptide is operably linked to at least one GCN4 peptide, and wherein the effector domain is operably linked to an antibody or antibody fragment specific for the at least one GCN4 peptide. In some embodiments, the antibody or antibody fragment is a scFv. In some embodiments, the effector domain comprises an amino acid sequence having at least 90% identity to an amino acid sequence selected from SEQ ID Nos: 1-35. In some embodiments, the effector domain comprises an amino acid sequence selected from SEQ ID Nos: 1-35. In some embodiments, the effector domain comprises an amino acid sequence having at least 90% identity to an amino acid sequence selected from SEQ ID Nos: 1-35 and 116. In some embodiments, the effector domain comprises an amino acid sequence selected from SEQ ID Nos: 1-35 and 116. In some embodiments, the target sequence is in or near a promoter region of the gene. In some embodiments, target sequence is in or near an enhancer region of the gene. In some embodiments, the effector domain demethylates a CpG island, methylates a histone, adds an acetyl group to a histone, binds to a methylated CpG island, binds to a protein to form heterochromatin, and / or binds a GATA sequence in DNA.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, the DNA-targeting moiety and the effector domain do not naturally occur in the same gene product. In some embodiments, the DNA binding moiety comprises a first polypeptide and the effector domain comprises a second polypeptide that is not covalently linked to the first polypeptide. In some embodiments, the DNA binding moiety and the effector domain comprise a single polypeptide. In some aspects, the disclosure provides a method of increasing expression of a target gene in a cell, comprising contacting the cell with an expression activator described herein. In some aspects, the disclosure provides a nucleic acid encoding an expression activator described herein. In some aspects, the disclosure provides a recombinant expression vector comprising ta nucleic acid described herein. In some aspects, the disclosure provide a messenger RNA (mRNA) encoding an expression activator described herein. In some aspects, the disclosure provides a lipid nanoparticle (LNP) comprising an expression activator, a nucleic acid, a recombinant expression vector, or an mRNA, described herein. In some aspects, the disclosure provides a pharmaceutical composition comprising an expression activator, a nucleic acid, a recombinant expression vector, an mRNA, or an LNP, described herein, and a pharmaceutically acceptable carrier. In some aspects, the disclosure provides a method of altering expression of a target gene in a cell, comprising contacting the cell with an expression activator, a nucleic acid, a recombinant expression vector, an mRNA, an LNP, or a pharmaceutical composition, described herein. In some embodiments, expression of the target gene is increased. BRIEF DESCRIPTION OF THE DRAWINGS FIGs.1A-1B provide graphs depicting Target Gene 1 mRNA expression following treatment with lipid nanoparticles (LNPs) having separate mRNAs encoding dCas9-SunTag and an scFv fused to an epigenetic activating domain of a polypeptide (VPR, VP64, NCOA2, LEUTX, E2F2, KLF15, INO80D, FOXO6, TP53, or PIP2), and gRNAs designed to target the distal promoter (FIG. 1A) or the proximal promoter (FIG.1B) of Target Gene 1 in K-562 cells as measured by RT-qPCR. mRNA expression was normalized based upon ACTB mRNA levels. Control cells were untreated. FIGs.2A-2B provide graphs depicting Target Gene 2 mRNA expression followingFH12877464.1 Attorney Docket: OGY-02925 treatment with LNPs having separate mRNAs encoding a dCas9-SunTag and an scFv fused to an epigenetic activating domain of a polypeptide (VPR, VP64, VP16, NCOA2, MYBL1, LEUTX, CREB3L1, E2F2, KLF15, UBN1, INO80D, FOXO6, or TP53), and gRNAs designed to target the enhancer, promoter, or enhancer and promoter of Target Gene 2 in HEP3B cells as measured by RT-qPCR. Control cells were untreated. mRNA expression was determined on Day 2 (FIG.2A) and Day 5 (FIG.2B). FIGs.3A-3B provide graphs depicting Target Gene 3 mRNA expression following treatment with LNPs having separate mRNAs encoding a dCas9-SunTag and an scFv fused to an epigenetic activating domain of a polypeptide (VPR, VP64, VP16, NCOA2, MYBL1, LEUTX, CREB3L1, E2F2, KLF15, UBN1, PIP2, INO80D, FOXO6, or TP53), and gRNAs designed to target the enhancer, promoter, or enhancer and promoter of Target Gene 3 in HEP3B cells as measured by RT-qPCR. Control cells were untreated. mRNA expression was determined on Day 2 (FIG.3A) and Day 5 (FIG.3B). FIGs.4A-4B provide graphs depicting Target Gene 4 mRNA expression following treatment with LNPs having separate mRNAs encoding a dCas9-SunTag and an scFv fused to an epigenetic activating domain of a polypeptide (MYBL1, E2F2, NCOA2, LEUTX, or CREB3L1), and gRNAs designed to target Site 1, Site 2, Site 3, Site 4, and Site 5 of Target Gene 4 in Hepa1-6 cells as measured by RT-qPCR. Control cells were untreated. mRNA expression was determined on Day 2 (FIG.4A) and Day 6 (FIG.4B). FIG.5 provides a graph depicting Target Gene 4 protein expression following treatment with LNPs having separate mRNAs encoding a dCas9-SunTag and an scFv fused to an epigenetic activating domain of a polypeptide (MYBL1, or E2F2), and gRNAs designed to target Site 1, Site 2, Site 3, Site 4, Site 5, or a combination thereof of Target Gene 4 in Hepa1-6 cells as measured by ELISA. Control cells were treated with mRNAs encoding a PIP2 polypeptide. Target Gene 4 protein expression was determined on Day 2. FIGs.6A-6D provide graphs depicting Target Gene 5 mRNA expression following treatment with LNPs having: an mRNA encoding a fusion polypeptide of a TAL designed to target Target Gene 5 and effector domain TET2 (TAL01-TET2) (control); mRNA encoding dCas9-SunTag and pooled gRNA targeting Target Gene 5 (control); mRNA encoding dCas9- SunTag, pooled gRNA, and mRNA encoding an scFv fused to an epigenetic activating domain of a polypeptide (NCOA2 or LEUTX), with or without mRNA encoding TAL01- TET2. Target Gene 5 mRNA expression was determined by RT-PCR either before (FIG.6A) or after (FIG.6B) cells were sorted for GFP expression. After 15 days, unsorted (FIG.6C) or sorted (FIG.6D) cells were re-transfected and mRNA expression was determined.FH12877464.1 Attorney Docket: OGY-02925 FIGs.7A-7B provide graphs depicting Target Gene 6 mRNA expression following treatment with LNPs having separate mRNAs encoding a dCas9-SunTag and an scFv fused to an epigenetic activating domain of a polypeptide (VP64, VP16, NCOA2, MYBL1, LEUTX, CREB3L1, E2F2, KLF15, FOXO3, UBN1, INO80D, or FOXO6), and gRNAs designed to target a site in Target Gene 6 in K-562 cells as measured by RT-qPCR. Control cells were untreated. mRNA expression was determined on Days 1, 2, 3, 4, 7, 8, 11, 14, 17, 21, 25, 28, 32, and 35. FIGs.8A-8B provide graphs depicting Target Gene 7 mRNA expression following treatment with LNPs having separate mRNAs encoding a dCas9-VPR and an scFv fused to an epigenetic activating domain of a polypeptide (NCOA2, MYBL1, LEUTX, CREB3L1, or E2F2), and gRNAs designed to target Site 1 and Site 2 of Target Gene 7 in Hepa1-6 cells as measured by RT-qPCR. Control cells were untreated. mRNA expression was determined on Days 4, 12, and 18. FIGs.9A-9B provide graphs depicting Target Gene 8 mRNA expression following treatment with LNPs having separate mRNAs encoding an scFv fused to an epigenetic activating domain of a NCOA2 or a PA.v1b polypeptide, and gRNAs designed to target Site 1, Site 2, Site 3, and Site 4 of Target Gene 8 in Hepa1-6 cells as measured by RT-qPCR. Control cells were untreated. mRNA expression was determined on Days 3, and 7. mRNA expression was determined using gRNAs targeting Site 1, Site 2, Site 3, and Site 4 of Target Gene 8 either in combination (FIG.9A) or individually (FIG.9B). FIG.10 provides graphs depicting Target Gene 9 mRNA expression following treatment with LNPs having separate mRNAs encoding a dCas9-SunTag and an scFv fused to an epigenetic activating domain of a polypeptide (LEUTX, or NOCA2), and gRNAs designed to target the promoter, enhancer or both regions of Target Gene 9 in Hepa1-6 cells as measured by RT-qPCR. Control cells were untreated. mRNA expression was determined on Day 2. FIG.11A provides a graph depicting Target Gene 4 protein expression in serum extracted from C57BL / J6 mice following treatment with LNPs having separate mRNAs encoding a dCas9-SunTag and an scFv fused to an epigenetic activating domain of a polypeptide (NCOA2, or LEUTX), and a gRNA designed to target Site 1 of Target Gene 4. Target Gene 4 protein levels were measured by ELISA at 0, 3, and 8 days post- administration. Buffer (PBS) containing no LNPs were used as a control. FIG.11B provides a graph depicting normalized serum Target Gene 4 protein levels, expressed as a percentage of Day 0 baseline, in male C57BL / J6 mice treated with PBS,FH12877464.1 Attorney Docket: OGY-02925 NCOA2, or LEUTX LNPs as described in FIG.11A. FIG.11C provides a graph depicting relative Target Gene 4 mRNA expression in liver tissue collected 8 days after treatment with PBS, NCOA2, or LEUTX LNPs as described in FIG.11A. The expression levels were normalized to the housekeeping gene 36b4 and measured using RT-qPCR. FIG.12 provides a graph depicting Target Gene 4 protein expression in serum extracted from C57BL / J6 mice following treatment with LNPs having separate mRNAs encoding a dCas9-SunTag and an scFv fused to an epigenetic activating domain of a polypeptide (NCOA2, TET2-XTEN80-dCas9+NCOA2, PA.v1b, E2F2, MYBL1, KLF15, or PRDM9), and a gRNA designed to target Site 1 of Target Gene 4. Target Gene 4 protein levels were measured by ELISA at -1, 2, and 6 days post-administration. Buffer (PBS) containing no LNPs was used as a control. FIG.13A provides a graph depicting Target Gene 4 protein expression in serum extracted from C57BL / J6 mice following treatment with LNPs having separate mRNAs encoding a dCas9-SunTag and an scFv fused to an epigenetic activating domain of a polypeptide (NCOA2, PA.v1b, E2F2, MYBL1, or KLF15), and a gRNA designed to target Site 1 of Target Gene 4. Target Gene 4 protein levels were measured by ELISA at -1, 2, and 6 days post-administration. Buffer (PBS) containing no LNPs was used as a control and data was normalized as a percentage of Day 0. FIG.13B provides a graph depicting Target Gene 4 protein expression in serum extracted from C57BL / J6 mice following treatment with LNPs having an mRNAs encoding a dCas9-SunTag, an scFv fused to an epigenetic activating domain of a TET2-XTEN80- dCas9+NCOA2 polypeptide, and a gRNA designed to target Site 1 of Target Gene 4. Target Gene 4 protein levels were measured by ELISA at -1, 2, and 6 days post-administration. Buffer (PBS) containing no LNPs was used as a control and data was normalized as a percentage of Day 0. FIG.13C provides a graph depicting Target Gene 4 protein expression in serum extracted from C57BL / J6 mice following treatment with LNPs having an mRNAs encoding a dCas9-SunTag, an scFv fused to an epigenetic activating domain of a PRDM9 polypeptide, and a gRNA designed to target Site 1 of Target Gene 4. Target Gene 4 protein levels were measured by ELISA at -1, 2, and 6 days post-administration. Buffer (PBS) containing no LNPs was used as a control and data was normalized as a percentage of Day 0. FIG.14 provides a graph depicting relative Target Gene 8 mRNA expression in liver tissue from C57BL / J6 mice following treatment with LNPs having separate mRNAsFH12877464.1 Attorney Docket: OGY-02925 encoding a an scFv fused to an epigenetic activating domain of a NCOA2 polypeptide, and a gRNA designed to target Site 4 of Target Gene 8. Target Gene 8 mRNA levels were measured by RT-qPCR at 3, 22, and 36 days after administration of the first dose. Buffer (PBS) containing no LNPs was used as a control. FIG.15 provides a graph depicting relative body weight data C57BL / J6 mice following treatment with LNPs having separate mRNAs encoding an scFv fused to an epigenetic activating domain of a NCOA2 polypeptide, and a gRNA designed to target Site 4 of Target Gene 8. Body weight was measured out to 36-days after administration of the first dose. Buffer (PBS) containing no LNPs was used as a control and data was normalized as a percentage of Day 0. FIG.16 provides a graph depicting the levels of Target Gene 6 mRNA, following treatment of human K562 cells with MC3 LNP-formulated ZF-NCOA2 or ZF-LEUTX (ZF: engineered zinc finger protein targeting the promoter DNA sequence of Target Gene 6 and fused to a transcriptional co-activator NCOA2 or LEUTX), as measured by RT-qPCR. mRNA expression was normalized based upon ACTB (housekeeper) mRNA levels. Control cells were untreated. mRNA expression was determined on Days 1, 2, 7, and 14. DETAILED DESCRIPTION The present disclosure is based, at least in part, on the discovery of epigenetic activating domains of polypeptides. Use of the activating domains as an effector domain in combination with a DNA-targeting moiety specific for a target sequence (e.g., one or more transcriptional control elements) allows for upregulation of a gene. In some aspects, the present disclosure provides epigenomic controllers (ECs) comprising a DNA-targeting moiety and an epigenetic activating domain encoded by a fragment of a gene selected from MYBL1, DUX4, MYB, CEPBPD, ATF4, NCOA2, TP53, FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2 and STB3. In some aspects, the present disclosure provides epigenomic controllers (ECs) comprising a DNA- targeting moiety and an epigenetic activating domain encoded by a fragment of a gene selected from MYBL1, DUX4, MYB, CEPBPD, ATF4, NCOA2, TP53, FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2, STB3, and PA.v1b. As used herein, the term “expression activator” refers to an agent or entity with one or more functionalities that increases expression of a target gene in a cell andFH12877464.1 Attorney Docket: OGY-02925 that specifically binds to a DNA sequence (e.g., a DNA sequence associated with a target gene or a transcription control element operably linked to a target gene). As demonstrated herein, introducing an mRNA encoding an exemplary expression activator of the disclosure to a cell, wherein the exemplary expression activator comprised (i) a DNA-targeting moiety that binds a target sequence in a region of the genome comprising a gene transcriptional control element (e.g., a promoter); and (ii) an effector domain comprising an epigenetic activating domain, increased expression of the gene. Accordingly, in some aspects, the present disclosure provides an expression activator comprising (i) a DNA-targeting moiety that binds a target sequence; and (ii) an effector domain comprising an epigenetic activating domain. In some embodiments, the expression activator comprises a single DNA-targeting moiety. In some embodiments, the expression activator comprises more than one DNA-targeting moiety. In some embodiments, the expression activator comprises a single effector domain. In some embodiments, the expression activator comprises one or more effector domains. In some embodiments, the expression activator comprises more than one effector domain. In some embodiments, the expression activator comprises one to four effector domains. In some embodiments, the expression activator comprises two effector domains. In some embodiments, the target sequence is a span of nucleotides (e.g., 10-50, 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in or near an insulated genomic domain (IGD) comprising a target gene. As further described herein and understood by one of ordinary skill in the art, IGDs are units of genomic space with boundaries defined by factors that mechanistically drive functional insulation between gene transcription activities. Thus, IGDs are physical units that serve to parse chromosomes into discrete functional segments. For example, in some embodiments, an IGD comprises a DNA loop formed by interactions between two DNA sites bound by homodimerized CTCF and cohesin (see Dowen, et al (2014) Cell 159:374-87). In such an IGD, occupation of each of the DNA sites bound by CTCF and cohesin inhibits DNA-bound components on one chromosomal side of the DNA site from interacting with DNA-bound components on the opposite chromosomal side. Consequently, the DNA sites occupied by CTCF and cohesin in such DNA loops act as boundaries for the IGD. In some embodiments, the formation of such DNA loops facilitates (i) enhancer-promoter interactions in which both the enhancer and promoter are within the loop, (ii) inhibition of enhancer-promoter interactions in which one of those elements is within the loop and the other is outside the loop, or (iii) both (i) and (ii).FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, the target sequence is in or near a promoter. In some embodiments, the target sequence is in or near an enhancer element. In some embodiments, the DNA-targeting moiety comprises a polypeptide that binds the target sequence. In some embodiments, the DNA-targeting moiety comprises a zinc finger (ZF) domain that binds the target sequence. In some embodiments, the DNA-targeting moiety comprises a transcription activator-like effector (TALE) domain that binds the target sequence. In some embodiments, the DNA-targeting moiety comprises a catalytically inactive site-directed nuclease (e.g., a catalytically inactive Cas nuclease) and a guide sequence, wherein the guide sequence is complementary, or substantially complementary, to the target sequence. In some embodiments, the effector domain induces one or more epigenetic changes. In some embodiments, the effector domain recruits components of the endogenous transcriptional machinery to increase expression of the target gene. In some embodiments, the effector domain is a polypeptide, that upon binding to a transcriptional control element, recruits one or more activator proteins and / or transcription factors to activate, or substantially activate, gene transcription. In some embodiments, the effector domain promotes recruitment of transcription factors, thereby increasing expression of the target gene. In some embodiments, the effector domain comprises an epigenetic modifying moiety (e.g., a moiety for introducing an epigenetic modification in or near the target gene). In some embodiments, the effector domain is an enzyme, that upon binding to a transcriptional control element, catalyzes one or more modifications of a genomic region comprising the transcriptional control element, wherein the one or more modifications activates, or substantially activates, gene transcription. In some embodiments, the one or more modifications are selected from a DNA modification and a histone modification. In some aspects, the disclosure provides a nucleic acid encoding an expression activator described herein. In some embodiments, the nucleic acid is an mRNA. In some aspects, the disclosure provides a recombinant expression vector comprising the nucleic acid. In some embodiments, the expression activator , the nucleic acid (e.g., mRNA), or the recombinant expression vector is formulated in a lipid nanoparticle (LNP). In some aspects, the disclosure provides a system comprising two or more expression activators described herein. In some embodiments, the system comprises 2, 3, 4, 5, 6, 7, 8, 9, or 10 expression activators described herein. In some embodiments, the system comprises two or more nucleic acids, wherein each nucleic acid encodes an expression activator described herein. In some embodiments, the two or more nucleic acids are each mRNAs. In some embodiments, the system comprises two or more recombinant expression vectors,FH12877464.1 Attorney Docket: OGY-02925 wherein each recombinant expression vector comprises a nucleic acid encoding an expression activator described herein. In some embodiments, the two or more expression activators, the two or more nucleic acids, or the two or more recombinant expression vectors are formulated in the same LNP or in different LNPs. In some aspects, the disclosure provides a nucleic acid encoding two or more expression activators (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 expression activators) described herein. In some embodiments, the nucleic acid is an mRNA. In some embodiments, the disclosure provides a recombinant expression vector comprising the nucleic acid. In some embodiments, the nucleic acid or the recombinant expression vector is formulated in an LNP. In some aspects, the disclosure provides a pharmaceutical composition comprising an expression activator described herein, a nucleic acid described herein, a recombinant expression vector described herein, an LNP described herein, or a system described herein, and a pharmaceutically acceptable carrier. In some aspects, the disclosure provides a method of altering (e.g., increasing) expression of a target gene in a cell, comprising contacting the cell with an expression activator described herein, a nucleic acid described herein, a recombinant expression vector described herein, an LNP described herein, a system described herein, or a pharmaceutical composition described herein. In some embodiments, expression of target gene is increased compared to a control cell not contacted with the expression activator, nucleic acid, recombinant expression vector, LNP, system, or pharmaceutical composition. In some aspects, the disclosure provides a method of introducing one or more epigenetic modifications to a region comprising a transcriptional control element of a target gene in a cell, the method comprising contacting the cell with an expression activator described herein, a nucleic acid described herein, a recombinant expression vector described herein, an LNP described herein, a system described herein, or a pharmaceutical composition described herein. In some embodiments, the transcriptional control element comprises a promoter of the target gene. In some embodiments, the one or more epigenetic modifications comprises DNA demethylation and / or histone modification. Expression Activators In some embodiments, the disclosure provides an expression activator for altering (e.g., increasing) expression of one or more target genes (e.g., human target genes). In some embodiments, the disclosure provides an expression activator for increasing expression of human target genes.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, an expression activator of the disclosure has a targeting function and an effector function. In some embodiments, the targeting function localizes the effector function of the expression activator to a region of the genome. In some embodiments, the region of the genome comprises an IGD of a target gene. In some embodiments, the region of the genome is in the IGD of the target gene. In some embodiments, the effector function comprises introducing one or more epigenetic modifications to the region of the genome. In some embodiments, the expression activator comprises a DNA-targeting moiety and an effector domain. In some embodiments, the targeting function of the expression activator is mediated by the DNA-targeting moiety. In some embodiments, the targeting function is mediated by the DNA-targeting moiety binding to a target sequence in the region of the genome. In some embodiments, the effector domain is a transcriptional activator moiety described herein. In some embodiments, the DNA-targeting moiety binds to a target sequence in the target gene, whereupon the effector domain of the expression activator functions to introduce one or more epigenetic modifications to a region in the target gene. In some embodiments, the DNA-targeting moiety binds to a target sequence in a genomic region comprising the target gene IGD (e.g., the human target gene IGD), whereupon the effector domain of the expression activator functions to introduce one or more epigenetic modifications to a region in or near the target gene IGD (e.g., the human target gene IGD). In some embodiments, the DNA-targeting moiety binds to a target sequence in the target gene IGD (e.g., the human target gene IGD), whereupon the effector domain of the expression activator functions to introduce one or more epigenetic modifications to a region in the target gene IGD (e.g., the human target gene IGD). In some embodiments, one or more epigenetic modifications is introduced to a transcriptional control element (e.g., promoter or enhancer) of a target gene (e.g., a human target gene), or a portion thereof. In some embodiments, the one or more epigenetic modifications results in increased expression of a target gene (e.g., a human target gene), e.g., as compared to a control cell not contacted with the expression activator. Target Sequences In some embodiments, the DNA-targeting moiety binds to a target sequence in a target gene. In some embodiments, the DNA-targeting moiety binds to a target sequence in aFH12877464.1 Attorney Docket: OGY-02925 genomic region comprising the IGD of the target gene . In some embodiments, the DNA- targeting moiety binds to a target sequence in the IGD of the target gene. In some embodiments, the DNA-targeting moiety comprises a ZF that binds the target sequence in a genomic region comprising the IGD of the target gene. In some embodiments, the DNA-targeting moiety comprises a ZF that binds the target sequence in the IGD. In some embodiments, the DNA-targeting moiety comprises a TALE that binds the target sequence in a genomic region comprising the IGD of the target gene. In some embodiments, the DNA- targeting moiety comprises a TALE that binds the target sequence in the IGD. In some embodiments, the DNA-targeting moiety comprises a site-directed nuclease (e.g., a catalytically inactive site-directed nuclease) that binds the target sequence in a genomic region comprising the IGD of the target gene. In some embodiments, the DNA-targeting moiety comprises a site-directed nuclease (e.g., a catalytically inactive site-directed nuclease) that binds the target sequence in the IGD. In some embodiments, the site-directed nuclease comprises a Cas nuclease described herein (e.g., a catalytically inactive Cas nuclease) and a gRNA comprising a spacer sequence corresponding to the target sequence. The spacer sequence is a sequence that defines the target sequence. The target sequence is present in a double-stranded genomic DNA having one strand comprising the target sequence comprising a protospacer sequence adjacent to a PAM sequence that is referred to as the “PAM strand,” and a second strand that is referred to as the “non-PAM strand” and is complementary to the PAM strand. Both the gRNA spacer sequence and the target sequence are complementary to the non-PAM strand of the genomic DNA molecule. As used herein, a spacer sequence “corresponding to” a target sequence refers to a guide sequence that binds to the non-PAM strand of the target sequence by Watson-Crick base-pairing, wherein the spacer sequence has sufficient complementarity to the non-PAM strand as to enable targeting of the Cas nuclease to the target sequence in the genomic DNA molecule. In some embodiments, the spacer sequence has up to 1, 2, or 3 mismatches relative to the target sequence in the genomic DNA molecule, wherein the spacer sequence has sufficient complementarity to the non-PAM strand as to enable targeting of the Cas nuclease to the target sequence in the genomic DNA molecule. In some embodiments, the DNA-targeting moiety binds to a target sequence in a genomic region comprising the IGD, wherein the target sequence is upstream of or in a 5^boundary of the IGD. In some embodiments, the target sequence is between a 5^ and 3^boundary of the IGD. In some embodiments, the target sequence is downstream of or in the 3^boundary of the IGD. In some embodiments, the DNA-targeting moiety binds to a targetFH12877464.1 Attorney Docket: OGY-02925 sequence in the IGD, wherein the target sequence is in a region (e.g., a 0.5-2kb region) comprising a transcriptional control element (e.g., a promoter or enhancer). In some embodiments, the region comprises a promoter. In some embodiments, the target sequence is in a promoter. In some embodiments, the region comprises an enhancer. In some embodiments, the target sequence is in an enhancer. In some embodiments, the target sequence is in or near a CpG island in the IGD. In some embodiments, the target is in a region of about 100 bases, about 200 bases, about 300 bases, about 400 bases, about 500 bases, about 600 bases, about 700 bases, about 800 bases, about 900 bases, about 1,000 bases, about 1,100 bases, about 1,200 bases, about 1,300 bases, about 1,400 bases, about 1,500 bases, about 1,600 bases, about 1,700 bases, about 1,800 bases, about 1,900 bases, or about 2,000 bases comprising the CpG island. In some embodiments, the target is in a region of about 100 bases, about 200 bases, about 300 bases, about 400 bases, about 500 bases, about 600 bases, about 700 bases, about 800 bases, about 900 bases, or about 1,000 bases comprising the CpG island. In some embodiments, the target sequence is not more than about 300 bases, about 400 bases, or about 500 bases upstream or downstream the CpG island. In some embodiments, the target sequence is in the CpG island. In some embodiments, the DNA-targeting moiety binds to a target sequence in the IGD, wherein the target sequence is in a region (e.g., a 0.5-2kb region) comprising a transcriptional control element (e.g., a promoter) of the gene. In some embodiments, the target sequence is in a region comprising a promoter of the gene. As used herein, “promoter” refers to a genomic region upstream of a transcriptional start sequence (TSS) of a transcript of interest. The promoter may include 50 bp, 100 bp, 150 bp, 200 bp, 250 bp, 300 bp, 400 bp, 500 bp, 600 bp, 700 bp, 800 bp, 900 bp, or 1000 bp upstream of a TSS. In some embodiments, the target sequence is in a region comprising an enhancer of the gene. In some embodiments, the target sequence is in a coding region of the gene. The length of the target sequence depends on the DNA-targeting moiety used. In some embodiments, the DNA-targeting moiety comprises a ZF and the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides. In some embodiments, the DNA-targeting moiety comprises a ZF and the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides. In some embodiments, the DNA-targeting moiety comprises a ZF and the target sequence is 15 nucleotides. In some embodiments, the DNA-targeting moiety comprises a ZF and the target sequence is 16 nucleotides. In some embodiments, the DNA-FH12877464.1 Attorney Docket: OGY-02925 targeting moiety comprises a ZF and the target sequence is 17 nucleotides. In some embodiments, the DNA-targeting moiety comprises a ZF and the target sequence is 18 nucleotides. In some embodiments, the DNA-targeting moiety comprises a ZF and the target sequence is 19 nucleotides. In some embodiments, the DNA-targeting moiety comprises a ZF and the target sequence is 20 nucleotides. In some embodiments, the DNA-targeting moiety comprises a TALE and the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides. In some embodiments, the DNA-targeting moiety comprises a TALE and the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides. In some embodiments, the DNA-targeting moiety comprises a TALE and the target sequence is 15 nucleotides. In some embodiments, the DNA-targeting moiety comprises a TALE and the target sequence is 16 nucleotides. In some embodiments, the DNA-targeting moiety comprises a TALE and the target sequence is 17 nucleotides. In some embodiments, the DNA-targeting moiety comprises a TALE and the target sequence is 18 nucleotides. In some embodiments, the DNA-targeting moiety comprises a TALE and the target sequence is 19 nucleotides. In some embodiments, the DNA-targeting moiety comprises a TALE and the target sequence is 20 nucleotides. In some embodiments, the DNA-targeting moiety comprises a site-directed nuclease (e.g., a catalytically inactive site-directed nuclease) and the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides. In some embodiments, the DNA-targeting moiety comprises a site-directed nuclease (e.g., a catalytically inactive site-directed nuclease) and the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides. In some embodiments, the DNA-targeting moiety comprises a site-directed nuclease (e.g., a catalytically inactive site-directed nuclease) and the target sequence is 15 nucleotides. In some embodiments, the DNA-targeting moiety comprises a site-directed nuclease (e.g., a catalytically inactive site-directed nuclease) and the target sequence is 16 nucleotides. In some embodiments, the DNA-targeting moiety comprises a site-directed nuclease (e.g., a catalytically inactive site-directed nuclease) and the target sequence is 17 nucleotides. In some embodiments, the DNA-targeting moiety comprises a site-directed nuclease (e.g., a catalytically inactive site-directed nuclease) and the target sequence is 18 nucleotides. In some embodiments, the DNA-targeting moiety comprises a site-directed nuclease (e.g., aFH12877464.1 Attorney Docket: OGY-02925 catalytically inactive site-directed nuclease) and the target sequence is 19 nucleotides. In some embodiments, the DNA-targeting moiety comprises a site-directed nuclease (e.g., a catalytically inactive site-directed nuclease) and the target sequence is 20 nucleotides. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a genomic region comprising an IGD. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a genomic region comprising the IGD. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in a genomic region comprising the IGD. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in the IGD. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in the IGD. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in the IGD. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a region (e.g., a 0.1-2kb region) of the IGD, wherein the region comprises a transcriptional control element (e.g., a promoter or enhancer). In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises a transcriptional control element (e.g., a promoter or enhancer). In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises a transcriptional control element (e.g., a promoter or enhancer). In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a transcriptional control element (e.g., a promoter or enhancer) in the IGD. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a transcriptional control element (e.g., a promoter or enhancer) in the IGD. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19,FH12877464.1 Attorney Docket: OGY-02925 or about 20 nucleotides in a transcriptional control element (e.g., a promoter or enhancer) in the IGD. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises a promoter. In some embodiments, the target sequence is within or overlapping the promoter. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises a promoter. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises a promoter. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a promoter in the IGD. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a promoter in the IGD. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in a promoter in the IGD. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a region (e.g., a 0.1-2kb region) of the IGD, wherein the region comprises an enhancer. In some embodiments, the target sequence is within or overlapping the enhancer. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a region (e.g., a 0.1-2kb region) of the IGD, wherein the region comprises an enhancer. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in a region (e.g., a 0.1-2kb region) of the IGD, wherein the region comprises an enhancer. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in an enhancer in the IGD. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in an enhancer in the IGD. In some embodiments, the target sequence is about 10,FH12877464.1 Attorney Docket: OGY-02925 about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in an enhancer in the IGD. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a region (e.g., a 0.1-2kb region) of the IGD, wherein the region comprises a CTCF binding site (e.g., a CTCF binding site at a boundary of the IGD or a CTCF binding site in the IGD). In some embodiments, the target sequence is within or overlapping the CTCF binding site. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a region (e.g., a 0.1- 2kb region) of the IGD, wherein the region comprises a CTCF binding site (e.g., a CTCF binding site at a boundary of the IGD or a CTCF binding site in the IGD). In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in a region (e.g., a 0.1-2kb region) of the IGD, wherein the region comprises a CTCF binding site (e.g., a CTCF binding site at a boundary of the IGD or a CTCF binding site in the IGD). In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises an enhancer. In some embodiments, the target sequence is within or overlapping the enhancer. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises an enhancer. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises an enhancer. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises a CpG island. In some embodiments, the target sequence is within or overlapping the CpG island. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a region (e.g., a 0.1-2kb region) of the of the IGD, wherein the region comprises a CpG island. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16,FH12877464.1 Attorney Docket: OGY-02925 about 17, about 18, about 19, or about 20 nucleotides in a region (e.g., a 0.1-2 kb region) of the of the IGD, wherein the region comprises a CpG island. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in an enhancer. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in an enhancer. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in an enhancer. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises a promoter. In some embodiments, the target sequence is within or overlapping a target gene promoter. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises a promoter. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in a region (e.g., a 0.1-2 kb region) of the IGD, wherein the region comprises a promoter. In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a promoter. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a promoter. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in a promote). In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) in a region (e.g., a 0.1-2 kb region) of the target gene. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides in a region (e.g., a 0.1-2 kb region) of the target gene. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides in a region (e.g., a 0.1-2 kb region) of the target gene.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, the target sequence is 10-50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides). In some embodiments, the target sequence is about 10- 50 nucleotides (e.g., 10-40, 10-30, 15-30, 15-25, or 15-20 nucleotides) within a region of about 200 or fewer nucleotides. In some embodiments, the target sequence is about 10 to about 50 nucleotides, about 10 to about 40 nucleotides, about 10 to about 30 nucleotides, about 10 to about 20 nucleotides, or about 15 to about 20 nucleotides within a region of about 200 or fewer nucleotides. In some embodiments, the target sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 nucleotides within a region of about 200 or fewer nucleotides. In some embodiments, the region comprises 10, 11, 12, 13, 14, 15, 16, 17, or 18 contiguous nucleotides of the sequence. In some embodiments, the region is about 175, about 150, about 125, about 100, about 90, about 80, about 70, about 60, about 50, about 45, about 40, about 35, about 30, about 25, or about 20 nucleotides. In some embodiments, the target sequence is 15, 16, 17, 18, 19, or 20 nucleotides. In some embodiments, the DNA-targeting moiety binds to the target sequence with submicromolar or nanomolar binding affinity (KD). Binding affinity is typically measured and reported by the equilibrium dissociation constant (KD), which is used to evaluated and rank strengths of bimolecular interactions. As used herein, the term “KD” or “KD” refers to the equilibrium dissociation constant of a binding reaction between an DNA-targeting moiety and a target sequence. The value of KD is a numeric representation of the ratio of the DNA- targeting moiety off-rate constant (kd) to the on-rate constant (ka). The value of KD is inversely related to the binding affinity of the DNA-targeting moiety and target sequence. The smaller the KD value the greater the affinity. As used herein, the term “kd” or “kd” (alternatively “koff” or “koff”) is intended to refer to the off- rate constant for the dissociation of the DNA-targeting moiety from a complex of the DNA-targeting moiety and the target sequence. The value of kd is a numeric representation of the fraction of complexes that decay or dissociate per second, and is expressed in units sec-1. As used herein, the term “ka” or “ka” (alternatively “kon” or “kon”) is intended to refer to the on-rate constant for the association of the DNA-targeting moiety and the target sequence. The value of ka is a numeric representation of the number of DNA-targeting moiety / target DNA complexes formed per second in a 1 molar (1M) solution of the DNA-targeting moiety and the target DNA, and is expressed in units M-1sec-1. Methods to measure binding affinity (KD) of a DNA-targeting moiety to the target sequence include, but are not limited to, DNA electrophoretic mobility shift assay (EMSA) and surface plasmon resonance.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, the DNA-targeting moiety (e.g., TALE, ZF, dCas9 / gRNA) binds to the target sequence with an affinity (KD) of less than about 5^M, about 4.5^M, about 4^M, about 3.5^M, about 3^M, about 2.5^M, about 2^M, about 1.5^M, about 1^M, about 0.5 ^M, or about 0.1^M. In some embodiments, the DNA-targeting moiety (e.g., TALE, ZF, dCas9 / gRNA) binds to the target sequence with an affinity (KD) that is no greater than about 950, 900, 850, 800, 750, 700, 650, 600, 500, 500, 450, 400, 350, 300, 250, 200, 250, 200, 175, 150, 125, 110, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 nM. In some embodiments, the DNA-targeting moiety binds to the target sequence with an affinity (KD) of about 1 nM to about 100 nM, about 10 nM to about 500 nM, about 100 nM to about 1^M, about 500 nM to about 1 ^M, about 500 nM to about 2 ^M, about 1 ^M to about 2 ^M, about 1 ^M to about 3 ^M, about 1 ^M to about 4 ^M, or about 1 ^M to about 5 ^M. In some embodiments, the DNA-targeting moiety binds to the target sequence with an affinity (KD) of about 1 nM to about 10 nM, about 1 nM to about 20 nM, about 1 nM to about 30 nM, about 1 nM to about 40 nM, about 1 nM to about 50 nM, about 10 nM to about 50 nM, about 10 nM to about 100 nM, about 10 nM to about 200 nM, about 50 nM to about 200 nM, about 50 nM to about 300 nM, about 50 nM to about 400 nM, or about 50 nM to about 50 nM. DNA-targeting moiety The present disclosure provides, e.g., expression activators comprising a DNA- targeting moiety that specifically targets, e.g., binds, a genomic sequence element (e.g., a promoter, a TSS, or an anchor sequence) in, proximal to, and / or operably linked to a target gene. In some embodiments, the DNA-targeting moiety specifically binds to a DNA sequence, e.g., a DNA sequence associated with a target gene. Any molecule or compound that specifically binds a DNA sequence may be used as a DNA-targeting moiety. In some embodiments, the DNA-targeting moiety targets, e.g., binds, a component of a genomic complex. In some embodiments, the DNA-targeting moiety targets, e.g., binds, a transcriptional control sequence (e.g., a promoter or enhancer) operably linked to the target gene. In some embodiments, the DNA-targeting moiety targets, e.g., binds, a target gene or a part of a target gene. The target of a DNA-targeting moiety may be referred to as its targeted component. A targeted component may be any genomic sequence element operably linked to a target gene, or the target gene itself, including but not limited to a promoter, enhancer, anchor sequence, exon, intron, UTR encoding sequence, a splice site, or a transcription start site. In some embodiments, the DNA-targeting moiety binds specifically to one or moreFH12877464.1 Attorney Docket: OGY-02925 target anchor sequences (e.g., within a cell) and not to non-targeted anchor sequences (e.g., within the same cell). In some embodiments, the DNA-targeting moiety comprises a CRISPR / Cas domain (e.g., a catalytically inactive CRISPR / Cas domain), a TAL effector domain, a Zn finger domain, a peptide nucleic acid (PNA), or a nucleic acid molecule. In some embodiments, an expression activator of the disclosure comprises one DNA- targeting moiety. In some embodiments, the expression activator comprises a plurality of DNA targeting moieties, wherein each DNA-targeting moiety does not detectably bind, e.g., does not bind, to another DNA-targeting moiety. In some embodiments, the DNA-targeting moiety binds to its target sequence with a KD of less than or equal to 500, 450, 400, 350, 300, 250, 200, 150, 100, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.005, 0.002, or 0.001 nM (and optionally, a KD of at least 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.005, 0.002, or 0.001 nM). In some embodiments, the DNA-targeting moiety binds to its target sequence with a KD of 0.001 nM to 500 nM, e.g., 0.1 nM to 5 nM, e.g., about 0.5 nM. In some embodiments, a DNA-targeting moiety binds to a non-target sequence with a KD of at least 500, 600, 700, 800, 900, 1000, 2000, 5000, 10,000, or 100,000 nM (and optionally, does not appreciably bind to a non-target sequence). In some embodiments, the DNA-targeting moiety does not substantially bind to a non-target sequence. CRISPR / Cas Domains In some embodiments, the DNA-targeting moiety comprises a CRISPR / Cas domain. A CRISPR / Cas protein can comprise a CRISPR / Cas effector and optionally one or more other domains. A CRISPR / Cas domain typically has structural and / or functional similarity to a protein involved in the clustered regulatory interspaced short palindromic repeat (CRISPR) system, e.g., a Cas protein. The CRISPR / Cas domain optionally comprises a guide RNA, e.g., single guide RNA (sgRNA). In some embodiments, the gRNA comprised by the CRISPR / Cas domain is noncovalently bound by the CRISPR / Cas domain. CRISPR systems are adaptive defense systems originally discovered in bacteria and archaea. CRISPR systems use RNA-guided nucleases termed CRISPR-associated or “Cas” endonucleases (e.g., Cas9 or Cpfl) to cleave foreign DNA. For example, in a typical CRISPR / Cas system, an endonuclease is directed to a target nucleotide sequence (e. g., a siteFH12877464.1 Attorney Docket: OGY-02925 in the genome that is to be sequence-edited) by sequence specific, non-coding “guide RNAs” that target single- or double-stranded DNA sequences. Three classes (I-III) of CRISPR systems have been identified. The class II CRISPR systems use a single Cas endonuclease (rather than multiple Cas proteins). One class II CRISPR system includes a type II Cas endonuclease such as Cas9, a CRISPR RNA (“crRNA”), and a trans-activating crRNA (“tracrRNA”). The crRNA contains a “guide RNA”, typically about 20-nucleotide RNA sequence that corresponds to a target DNA sequence. crRNA also contains a region that binds to the tracrRNA to form a partially double-stranded structure which is cleaved by Rnase III, resulting in a crRNA / tracrRNA hybrid. A crRNA / tracrRNA hybrid then directs Cas9 endonuclease to recognize and cleave a target DNA sequence. A target DNA sequence must generally be adjacent to a “protospacer adjacent motif’ (“PAM”) that is specific for a given Cas endonuclease; however, PAM sequences appear throughout a given genome. CRISPR endonucleases identified from various prokaryotic species have unique PAM sequence requirements; examples of PAM sequences include 5’-NGG (Streptococcus pyogenes), 5’- NNAGAA (Streptococcus thermophilus CRISPR1), 5’-NGGNG (Streptococcus thermophilus CRISPR3), and 5’-NNNGATT (Neisseria meningiditis). Some endonucleases, e.g., Cas9 endonucleases, are associated with G-rich PAM sites, e. g., 5’-NGG, and perform blunt-end cleaving of the target DNA at a location 3 nucleotides upstream from (5’ from) the PAM site. Another class II CRISPR system includes the type V endonuclease Cpfl , which is smaller than Cas9; examples include AsCpfl (from Acidaminococcus sp.) and LbCpfl (from Lachnospiraceae sp.). Cpfl -associated CRISPR arrays are processed into mature crRNAs without the requirement of a tracrRNA; in other words, a Cpfl system requires only Cpfl nuclease and a crRNA to cleave a target DNA sequence. Cpfl endonucleases, are associated with T-rich PAM sites, e.g., 5’-TTN. Cpfl can also recognize a 5’-CTA PAM motif. Cpfl cleaves a target DNA by introducing an offset or staggered double-strand break with a 4- or 5-nucleotide 5’ overhang, for example, cleaving a target DNA with a 5-nucleotide offset or staggered cut located 18 nucleotides downstream from (3^ from) from a PAM site on the coding strand and 23 nucleotides downstream from the PAM site on the complimentary strand; the 5-nucleotide overhang that results from such offset cleavage allows more precise genome editing by DNA insertion by homologous recombination than by insertion at blunt- end cleaved DNA. See, e.g., Zetsche et al. (2015) Cell, 163:759-771. A variety of CRISPR associated (Cas) genes or proteins can be used in the technologies provided by the present disclosure and the choice of Cas protein will depend upon the particular conditions of the method. Specific examples of Cas proteins include classFH12877464.1 Attorney Docket: OGY-02925 II systems including Casl, Cas2, Cas3, Cas4, Cas5, Cas6, Casl, Cas8, Cas9, Cas10, Cpfl, C2C1, or C2C3. In some embodiments, a Cas protein, e.g., a Cas9 protein, may be from any of a variety of prokaryotic species. In some embodiments a particular Cas protein, e.g., a particular Cas9 protein, is selected to recognize a particular protospacer-adjacent motif (PAM) sequence. In some embodiments, a DNA-targeting moiety includes a sequence targeting polypeptide, such as a Cas protein, e.g., Cas9. In certain embodiments a Cas protein, e.g., a Cas9 protein, may be obtained from a bacteria or archaea or synthesized using known methods. In certain embodiments, a Cas protein may be from a gram-positive bacteria or a gram-negative bacteria. In certain embodiments, a Cas protein may be from a Streptococcus (e.g., an S. pyogenes, or an S. thermophilus), a Francisella (e.g., an F. novicida), a Staphylococcus (e.g., an S. aureus), an Acidaminococcus (e.g., an Acidaminococcus sp. BV3L6), a Neisseria (e.g., an N. meningitidis), a Cryptococcus, a Corynebacterium, a Haemophilus, a Eubacterium, a Pasteurella, a Prevotella, a Veillonella, or a Marinobacter. In some embodiments, a Cas protein requires a protospacer adjacent motif (PAM) to be present in or adjacent to a target DNA sequence for the Cas protein to bind and / or function. In some embodiments, the PAM is or comprises, from 5^ to 3^, NGG, YG, NNGRRT, NNNRRT, NGA, TYCV, TATV, NTTN, or NNNGATT, where N stands for any nucleotide, Y stands for C or T, R stands for A or G, and V stands for A or C or G. In some embodiments, a Cas protein is a protein listed in Table 1. In some embodiments, a Cas protein comprises one or more mutations altering its PAM. In some embodiments, a Cas protein comprises E1369R, E1449H, and R1556A mutations or analogous substitutions to the amino acids corresponding to said positions. In some embodiments, a Cas protein comprises E782K, N968K, and R1015H mutations or analogous substitutions to the amino acids corresponding to said positions. In some embodiments, a Cas protein comprises DI 135V, R1335Q, and T1337R mutations or analogous substitutions to the amino acids corresponding to said positions. In some embodiments, a Cas protein comprises S542R and K607R mutations or analogous substitutions to the amino acids corresponding to said positions. In some embodiments, a Cas protein comprises S542R, K548V, and N552R mutations or analogous substitutions to the amino acids corresponding to said positions. Table 1: Exemplary Cas Proteins of the DisclosureFH12877464.1 Attorney Docket: OGY-02925 In some embodiments, the Cas protein is modified to deactivate the nuclease, e.g., nuclease-deficient Cas. In some embodiments, the Cas protein is a Cas9 protein. Whereas wild-type Cas9 generates double-strand breaks (DSBs) at specific DNA sequences targeted by a gRNA, a number of CRISPR endonucleases having modified functionalities are available, for example: a “nickase” version of Cas9 generates only a single-strand break; a catalytically inactive Cas9 (“dCas9”) does not cut target DNA. In some embodiments, dCas binding to a DNA sequence may interfere with transcription at that site by steric hindrance. In some embodiments, a DNA-targeting moiety is or comprises a catalytically inactive Cas, e.g., dCas. Many catalytically inactive Cas proteins are known in the art. In some embodiments, dCas9 comprises mutations in each endonuclease domain of the Cas protein, e.g., D10A and H840A mutations. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a D11A mutation or an analogous substitution to the amino acid corresponding to said position.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a H969A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a N995A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises D11A, H969A, and N995A mutations or analogous substitutions to the amino acids corresponding to said positions. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a D10A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a H557A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises D10A and H557A mutations or analogous substitutions to the amino acids corresponding to said positions. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a D839A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a H840A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a N863A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises D10A, D839A, H840A, and N863A mutations or analogous substitutions to the amino acids corresponding to said positions. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a E993A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a D917A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a E1006A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a D1255A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprisesFH12877464.1 Attorney Docket: OGY-02925 D917A, E1006A, and D1255A mutations or analogous substitutions to the amino acids corresponding to said positions. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a D16A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a D587A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises a H588A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises an N611A mutation or an analogous substitution to the amino acid corresponding to said position. In some embodiments, a catalytically inactive Cas9 protein, e.g., dCas9, comprises D16A, D587A, H588A, and N611A mutations or analogous substitutions to the amino acids corresponding to said positions. In another aspect, the disclosure is directed to an expression activator or a polypeptide comprising one or more (e.g., one) DNA-targeting moiety and one or more effector domain, wherein the one or more DNA-targeting moiety is or comprises a CRISPR / Cas domain comprising a Cas protein, e.g., catalytically inactive Cas9 protein, e.g., dCas9, or a functional variant or fragment thereof. In some embodiments, dCas9 comprises an amino acid sequence of SEQ ID NO:108. In some embodiments, the dCas9 is encoded by a nucleic acid sequence of SEQ ID NO:109. In some embodiments, a DNA-targeting moiety comprises a Cas domain comprising or linked (e.g., covalently linked) to a gRNA. A gRNA is a short synthetic RNA composed of a “scaffold” sequence necessary for Cas-protein binding and a user-defined about 20 nucleotide targeting sequence for a genomic target. In practice, guide RNA sequences are generally designed to have a length of between 17-24 nucleotides (e.g., 19, 20, or 21 nucleotides) and be complementary to the targeted nucleic acid sequence. Custom gRNA generators and algorithms are available commercially for use in the design of effective guide RNAs. Gene editing has also been achieved using a chimeric “single guide RNA” (“sgRNA”), an engineered (synthetic) single RNA molecule that mimics a naturally occurring crRNA-tracrRNA complex and contains both a tracrRNA (for binding the nuclease) and at least one crRNA (to guide the nuclease to the sequence targeted for editing). Chemically modified sgRNAs have also been demonstrated to be effective for use with Cas proteins; see, for example, Hendel et al. (2015) Nature Biotechnol, 985 - 991.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, a gRNA comprises a nucleic acid sequence that is complementary to a target sequence described herein. In some embodiments, a gRNA comprises a nucleic acid sequence that is at least 90, 95, 99, or 100% complementary to a target sequence described herein. In some embodiments, a gRNA for use with a DNA- targeting moiety that comprises a Cas molecule is an sgRNA. In some embodiments, a gRNA is used with a dCas9 fused to one or more peptides (e.g., GCN4 peptides) and an expression activator comprising an antibody or antibody fragment specific for the one or more peptides, and operably linked to an effector domain. TAL Domains In some embodiments, a DNA-targeting moiety is or comprises a TAL effector (also sometimes referred to herein as a “TALE”) domain. A TAL effector domain, e.g., a TAL effector domain that specifically binds a DNA sequence, comprises a plurality of TAL effector repeats or fragments thereof, and optionally one or more additional portions of naturally occurring TAL effector repeats (e.g., N- and / or C-terminal of the plurality of TAL effector domains) wherein each TAL effector repeat recognizes a nucleotide. In some embodiments, a TAL effector protein can comprise a TAL effector domain and optionally one or more other domains. Many TAL effector domains are known to those of skill in the art and are commercially available, e.g., from Thermo Fisher Scientific. TALEs are natural effector proteins secreted by numerous species of bacterial pathogens including the plant pathogen Xanthomonas which modulates gene expression in host plants and facilitates bacterial colonization and survival. The specific binding of TAL effectors is based on a central repeat domain of tandemly arranged nearly identical repeats of typically 33 or 34 amino acids (the repeat variable di-residues, RVD domain). Members of the TAL effectors family differ mainly in the number and order of their repeats. The number of repeats ranges from 1.5 to 33.5 repeats and the C-terminal repeat is usually shorter in length (e.g., about 20 amino acids) and is generally referred to as a “half- repeat”. Each repeat of the TAL effector features a one-repeat-to-one-base-pair correlation with different repeat types exhibiting different base-pair specificity (one repeat recognizes one base-pair on the target gene sequence). Generally, the smaller the number of repeats, the weaker the protein-DNA interactions. A number of 6.5 repeats has been shown to be sufficient to activate transcription of a reporter gene (Scholze et al., 2010). Repeat to repeat variations occur predominantly at amino acid positions 12 and 13, which have therefore been termed “hypervariable” and which are responsible for theFH12877464.1 Attorney Docket: OGY-02925 specificity of the interaction with the target DNA promoter sequence, as shown in Table 2 listing exemplary repeat variable di-residues (RVD) and their correspondence to nucleic acid base targets. Table 2: RVDs and Nucleic Acid Base Specificity Accordingly, it is possible to modify the repeats of a TAL effector to target specific DNA sequences. Further studies have shown that the RVD NK can target G. Target sites of TAL effectors also tend to include a T flanking the 5' base targeted by the first repeat, but the exact mechanism of this recognition is not known. More than 113 TAL effector sequences are known to date. Non-limiting examples of TAL effectors from Xanthomonas include, Hax2, Hax3, Hax4, AvrXa7, AvrXa10 and AvrBs3. Accordingly, in some embodiments, the TAL effector repeat of the TAL effector domain of the present disclosure may be derived from a TAL effector from any bacterial species (e.g., Xanthomonas species such as the African strain of Xanthomonas oryzae pv. Oryzae (Yu et al.2011), Xanthomonas campestris pv. raphani strain strain 756C and Xanthomonas oryzae pv. Oryzicolastrain BLS256 (Bogdanove et al.2011). As used herein, the TAL effector domain in accordance with the present disclosure comprises an RVD domain as well as flanking sequence(s) (sequences on the N-terminal and / or C-terminal side of the RVD domain) also from the naturally occurring TAL effector. In some embodiments, it may comprise more or fewer repeats than the RVD of the naturally occurring TAL effector domain. The TAL effector domain of the present disclosure is designed to target a given DNA sequence based on the above code and others known in the art. The number of TAL effector repeats (e.g., monomers or modules) and their specific sequence(s) are selected based on the desired DNA target sequence. For example, TAL effector repeats may be removed or added in order to suit a specific target sequence. In an embodiment, the TAL effector domain of the present disclosure comprises between 6.5 and 33.5 TAL effector repeats. In an embodiment, TAL effector domain of the present disclosure comprises between 8 and 33.5FH12877464.1 Attorney Docket: OGY-02925 TAL effector repeats, e.g., between 10 and 25 TAL effector repeats, e.g., between 10 and 14 TAL effector repeats. In some embodiments, the TAL effector domain comprises TAL effector repeats that correspond to a perfect match to the DNA target sequence. In some embodiments, a mismatch between a repeat and a target base-pair on the DNA target sequence is permitted as along as it allows for the function of the expression activation system, e.g., the expression activator comprising the TAL effector domain. In general, TALE binding is inversely correlated with the number of mismatches. In some embodiments, the TAL effector domain of an expression activator of the present disclosure comprises no more than 7 mismatches, 6 mismatches, 5 mismatches, 4 mismatches, 3 mismatches, 2 mismatches, or 1 mismatch, and optionally no mismatch, with the target DNA sequence. Without wishing to be bound by theory, in general the smaller the number of TAL effector repeats in the TAL effector domain, the smaller the number of mismatches will be tolerated while still allowing for the function of the expression activator or expression activation system, e.g., the expression activator comprising the TAL effector domain. The binding affinity is thought to depend on the sum of matching repeat-DNA combinations. For example, TAL effector domains having 25 TAL effector repeats or more may be able to tolerate up to 7 mismatches. In addition to the TAL effector repeats, in some embodiments, the TAL effector domain of the present disclosure may comprise additional sequences derived from a naturally occurring TAL effector. The length of the C-terminal and / or N-terminal sequence(s) included on each side of the TAL effector repeat portion of the TAL effector domain can vary and be selected by one skilled in the art, for example based on the studies of Zhang et al. (2011). Zhang et al., have characterized a number of C-terminal and N-terminal truncation mutants in Hax3 derived TAL-effector based proteins and have identified key elements, which contribute to optimal binding to the target sequence and thus activation of transcription. Generally, it was found that transcriptional activity is inversely correlated with the length of the N-terminus. Regarding the C-terminus, an important element for DNA binding residues within the first 68 amino acids of the Hax 3 sequence was identified. Accordingly, in some embodiments, the first 68 amino acids on the C-terminal side of the TAL effector repeats of the naturally occurring TAL effector are included in the TAL effector domain of an expression activator of the present disclosure. Accordingly, in an embodiment, a TAL effector domain of the present disclosure comprises 1) one or more TAL effector repeats derived from a naturally occurring TAL effector; 2) at least 70, 80, 90, 100, 110, 120, 130, 140, 150, 170, 180, 190, 200, 220, 230, 240, 250, 260, 270, 280 or more amino acids from theFH12877464.1 Attorney Docket: OGY-02925 naturally occurring TAL effector on the N-terminal side of the TAL effector repeats; and / or 3) at least 68, 80, 90, 100, 110, 120, 130, 140, 150, 170, 180, 190, 200, 220, 230, 240, 250, 260 or more amino acids from the naturally occurring TAL effector on the C-terminal side of the TAL effector repeats. In some embodiments, a modulating agent comprises a DNA-targeting moiety comprising an engineered DNA binding domain (DBD), e.g., a TAL effector comprising a TAL effector repeat that binds to a target sequence, e.g., a promoter or transcription start site (TSS)) sequence operably linked to a target gene, e.g., a sequence proximal to the transcription regulatory element, e.g., an anchor sequence of an anchor sequence mediated conjunction (ASMC) comprising a target gene , e.g., a sequence proximal to the anchor sequence. In some embodiments, the TAL effector binds to a target sequence described herein. In some embodiments, the TAL effector domain can be engineered to carry epigenetic effector domains to target sites. Zn Finger domains In some embodiments, a DNA-targeting moiety is or comprises a Zn finger domain. A Zn finger domain comprises a Zn finger, e.g., a naturally occurring Zn finger or engineered Zn finger, or fragment thereof. Many Zn fingers are known to those of skill in the art and are commercially available, e.g., from Sigma-Aldrich. Generally, a Zn finger domain comprises a plurality of Zn fingers, wherein each Zn finger recognizes three nucleotides. A Zn finger protein can comprise a Zn finger domain and optionally one or more other domains. In some embodiments, a Zn finger molecule comprises a non-naturally occurring Zn finger protein that is engineered to bind to a target DNA sequence of choice. See, for example, Beerli, et al. (2002) Nature Biotechnol.20:135-141; Pabo, et al. (2001) Ann. Rev. Biochem.70:313-340; Isalan, et al. (2001) Nature Biotechnol.19:656-660; Segal, et al. (2001) Curr. Opin. Biotechnol.12:632-637; Choo, et al. (2000) Curr. Opin. Struct. Biol. 10:411-416; U.S. Pat. Nos.6,453,242; 6,534,261; 6,599,692; 6,503,717; 6,689,558; 7,030,215; 6,794,136; 7,067,317; 7,262,054; 7,070,934; 7,361,635; 7,253,273; and U.S. Patent Publication Nos.2005 / 0064474; 2007 / 0218528; 2005 / 0267061, all incorporated herein by reference in their entireties. An engineered Zn finger may have a novel binding specificity, compared to a naturally-occurring Zn finger. Engineering methods include, but are not limited to, rational design and various types of selection. Rational design includes, for example, using databases comprising triplet (or quadruplet) nucleotide sequences and individual Zn finger amino acidFH12877464.1 Attorney Docket: OGY-02925 sequences, in which each triplet or quadruplet nucleotide sequence is associated with one or more amino acid sequences of zinc fingers which bind the particular triplet or quadruplet sequence. See, for example, U.S. Pat. Nos.6,453,242 and 6,534,261, incorporated by reference herein in their entireties. Exemplary selection methods, including phage display and two-hybrid systems, are disclosed in U.S. Pat. Nos.5,789,538; 5,925,523; 6,007,988; 6,013,453; 6,410,248; 6,140,466; 6,200,759; and 6,242,568; as well as International Patent Publication Nos. WO 98 / 37186; WO 98 / 53057; WO 00 / 27878; and WO 01 / 88197 and GB 2,338,237. In addition, enhancement of binding specificity for zinc finger proteins has been described, for example, in International Patent Publication No. WO 02 / 077227. In addition, as disclosed in these and other references, zinc fingers and / or multi- fingered zinc finger domains may be linked together using any suitable linker sequences, including for example, linkers of 5 or more amino acids in length. See, also, U.S. Pat. Nos. 6,479,626; 6,903,185; and 7,153,949 for exemplary linker sequences 6 or more amino acids in length. The proteins described herein may include any combination of suitable linkers between the individual zinc fingers of the protein. In addition, enhancement of binding specificity for zinc finger binding domains has been described, for example, in International Patent Publication No. WO 02 / 077227. Zn fingers and methods for design and construction of expression activators (and polynucleotides encoding same) are known to those of skill in the art and described in detail in U.S. Pat. Nos.6,140,0815; 789,538; 6,453,242; 6,534,261; 5,925,523; 6,007,988; 6,013,453; and 6,200,759; International Patent Publication Nos. WO 95 / 19431; WO 96 / 06166; WO 98 / 53057; WO 98 / 54311; WO 00 / 27878; WO 01 / 60970; WO 01 / 88197; WO 02 / 099084; WO 98 / 53058; WO 98 / 53059; WO 98 / 53060; WO 02 / 016536; and WO 03 / 016496. In certain embodiments, the DNA-targeting moiety comprises a Zn finger domain comprising an engineered zinc finger that binds (in a sequence-specific manner) to a target DNA sequence. In some embodiments, the Zn finger domain comprises one Zn finger or fragment thereof. In some embodiments, the Zn finger domain comprises a plurality of Zn fingers (or fragments thereof), e.g., 2, 3, 4, 5, 6 or more Zn fingers (and optionally no more than 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 Zn fingers). In some embodiments, the Zn finger domain comprises at least three Zn fingers. In some embodiments, the Zn finger domain comprises four, five or six Zn fingers. In some embodiments, the Zn finger domain comprises 8, 9, 10, 11 or 12 Zn fingers. In some embodiments, a Zn finger domain comprising three ZnFH12877464.1 Attorney Docket: OGY-02925 fingers recognizes a target DNA sequence comprising 9 or 10 nucleotides. In some embodiments, a Zn finger domain comprising four Zn fingers recognizes a target DNA sequence comprising 12 to 14 nucleotides. In some embodiments, a Zn finger domain comprising six Zn fingers recognizes a target DNA sequence comprising 18 to 21 nucleotides. In some embodiments, a DNA targeting domain comprises a two-handed Zn finger protein. Two handed zinc finger proteins are those proteins in which two clusters of zinc fingers are separated by intervening amino acids so that the two zinc finger domains bind to two discontinuous target DNA sequences. An example of a two-handed type of zinc finger binding protein is SIP1, where a cluster of four zinc fingers is located at the amino terminus of the protein and a cluster of three Zn fingers is located at the carboxyl terminus (see Remade, et al. (1999) EMBO Journal 18(18):5073-5084). Each cluster of zinc fingers in these domains is able to bind to a unique target sequence and the spacing between the two target sequences can comprise many nucleotides. In some embodiments, an expression activator comprises a DNA-targeting moiety comprising an engineered DNA binding domain (DBD), e.g., a Zn finger domain comprising a Zn finger (ZFN) that binds to a target sequence, e.g., a promoter or transcription start site (TSS)) sequence operably linked to a target gene, e.g., a sequence proximal to the transcription regulatory element, e.g., an anchor sequence of an anchor sequence mediated conjunction (ASMC) comprising a target gene, e.g., a sequence proximal to the anchor sequence. In some embodiments, the ZFN binds to a target sequence described herein. In some embodiments, the ZFN can be engineered to carry epigenetic effector molecules to target sites. Effector Domain In some embodiments, expression activators of the present disclosure comprise one or more effector domains. In some embodiments, an effector domain, when used as part of an expressor activator or an expression activation system described herein, increases expression of a target gene in a cell. In some embodiments, the expression activator comprises a single effector domain. In some embodiments, the expression activator comprises one or more effector domains. In some embodiments, the expression activator comprises more than one effector domain. In some embodiments, the expression activator comprises one to four effector domains. In some embodiments, the expression activator comprises two effectorFH12877464.1 Attorney Docket: OGY-02925 domains. In some embodiments, the expression activator comprises three effector domains. In some embodiments, the expression activator comprises four effector domains. In some embodiments, the effector domain has functionality unrelated to the binding of the DNA-targeting moiety. For example, effector domains may target, e.g., bind, a genomic sequence element or genomic complex component proximal to the genomic sequence element targeted by the DNA-targeting moiety or recruit a transcription factor. As a further example, an effector domain may comprise an enzymatic activity, e.g., a genetic modification functionality. In some embodiments, the effector domain induces DNA demethylation. In some embodiments, the effector domain induces DNA demethylation of a CpG island (i.e., a region of the genome comprising a high concentration of CpG residues). In some embodiments, the effector domain induces histone modification. In some embodiments, the effector domain comprises a histone modifying enzyme. In some embodiments, the histone modifying enzyme is selected from a histone acetyltransferase, a histone deacetylase (HDAC), a histone lysine methyl-transferase, and a histone lysine demethylase. In some embodiments, the effector domain forms a complex for epigenetic modification. In some embodiments, the effector domain forms a complex that induces DNA modification and / or histone modification. In some embodiments, an effector domain comprises an epigenetic activating domain. As used herein, an “epigenetic activating domain” refers to a polypeptide capable of inducing an epigenetic change such that expression of a target gene is increased. In some embodiments, an epigenetic activating domain is encoded by a fragment of a gene. In some embodiments, the fragment of a gene is of a gene selected from MYBL1, DUX4, MYB, CEPBPD, ATF4, NCOA2, TP53, FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2 and STB3. In some embodiments, the fragment of a gene is of a gene selected from MYBL1, DUX4, MYB, CEPBPD, ATF4, NCOA2, TP53, FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2, STB3, and PA.v1b. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene MYBL1. MYBL1 is a transcription factor involved in regulating gene expression, cell cycle progression, differentiation, and proliferation, and belongs to the MYB family characterized by DNA-binding domains that mediate sequence-specific DNA interactions. InFH12877464.1 Attorney Docket: OGY-02925 some embodiments, the epigenetic activating domain encoded by a fragment of gene MYBL1 is set forth in SEQ ID NO: 1. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the epigenetic activating domain encoded by a fragment of gene MYBL1 is set forth in SEQ ID NO: 2. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene DUX4. DUX4 is a transcription factor encoded by the double homeobox 4 gene, characterized by its role in regulating early embryonic gene expression, and involvement in epigenetic reprogramming. In some embodiments, the epigenetic activating domain encoded by a fragment of gene DUX4 is set forth in SEQ ID NO: 3. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 3. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 3. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 3. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene MYB. MYB is a transcription factor belonging to the MYB family, characterized by its DNA-binding domain and critical role in regulating gene expression programs involved in cellular proliferation, differentiation, and apoptosis. In some embodiments, the epigenetic activating domain encoded by a fragment of gene MYB is set forth in SEQ ID NO: 4. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 4. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 4.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, the epigenetic activating domain is encoded by a fragment of gene CEBPD. CEBPD is a member of the CCAAT / enhancer-binding protein (C / EBP) family of transcription factors, and plays a key role in regulating genes involved in immune and inflammatory responses, cell cycle arrest, and differentiation. In some embodiments, the epigenetic activating domain encoded by a fragment of gene CEBPD is set forth in SEQ ID NO: 5. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 5. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 5. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene ATF4. ATF4 is a member of the activating transcription factor (ATF) family and functions as a stress-responsive transcription factor that regulates gene expression programs involved in amino acid metabolism, oxidative stress response, and the integrated stress response (ISR). In some embodiments, the epigenetic activating domain encoded by a fragment of gene ATF4 is set forth in SEQ ID NO: 6. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 6. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene NCOA2. NCOA2 is a nuclear receptor coactivator that interacts with ligand-bound nuclear receptors to enhance transcription of target genes, functioning as part of a multiprotein coactivator complex and possessing intrinsic histone acetyltransferase activity that contributes to chromatin remodeling and epigenetic regulation of gene expression. In some embodiments, the epigenetic activating domain encoded by a fragment of gene of NCOA2 is set forth in SEQ ID NO: 7. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 7. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 7. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 7.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, the epigenetic activating domain is encoded by a fragment of gene TP53. TP53 is a critical transcription factor that regulates the expression of genes involved in cell cycle arrest, DNA repair, apoptosis, and senescence in response to cellular stress and DNA damage. In some embodiments, the epigenetic activating domain encoded by a fragment of gene TP53 is set forth in SEQ ID NO: 8. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 8. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 8. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene FOXO1. FOXO1 is a member of the forkhead box O (FOXO) family of transcription factors, which plays a pivotal role in regulating gene expression programs involved in cell cycle control, apoptosis, oxidative stress resistance, and metabolism. In some embodiments, the epigenetic activating domain encoded by a fragment of gene FOXO1 is set forth in SEQ ID NO: 9. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 9. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene NFE2. NFE2 is a transcription factor that is part of the cap ‘n’ collar-basic leucine zipper (CNC-bZIP) family and functions primarily in regulating gene expression programs related to erythroid and megakaryocytic differentiation, as well as oxidative stress responses. In some embodiments, the epigenetic activating domain encoded by a fragment of gene NFE2 is set forth in SEQ ID NO: 10. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 10. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 10. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene E2F2. E2F2 is a member of the E2F family of transcription factors, which play essentialFH12877464.1 Attorney Docket: OGY-02925 roles in regulating the expression of genes involved in cell cycle progression, DNA replication, and apoptosis. In some embodiments, the epigenetic activating domain encoded by a fragment of gene E2F2 is set forth in SEQ ID NO: 11. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 11. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 11. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene UBN1. UBN1 is a component of the HIRA histone chaperone complex, which plays a key role in the replication-independent deposition of the histone variant H3.3 into chromatin, thereby contributing to the regulation of gene expression, maintenance of chromatin structure, and epigenetic memory during cellular differentiation and development. In some embodiments, the epigenetic activating domain encoded by a fragment of gene UBN1 is set forth in SEQ ID NO: 12. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 12. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 12. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene CREB3L1. CREB3L1 is a transcription factor belonging to the CREB3 subfamily of basic leucine zipper (bZIP) proteins, which is activated through regulated intramembrane proteolysis in response to cellular stress, and regulates genes involved in secretion, extracellular matrix production, and cellular differentiation. In some embodiments, the epigenetic activating domain encoded by a fragment of gene of CREB3L1 is set forth in SEQ ID NO: 13. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 13. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 13. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 13. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene FOXO3. FOXO3 is a transcription factor belonging to the forkhead box O (FOXO)FH12877464.1 Attorney Docket: OGY-02925 family, which regulates the expression of genes involved in apoptosis, cell cycle arrest, oxidative stress resistance, DNA repair, and longevity. In some embodiments, the epigenetic activating domain encoded by a fragment of gene FOXO3 is set forth in SEQ ID NO: 14. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 14. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 14. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene KLF15. KLF15 is a member of the Krüppel-like factor (KLF) family of zinc finger transcription factors, and it regulates the expression of genes involved in metabolism, circadian rhythm, cellular differentiation, and plays a critical role in glucose and lipid homeostasis. In some embodiments, the epigenetic activating domain encoded by a fragment of gene KLF15 is set forth in SEQ ID NO: 15. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 15. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 15. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene MLXIPL. MLXIPL is a transcription factor that forms a heterodimer with MLX and regulates the expression of genes involved in glycolysis and lipogenesis in response to glucose levels, thereby playing a key role in metabolic homeostasis, particularly in the liver and adipose tissue. In some embodiments, the epigenetic activating domain encoded by a fragment of gene of MLXIPL is set forth in SEQ ID NO: 16. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 16. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 16. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene LEUTX. LEUTX is a homeobox-containing transcription factor expressed transiently during early embryonic development, where it plays a role in activating genes associated with zygotic genome activation and early cell fate determination. In some embodiments, theFH12877464.1 Attorney Docket: OGY-02925 epigenetic activating domain encoded by a fragment of gene LEUTX is set forth in SEQ ID NO: 17. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 17. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 17. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene INO80D. INO80D is a component of the INO80 chromatin remodeling complex, which plays a critical role in regulating DNA accessibility by repositioning or restructuring nucleosomes, thereby contributing to processes such as transcriptional regulation, DNA replication, and DNA damage repair through ATP-dependent chromatin remodeling activity. In some embodiments, the epigenetic activating domain encoded by a fragment of gene INO80D is set forth in SEQ ID NO: 18. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 18. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 18. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 18. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene CR3L1. CR3L1, also known as CREB3L1, is a transcription factor belonging to the CREB3 subfamily of basic leucine zipper (bZIP) proteins, which is activated through regulated intramembrane proteolysis in response to cellular stress, and regulates genes involved in secretion, extracellular matrix production, and cellular differentiation. In some embodiments, the epigenetic activating domain encoded by a fragment of gene CR3L1 is set forth in SEQ ID NO: 19. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 19. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 19. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 19. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene ATF6A. ATF6A is a transcription factor that regulate genes involved in protein folding, endoplasmic reticulum-associated degradation (ERAD), and restoration of ER homeostasis InFH12877464.1 Attorney Docket: OGY-02925 some embodiments, the epigenetic activating domain encoded by a fragment of gene ATF6A is set forth in SEQ ID NO: 20. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 20. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 20. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene CSN9. CSN9 is a protein component associated with the COP9 signalosome, a conserved multi-subunit complex involved in the regulation of protein degradation via the ubiquitin-proteasome system, particularly through modulation of cullin-RING E3 ubiquitin ligases. In some embodiments, the epigenetic activating domain encoded by a fragment of gene CSN9 is set forth in SEQ ID NO: 21. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 21. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 21. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 21. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene FOXO6. FOXO6 is a member of the forkhead box O (FOXO) family of transcription factors, which regulate gene expression programs involved in various cellular processes, including metabolism, stress response, and neurogenesis. In some embodiments, the epigenetic activating domain encoded by a fragment of gene FOXO6 is set forth in SEQ ID NO: 22. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 22. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 22. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 22. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene CACTIN. CACTIN is a protein subunit of the spliceosome C complex which is involved in pre-mRNA splicing, ensuring accurate removal of introns during transcription. In some embodiments, the epigenetic activating domain encoded by a fragment of gene CACTIN is set forth in SEQ ID NO: 23. In some embodiments, the epigenetic activatingFH12877464.1 Attorney Docket: OGY-02925 domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 23. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 23. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene C1QBP. C1QBP is a multifunctional and multicompartmental protein involved in inflammation and infection processes, ribosome biogenesis, protein synthesis in mitochondria, regulation of apoptosis, transcriptional regulation, and pre-mRNA splicing. In some embodiments, the epigenetic activating domain encoded by a fragment of gene C1QBP is set forth in SEQ ID NO: 24. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 24. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 24. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 24. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene FOXO3. In some embodiments, the epigenetic activating domain encoded by a fragment of gene FOXO3 is set forth in SEQ ID NO: 25. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 25. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 25. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 25. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene KLF4. KLF4 is a member of the Krüppel-like factor (KLF) family of zinc finger transcription factors, and it regulates the expression of genes involved in various cellular processes, including proliferation, differentiation, and apoptosis. In some embodiments, the epigenetic activating domain encoded by a fragment of gene KLF4 is set forth in SEQ ID NO: 26. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 26. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 26. In someFH12877464.1 Attorney Docket: OGY-02925 embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 26. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene MYC. MYC is a proto-oncogene transcription factor regulating gene expression programs involved in cell growth, proliferation, metabolism, and apoptosis. In some embodiments, the epigenetic activating domain encoded by a fragment of gene MYC is set forth in SEQ ID NO: 27. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 27. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 27. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 27. . In some embodiments, the epigenetic activating domain encoded by a fragment of gene MYC is set forth in SEQ ID NO: 28. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 28. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 28. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 28. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene NUTM1. NUTM1 is a nuclear protein involved in chromatin regulation and transcription. NUTM1 is best known for forming oncogenic fusion proteins, such as BRD4- NUT, which drive aggressive cancers like NUT carcinoma by promoting widespread histone acetylation and blocking cellular differentiation. In some embodiments, the epigenetic activating domain encoded by a fragment of gene NUTM1 is set forth in SEQ ID NO: 29. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 29. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 29. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 29. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene E2F2. E2F2 is a member of the E2F family of transcription factors, which play essential roles in regulating the expression of genes involved in cell cycle progression, DNA replication, and apoptosis. In some embodiments, the epigenetic activating domain encodedFH12877464.1 Attorney Docket: OGY-02925 by a fragment of gene E2F2 is set forth in SEQ ID NO: 30. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 30. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 30. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 30. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene VP16. VP16 is a potent transcriptional activator encoded by the UL48 gene of herpes simplex virus (HSV) and plays a crucial role in initiating the viral lytic cycle by forming a complex with host transcription factors to activate immediate-early viral gene expression. In some embodiments, the epigenetic activating domain encoded by a fragment of gene VP16 is set forth in SEQ ID NO: 31. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 31. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 31. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 31. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene VP64. VP64 is a synthetic transcriptional activation domain composed of four tandem repeats of the herpes simplex virus VP16 protein's activation domain. VP64 is commonly fused to catalytically inactive Cas9 (dCas9) in CRISPR activation (CRISPRa) systems to upregulate target gene expression. In some embodiments, the epigenetic activating domain encoded by a fragment of gene VP64 is set forth in SEQ ID NO: 32. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 32. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 32. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 32. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene YLR278C. YLR278C is a predicted zinc-cluster DNA-binding transcription factor active in the nucleus, with roles in sequence-specific transcriptional activation by RNA polymerase II. In some embodiments, the epigenetic activating domain encoded by a fragment of gene YLR278C is set forth in SEQ ID NO: 33. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%,FH12877464.1 Attorney Docket: OGY-02925 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 33. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 33. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 33. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene PIP2. PIP2, also known as Pip2p or Oaf2, is a transcription factor in Saccharomyces cerevisiae that forms a heterodimer with Oaf1p to regulate genes involved in peroxisome proliferation and fatty acid metabolism. In some embodiments, the epigenetic activating domain encoded by a fragment of gene PIP2 is set forth in SEQ ID NO: 34. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 34. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 34. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 34. In some embodiments, the epigenetic activating domain is encoded by a fragment of gene STB3. STB3 is a gene in Saccharomyces cerevisiae encoding a transcriptional regulator that binds to ribosomal RNA processing element (RRPE) motifs, playing a role in the glucose-induced transition from quiescence to growth. In some embodiments, the epigenetic activating domain encoded by a fragment of gene STB3 is set forth in SEQ ID NO: 35. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 35. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQ ID NO: 35. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 35. In some embodiments, the epigenetic activating domain is encoded by PA.v1b, a fragment of gene vIRF-2. PA.v1b is a synthetic construct derived from vIRF-2, a viral interferon regulatory factor encoded by Human gamma herpesvirus 8 (HHV-8), known to modulate host transcription and interfere with immune signaling pathways. In some embodiments, the epigenetic activating domain encoded by a fragment of gene vIRF-2, PA.v1b, is set forth in SEQ ID NO: 116. In some embodiments, the epigenetic activating domain comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 116. In some embodiments, the epigenetic activating domain comprises the amino acid sequence of SEQFH12877464.1 Attorney Docket: OGY-02925 ID NO: 116. In some embodiments, the epigenetic activating domain consists of the amino acid sequence of SEQ ID NO: 116. In some embodiments, an effector domain stimulates or promotes transcription, e.g., of the target gene. In some embodiments, the effector domain recruits a factor that induces transcription, e.g., of the target gene. In some embodiments the effector domain promotes epigenetic modification, e.g., directly or indirectly. For example, an effector domain can indirectly promote epigenetic modification by recruiting an endogenous protein that epigenetically modifies the chromatin. An effector domain can directly promote epigenetic modification by catalyzing epigenetic modification, wherein the effector domain comprises enzymatic activity and directly places an epigenetic mark on the chromatin. In some embodiments, an effector domain may comprise a peptide ligand, a full- length protein, a protein fragment. In some embodiments, an effector domain comprises a dominant negative component (e.g., dominant negative moiety), e.g., a protein that recognizes and binds a sequence (e.g., an anchor sequence, e.g., a CTCF binding motif), but with an inactive (e.g., mutated) dimerization domain, e.g., a dimerization domain that is unable to form a functional anchor sequence-mediated conjunction), or binds to a component of a genomic complex (e.g., a transcription factor subunit, etc.) preventing formation of a functional transcription factor, etc. For example, the Zinc Finger domain of CTCF can be altered so that it binds a specific anchor sequence (by adding zinc fingers that recognize flanking nucleic acids), while the homo-dimerization domain is altered to prevent the interaction between engineered CTCF and endogenous forms of CTCF. In some embodiments, a dominant negative component comprises a synthetic nucleating polypeptide with a selected binding affinity for an anchor sequence within a target anchor sequence-mediated conjunction. In some embodiments, binding affinity may be at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or higher or lower than binding affinity of an endogenous nucleating polypeptide (e.g., CTCF) that associates with a target anchor sequence. In some embodiments, A synthetic nucleating polypeptide may have between 30- 90%, 30-85%, 30-80%, 30-70%, 50-80%, 50-90% amino acid sequence identity to a corresponding endogenous nucleating polypeptide. A nucleating polypeptide may modulate (e.g., disrupt), such as through competitive binding, e.g., competing with binding of an endogenous nucleating polypeptide to its anchor sequence.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, a candidate effector domain may be determined to be suitable for use as an effector domain by methods known to those of skill in the art. For example, a candidate effector domain may be tested by assaying whether, when the candidate effector domain is present in the nucleus of a cell and appropriately localized (e.g., to a target gene or transcription control element operably linked to said target gene, e.g., via a DNA-targeting moiety), the candidate effector domain increases expression of the target gene in the cell, e.g., increases the level of RNA transcript encoded by the target gene (e.g., as measured by RNASeq or Northern blot) or increases the level of protein encoded by the target gene (e.g., as measured by ELISA). In some embodiments, an expression activator comprises a plurality of effector domains, wherein each effector domain does not detectably bind, e.g., does not bind, to another effector domain. In some embodiments, an expression activation system comprises a first expression activator comprising a first effector domain and a second expression activator comprising a second effector domain, wherein the first effector domain does not detectably bind, e.g., does not bind, to the second effector domain. In some embodiments, an expression activation system comprises a plurality of expression activators, wherein each member of the plurality of expression activators comprises an effector domain, wherein each effector domain does not detectably bind, e.g., does not bind, to another effector domain. In some embodiments, an expression activation system comprises a first expression activator comprising a first effector domain and a second expression activator comprising a second effector domain, wherein the first effector domain does not detectably bind, e.g., does not bind, to the second effector domain. In some embodiments, an expression activation system comprises a first expression activator comprising a first effector domain and a second expression activator comprising a second effector domain, wherein the first effector domain does not detectably bind, e.g., does not bind, to another first effector domain, and the second effector domain does not detectably bind, e.g., does not bind, to another second effector domain. In some embodiments, an effector domain for use in the compositions and methods described herein is functional in a monomeric, e.g., non-dimeric, state. In some embodiments, the epigenetic activating domain modulates the two- dimensional structure of chromatin (i.e., modulates structure of chromatin in a way that would alter its two-dimensional representation). In some embodiments, an effector domain comprises a component of a gene editing system, e.g., a CRISPR / Cas domain, e.g., a Zn Finger domain, e.g., a TAL effector domain.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, an epigenetic activating domain may comprise a polypeptide (e.g., peptide or protein moiety) linked to a gRNA and a targeted nuclease, e.g., a Cas9, e.g., a wild type Cas9, a nickase Cas9 (e.g., Cas9 D10A), a catalytically inactive Cas9 (dCas9), eSpCas9, Cpfl, C2C1, or C2C3, or a nucleic acid encoding such a nuclease. In some embodiments, provided technologies are described as comprising a gRNA that specifically targets a target gene. Additional Moieties An expression activator may further comprise one or more additional moieties (e.g., in addition to one or more targeting moieties and one or more effector domains). In some embodiments, an additional moiety is selected from a tagging or monitoring moiety, a cleavable moiety (e.g., a cleavable moiety positioned between a DNA-targeting moiety and an effector domain or at the N- or C-terminal end of a polypeptide), a small molecule, a membrane translocating polypeptide, or a pharmaco-agent moiety. Linkers An expression activator or an expression activation system as disclosed herein may comprise one or more linkers. A linker may connect a targeting moiety to an effector moiety, an effector moiety to another effector moiety, or a targeting moiety to another targeting moiety. A linker may be a chemical bond, e.g., one or more covalent bonds or non-covalent bonds. In some embodiments, a linker is covalent. In some embodiments, a linker is non- covalent. In some embodiments, a linker is a peptide linker. Such a linker may be between 2-30, 5-30, 10-30, 15-30, 20-30, 25-30, 2-25, 5-25, 10-25, 15-25, 20-25, 2-20, 5-20, 10-20, 15-20, 2-15, 5-15, 10-15, 2-10, 5-10, or 2-5 amino acids in length, or greater than or equal to 2, 5, 10, 15, 20, 25, or 30 amino acids in length (and optionally up to 50, 40, 30, 25, 20, 15, 10, or 5 amino acids in length). In some embodiments, a linker can be used to space a first domain or moiety from a second domain or moiety, e.g., a DNA-targeting moiety from an effector moiety. In some embodiments, for example, a linker can be positioned between a DNA-targeting moiety and an effector moiety, e.g., to provide molecular flexibility of secondary and tertiary structures. A linker may comprise flexible, rigid, and / or cleavable linkers described herein. In some embodiments, a linker includes at least one glycine, alanine, and serine amino acids to provide for flexibility. In some embodiments, a linker is a hydrophobic linker, such as including a negatively charged sulfonate group, polyethylene glycol (PEG) group, or pyrophosphate diester group. In some embodiments, a linker isFH12877464.1 Attorney Docket: OGY-02925 cleavable to selectively release a moiety (e.g., polypeptide) from a modulating agent, but sufficiently stable to prevent premature cleavage. In some embodiments, one or more moieties and / or domains of an expression activator described herein are linked with one or more linkers. In some embodiments, an expression activator may comprise a linker situated between the targeting moiety and the effector moiety. In some embodiments, the linker may have a sequence of ASGSGGGSGGARD (SEQ ID NO:112), or ASGSGGGSGG (SEQ ID NO:110). In some embodiments, a system comprising a first and second activator may comprise a first linker situated between the first targeting moiety and the first effector moiety, and a second linker situated between the second targeting moiety and the second effector moiety. In some embodiments, the first and the second linker may be identical. In some embodiments, the first and the second linker may be different. In some embodiments, the first linker may comprise an amino acid sequence according to SEQ ID NO:110 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto and the second linker may comprise an amino acid sequence according to SEQ ID NO:112 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto. As will be known by one of skill in the art, commonly used flexible linkers have sequences consisting primarily of stretches of Gly and Ser residues (“GS” linker). Flexible linkers may be useful for joining domains / moieties that require a certain degree of movement or interaction and may include small, non-polar (e.g., Gly) or polar (e.g., Ser or Thr) amino acids. Incorporation of Ser or Thr can also maintain the stability of a linker in aqueous solutions by forming hydrogen bonds with water molecules, and therefore reduce unfavorable interactions between a linker and moieties / domains. In some embodiments, the linker is a GS linker or a variant thereof e.g., G4S (SEQ ID NO:111). Rigid linkers are useful to keep a fixed distance between domains / moieties and to maintain their independent functions. Rigid linkers may also be useful when a spatial separation of domains is critical to preserve the stability or bioactivity of one or more components in the fusion. Rigid linkers may have an alpha helix-structure or Pro-rich sequence, (XP)n, with X designating any amino acid, preferably Ala, Lys, or Glu. Cleavable linkers may release free functional domains in vivo. In some embodiments, linkers may be cleaved under specific conditions, such as presence of reducing reagents or proteases. In vivo cleavable linkers may utilize reversible nature of a disulfide bond. One example includes a thrombin-sensitive sequence (e.g., PRS) between the two Cys residues. In vitro thrombin treatment of CPRSC results in the cleavage of a thrombin-sensitiveFH12877464.1 Attorney Docket: OGY-02925 sequence, while a reversible disulfide linkage remains intact. Such linkers are known and described, e.g., in Chen et al.2013. Fusion Protein Linkers: Property, Design and Functionality. Adv Drug Deliv Rev.65(10): 1357–1369. In vivo cleavage of linkers in fusions may also be carried out by proteases that are expressed in vivo under certain conditions, in specific cells or tissues, or constrained within certain cellular compartments. Specificity of many proteases offers slower cleavage of the linker in constrained compartments. In some embodiment, the cleavable linker may be a self-cleaving linker, e.g., a T2A peptide linker. In some embodiments, the linker may comprise a “ribosome skipping” sequence, e.g., a tPT2A linker. Examples of molecules suitable for use in linkers described herein include a negatively charged sulfonate group; lipids, such as a poly (--CH2--) hydrocarbon chains, such as polyethylene glycol (PEG) group, unsaturated variants thereof, hydroxylated variants thereof, amidated or otherwise N-containing variants thereof; noncarbon linkers; carbohydrate linkers; phosphodiester linkers, or other molecule capable of covalently linking two or more components of an expression activator. Non-covalent linkers are also included, such as hydrophobic lipid globules to which the polypeptide is linked, for example through a hydrophobic region of a polypeptide or a hydrophobic extension of a polypeptide, such as a series of residues rich in leucine, isoleucine, valine, or perhaps also alanine, phenylalanine, or even tyrosine, methionine, glycine, or other hydrophobic residues. Components of an expression activator may be linked using charge-based chemistry, such that a positively charged component of an expression activator is linked to a negative charge of another component. Expression Activation Systems In some embodiments, the disclosure provides an expression activation system comprising two or more expression activators described herein. In some embodiments, an expression activation system comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more expression activators (and optionally no more than 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2). In some embodiments, the expression activation system comprises a first expression activator comprising (i) a first DNA-targeting moiety that binds a first target sequence described herein, and (ii) a first effector domain; and at least one additional expression activator comprising (i) a second DNA-targeting moiety that binds a second target sequence described herein, and (ii) a second effector domain. In some embodiments, the first target sequence is different from the second target sequence.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, the expression activation system comprises a first expression activator comprising (i) a first DNA-targeting moiety that binds a first target sequence described herein, and (ii) a first effector domain; and at least one additional expression activator comprising (i) a second DNA-targeting moiety that binds a second target sequence described herein, and (ii) a second effector domain, wherein the first target sequence is different from the second target sequence. In some embodiments, the first effector domain is the same as the second effector domain. In some embodiments, the first effector domain is different from the second effector domain. In some embodiments, the expression activation system comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional expression activators. In some embodiments, the expression activation system comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional expression activators. In some embodiments, the expression activation system comprises a first expression activator comprising (i) a first DNA-targeting moiety that binds a first target sequence described herein, and (ii) a first effector domain; and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional expression activators, wherein each of the additional expression activators comprises (i) a DNA-targeting moiety that binds a target sequence described herein; and (ii) an effector domain, wherein the target sequence of each of the additional expression activators is different from one another and from the first target sequence. In some embodiments, the first effector domain and the effector domain of each of the additional expression activator s are the same or different. In some embodiments, each of the expression activators of the expression activation system binds to a different target sequence described herein. In some embodiments, each of the expression activators of the expression activation system are formulated in the same composition. In some embodiments, each of the expression activators of the expression activation system are formulated in different compositions. In some embodiments, the expression activators of the expression activation system each comprise a different DNA-targeting moiety (e.g., the first, second, third, or further expression activators each comprise different targeting moieties from one another). For example, an expression activation system may comprise a first expression activator and a second expression activator wherein the first expression activator comprises a first targeting moiety (e.g., a Cas9 domain, TAL effector domain, or Zn Finger domain), and the second expression activator comprises a second targeting moiety (e.g., a Cas9 domain, TAL effector domain, or Zn Finger domain) different from the first targeting moiety. In someFH12877464.1 Attorney Docket: OGY-02925 embodiments, different is comprising distinct types of targeting moiety, e.g., the first targeting moiety comprises a Cas9 domain, and the second DNA-targeting moiety comprises a Zn finger domain. In some embodiments, different is comprising distinct variants of the same type of targeting moiety, e.g., the first targeting moiety comprises a first Cas9 domain (e.g., from a first species) and the second targeting moiety comprises a second Cas9 domain (e.g., from a second species). In an embodiment, when an expression activation system comprises two or more targeting moieties of the same type, e.g., two or more Cas9 or ZF domains, the targeting moieties specifically bind two or more different target sequences. For example, in an expression activation system comprising two or more Cas9 domains, the two or more Cas9 domains may be chosen or altered such that they only appreciably bind the gRNA corresponding to their target sequence (e.g., and do not appreciably bind the gRNA corresponding to the target of another Cas9 domain). In a further example, in an expression activation system comprising two or more effector moieties, the two or more effector moieties may be chosen or altered such that they only appreciably bind to their target sequence (e.g., and do not appreciably bind the target sequence of another effector moiety). In some embodiments, an expression activation system comprises three or more expression activators and two or more expression activators comprise the same DNA- targeting moiety. For example, an expression activation system may comprise three expression activators, wherein the first and second expression activators both comprise a first DNA-targeting moiety and the third expression activator comprises a second different DNA- targeting moiety. For a further example, an expression activation system may comprise four expression activators, wherein the first and second expression activators both comprise a first DNA-targeting moiety and the third and fourth expression activators comprises a second different DNA-targeting moiety. For a further example, an expression activation system may comprise five expression activators, wherein the first and second expression activators both comprise a first DNA-targeting moiety, the third and fourth expression activators both comprise a second different DNA-targeting moiety, and the fifth expression activator comprises a third different DNA-targeting moiety. As described above, different can mean comprising different types of DNA-targeting moieties or comprising distinct variants of the same type of targeting moiety. In some embodiments, the expression activators of the expression activation system each bind to a different target sequence described herein (e.g., the first, second, third, or further expression activators each bind DNA sequences that are different from one another). For example, an expression activation system may comprise a first expression activator and aFH12877464.1 Attorney Docket: OGY-02925 second expression activator wherein the first expression activator binds to a first target sequence described herein, and the second expression activator binds to a second target sequence described herein. In some embodiments, different can mean that: there is at least one position that is not identical between the target sequence bound by one expression activator and the target sequence bound by another expression activator, or that there is at least one position present in the target sequence bound by one expression activator that is not present in the target sequence bound by another expression activator. In some embodiments, the expression activators of the expression activation system each comprise a different effector domain (e.g., the first, second, third, or further expression activators each comprise a different effector domain from one another). For example, an expression activation system may comprise a first expression activator and a second expression activator wherein the first expression activator comprises a first effector moiety (e.g., comprising an epigenetic activating domain encoded by a fragment of gene MYC), and the second expression activator comprises a second effector moiety (e.g., comprising an epigenetic activating domain encoded by a fragment of gene MYBL1) or functional fragment thereof) different from the first effector moiety. In some embodiments, different can mean comprising distinct types of effector moiety. In other embodiments, different can mean comprising distinct variants of the same type of effector moiety. In some embodiments, an expression activation system comprises a first expression activator comprising a first effector moiety and a second expression activator comprising a second effector moiety, wherein the first effector moiety comprises an epigenetic activating domain encoded by a fragment of a gene selected from MYBL1, DUX4, MYB, CEPBPD, ATF4, NCOA2, TP53, FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2 and STB3, and the second effector moiety comprises a different epigenetic activating domain encoded by a fragment of a gene, wherein the gene is selected from MYBL1, DUX4, MYB, CEPBPD, ATF4, NCOA2, TP53, FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2 and STB3. In some embodiments, an expression activation system comprises a first expression activator comprising a first effector moiety and a second expression activator comprising a second effector moiety, wherein the first effector moiety comprises an epigenetic activating domain encoded by a fragment of a gene selected from MYBL1, DUX4, MYB, CEPBPD,FH12877464.1 Attorney Docket: OGY-02925 ATF4, NCOA2, TP53, FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2, STB3, and PA.v1b and the second effector moiety comprises a different epigenetic activating domain encoded by a fragment of a gene, wherein the gene is selected from MYBL1, DUX4, MYB, CEPBPD, ATF4, NCOA2, TP53, FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2, STB3, and PA.v1b. In some embodiments, an expression activation system comprises three or more expression activators and two or more expression activators comprise the same DNA- targeting moiety. For example, an expression activation system may comprise three expression activators, wherein the first and second expression activators both comprise a first effector moiety and the third expression activator comprises a second different effector moiety. For a further example, an expression activation system may comprise four expression activators, wherein the first and second expression activators both comprise a first effector moiety and the third and fourth expression activators comprises a second different effector moiety. For a further example, an expression activation system may comprise five expression activators, wherein the first and second expression activators both comprise a first effector moiety, the third and fourth expression activators both comprise a second different effector moiety, and the fifth expression activator comprises a third different effector moiety. As described above, different can mean comprising different types of effector moiety or comprising distinct variants of the same type of effector moiety. In some embodiments, two or more (e.g., all) expression activators of an expression activation system are not covalently associated with each other, e.g., each expression activator is not covalently associated with any other expression activator. In another embodiment, two or more expression activators of an expression activation system are covalently associated with one another. In an embodiment, an expression activation system comprises a first expression activator and a second expression activator disposed on the same polypeptide, e.g., as a fusion molecule, e.g., connected by a peptide bond and optionally a linker. In some embodiments, the peptide is a self-cleaving peptide, e.g., a T2A self-cleaving peptide. In an embodiment, an expression activation system comprises a first expression activator and a second expression activator that are connected by a non-peptide bond, e.g., are conjugated to one another.FH12877464.1 Attorney Docket: OGY-02925 Methods of Making Expression Activators In some embodiments, a protein or polypeptide of compositions of the present disclosure can be biochemically synthesized by employing standard solid phase techniques. Such methods include exclusive solid phase synthesis, partial solid phase synthesis methods, fragment condensation, classical solution synthesis. These methods can be used when a peptide is relatively short (e.g., 10 kDa) and / or when it cannot be produced by recombinant techniques (i.e., not encoded by a nucleic acid sequence) and therefore involves different chemistry. Solid phase synthesis procedures are well known in the art and further described by John Morrow Stewart and Janis Dillaha Young, Solid Phase Peptide Syntheses, 2nd Ed., Pierce Chemical Company, 1984; and Coin, I., et al., Nature Protocols, 2:3247-3256, 2007. For longer peptides, recombinant methods may be used. Methods of making a recombinant therapeutic polypeptide are routine in the art. See, e.g., Smales & James (Eds.), Therapeutic Proteins: Methods and Protocols (Methods in Molecular Biology), Humana Press (2005); and Crommelin, Sindelar & Meibohm (Eds.), Pharmaceutical Biotechnology: Fundamentals and Applications, Springer (2013). Exemplary methods for producing an expression activator or polypeptide described herein involve expression in mammalian cells, although recombinant proteins can also be produced using insect cells, yeast, bacteria, or other cells under control of appropriate promoters. Mammalian expression vectors may comprise non-transcribed elements such as an origin of replication, a suitable promoter, and other 5’ or 3’ flanking non-transcribed sequences, and 5’ or 3’ non-translated sequences such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and termination sequences. DNA sequences derived from the SV40 viral genome, for example, SV40 origin, early promoter, splice, and polyadenylation sites may be used to provide other genetic elements required for expression of a heterologous DNA sequence. Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts are described in Green & Sambrook, Molecular Cloning: A Laboratory Manual (Fourth Edition), Cold Spring Harbor Laboratory Press (2012). In some embodiments, large amounts of the expression activator or polypeptide are desired, it can be generated using techniques such as described by Brian Bray, Nature Reviews Drug Discovery, 2:587-593, 2003; and Weissbach & Weissbach, 1988, Methods for Plant Molecular Biology, Academic Press, NY, Section VIII, pp.421-463.FH12877464.1 Attorney Docket: OGY-02925 Various mammalian cell culture systems can be employed to express and manufacture recombinant protein. Examples of mammalian expression systems include, without limitation, CHO cells, COS cells, HeLA and BHK cell lines. Processes of host cell culture for production of protein therapeutics are described, for example, in Zhou and Kantardjieff (Eds.), Mammalian Cell Cultures for Biologies Manufacturing (Advances in Biochemical Engineering / Biotechnology), Springer (2014). Compositions described herein may include a vector, such as a viral vector, e.g., a lentiviral vector, encoding a recombinant protein. In some embodiments, a vector, e.g., a viral vector, may comprise a nucleic acid encoding a recombinant protein. Compositions described herein may include a lipid nanoparticle encapsulating a vector, such as a viral vector, e.g., a lentiviral vector, encoding a recombinant protein. In some embodiments, a lipid nanoparticle encapsulating a vector, e.g., a viral vector, may comprise a nucleic acid encoding a recombinant protein. Purification of protein therapeutics is described, for example, in Franks, Protein Biotechnology: Isolation, Characterization, and Stabilization, Humana Press (2013); and in Cutler, Protein Purification Protocols (Methods in Molecular Biology), Humana Press (2010). Formulation of protein therapeutics is described in Meyer (Ed.), Therapeutic Protein Drug Products: Practical Approaches to formulation in the Laboratory, Manufacturing, and the Clinic, Woodhead Publishing Series (2012). Proteins comprise one or more amino acids. Amino acids include any compound and / or substance that can be incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)I-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L- amino acid. “Standard amino acid” refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. “Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. In some embodiments, an amino acid, including a carboxy- and / or amino-terminal amino acid in a polypeptide, can contain a structural modification as compared with the general structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, and / or the hydroxyl group) as compared with the general structure. In some embodiments, such modification may, for example, alter theFH12877464.1 Attorney Docket: OGY-02925 circulating half-life of a polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid. In some embodiments, such modification does not significantly alter a relevant activity of a polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified amino acid. As will be clear from context, in some embodiments, the term “amino acid” may be used to refer to a free amino acid; in some embodiments it may be used to refer to an amino acid residue of a polypeptide. Nucleic Acids of the Disclosure In another aspect, provided herein are nucleic acids encoding an expression activator or an expression activation system of the present disclosure. In some embodiments, an expression activator may be provided via a composition comprising a nucleic acid encoding the expression activator, wherein the nucleic acid is associated with sufficient other sequences to achieve expression in a system of interest (e.g., in a particular cell, tissue, organism, etc.). In some embodiments, the present disclosure provides compositions of nucleic acids that encode an expression activator or fragment thereof. In some embodiments, nucleic acids may be or may include DNA, RNA, or any other nucleic acid moiety or entity as described herein and may be prepared by any technology described herein or otherwise available in the art (e.g., synthesis, cloning, amplification, in vitro or in vivo transcription, etc.). In some embodiments, provided nucleic acids that encode an expression activator or fragment thereof may be operationally associated with one or more replication, integration, and / or expression signals appropriate and / or sufficient to achieve integration, replication, and / or expression of the provided nucleic acid in a system of interest (e.g., in a particular cell, tissue, organism, etc.). In some embodiments, a composition for delivering an expression activator or an expression activation system described herein is or comprises a vector, e.g., a viral vector, comprising one or more nucleic acids encoding an expression activator or one or more components of an expression activator as described herein. In some embodiments, the present disclosure provides compositions of nucleic acids that encode an expression activator, one or more expression activators, or fragments thereof. In some embodiments, provided nucleic acids may be or include DNA, RNA, or any other nucleic acid moiety or entity as described herein, and may be prepared by any technology described herein or otherwise available in the art (e.g., synthesis, cloning, amplification, inFH12877464.1 Attorney Docket: OGY-02925 vitro or in vivo transcription, etc.). The nucleic acid sequence may include, for example and without limitation, DNA, RNA, modified oligonucleotides (e.g., chemical modifications, such as modifications that alter the backbone linkages, sugar molecules, and / or nucleic acid bases), and artificial nucleic acids. In some embodiments, the nucleic acid sequence includes, for example and without limitation, genomic DNA, cDNA, peptide nucleic acids (PNA) or peptide oligonucleotide conjugates, locked nucleic acids (LNA), bridged nucleic acids (BNA), polyamides, triplex forming oligonucleotides, modified DNA, antisense DNA oligonucleotides, tRNA, mRNA, rRNA, modified RNA, miRNA, gRNA, and siRNA or other RNA or DNA molecules. In some embodiments, provided nucleic acids encoding an expression activator, one or more expression activators, or polypeptide fragments thereof may be operationally associated with one or more replication, integration, and / or expression signals appropriate and / or sufficient to achieve integration, replication, and / or expression of the provided nucleic acid in a system of interest (e.g., in a particular cell, tissue, organism, etc.). In some embodiments, the nucleic acid sequence has a length from about 2 to about 5000 nts, about 10 to about 100 nts, about 50 to about 150 nts, about 100 to about 200 nts, about 150 to about 250 nts, about 200 to about 300 nts, about 250 to about 350 nts, about 300 to about 500 nts, about 10 to about 1000 nts, about 50 to about 1000 nts, about 100 to about 1000 nts, about 1000 to about 2000 nts, about 2000 to about 3000 nts, about 3000 to about 4000 nts, about 4000 to about 5000 nts, or any range therebetween. In some embodiments, a composition for delivering an expression activator or an expression activation system described herein is or comprises RNA, e.g., mRNA, comprising one or more nucleic acids encoding an expression activator as described herein. In some embodiments, a composition for delivering an expression activator or an expression activation system described herein is or comprises RNA, e.g., mRNA, comprising one or more components of an expression activator, as described herein. In some embodiments, a nucleic acid of the disclosure comprises nucleosides, e.g., purines or pyrimidines, e.g., adenine, cytosine, guanine, thymine, and uracil. In some embodiments, the nucleic acid sequence includes one or more nucleoside analogs. The nucleoside analog includes, but is not limited to, a nucleoside analog, such as 5-fluorouracil; 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 4- methylbenzimidazole, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2- thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, dihydrouridine, beta-D- galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-FH12877464.1 Attorney Docket: OGY-02925 dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2- thiouracil, beta-D-mannosylqueosine, 5^-methoxycarboxymethyluracil, 5-methoxyuracil, 2- methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3- amino-3-N-2-carboxypropyl) uracil, (acp3)w, 2,6-diaminopurine, 3-nitropyrrole, inosine, thiouridine, queuosine, wyosine, diaminopurine, isoguanine, isocytosine, diaminopyrimidine, 2,4-difluorotoluene, isoquinoline, pyrrolo[2,3-^]pyridine, and any others that can base pair with a purine or a pyrimidine side chain. Additional modifications are known and described, e.g., in WO 2012 / 019168; WO 2015 / 038892; WO 2015 / 038892; WO 2015 / 089511; WO 2015 / 196130; WO 2015 / 196118, and WO 2015 / 196128. mRNA In one aspect, provided herein is an RNA, e.g., an mRNA, encoding an expression activator or an expression activation system as described herein. In some embodiments, an mRNA comprises an open reading frame (ORF), e.g., a sequence of codons that is translatable into a peptide or protein, e.g., into an expression activator or an expression activation system. Open Reading Frames (ORFs) An open reading frame includes a start codon at its 5'-end and a subsequent nucleotide region which usually exhibits a length which is a multiple of 3 nucleotides. In some embodiments, an ORF is terminated by a stop-codon (e.g., TAA, TAG, or TGA). In certain embodiments, the ORF may be isolated, or it may be incorporated in a longer nucleic acid sequence, e.g., in a vector or an mRNA. An ORF may also be known in the art as a protein coding region. In some embodiments, an mRNA of the disclosure comprises an ORF, e.g., encoding a DNA-targeting moiety and / or an effector domain of an expression activator or an expression activation system described herein. In certain embodiments, an ORF comprises a sequence that has been sequence optimized. Sequence-optimized nucleotide sequences disclosed herein are distinct from the corresponding wild-type nucleotide acid sequences and from other known sequence-optimized nucleotide sequences, e.g., these sequence-optimized nucleic acids have unique compositional characteristics.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, the mRNA comprises a bicistronic RNA. As used herein, a bicistronic RNA is typically an RNA, preferably an mRNA, comprising two ORFs. In some embodiments, the mRNA comprises a multicistronic RNA. As used herein, a multicistronic RNA is typically an RNA, preferably an mRNA, comprising more than two ORFs. In some embodiments, the nucleic acid encoding the expression activation system is a multicistronic sequence. In some embodiments, the multicistronic sequence is a bicistronic sequence. In some embodiments, the multicistronic sequence comprises a sequence encoding the first expression activator and a sequence encoding the second expression activator. In some embodiments, the multicistronic sequence encodes a self-cleavable peptide sequence, e.g., a 2A peptide sequence, e.g., a T2A peptide sequence or a P2A sequence. In some embodiments, the multicistronic sequence encodes a T2A peptide sequence and a P2A peptide sequence. In some embodiments, a bicistronic construct further comprises a polyA tail. In some embodiments, upon transcription of a bicistronic gene construct, a single mRNA transcript encoding the first expression activator, and the second expression activator are produced, which upon translation gets cleaved, e.g., after the glycine residue within the 2A peptide, to yield the first expression activator and the second expression activator as two separate proteins. In some embodiments, the first and the second expression activator are separated by “ribosome-skipping.” In some embodiments, the first expression activator and / or the second expression activator retains a fragment of the 2A peptide after ribosome skipping. In some embodiments, the expression level of the first and second expression activator are equal. In some embodiments, the expression level of the first and the second expression activator are different. In some embodiments, the protein level of the first expression activator is within about 1%, 2%, 5%, or 10% of (greater than or less than) the protein level of the second expression activator. In some embodiments, a system encoded by a bicistronic nucleic acid increases expression of a target gene at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, in a cell, as compared to an otherwise similar system wherein the first and second expression activator are encoded by monocistronic nucleic acids. Untranslated Regions (UTRs) In certain embodiments, a polynucleotide (e.g., mRNA) encoding an expression activator or an expression activation system of the present disclosure further comprises a 5'FH12877464.1 Attorney Docket: OGY-02925 UTR and / or a translation initiation sequence. Natural 5 'UTRs bear features which function in initiation of protein translation. They harbor signatures, e.g., Kozak sequences, which are commonly involved in ribosomal initiation of translation of many genes.5 'UTRs also may form secondary structures that function in elongation factor binding to further facilitate translation. The skilled person would recognize that engineering these features may enhance the stability and protein production of the polynucleotides of the disclosure. Untranslated regions useful in the design and manufacture of polynucleotides include, for example and without limitation, those disclosed in International Patent Publication No. WO 2014 / 164253 (see also US 2016 / 0022840). Other non-UTR sequences may be used as regions or subregions within the polynucleotides. For example and without limitation, introns or fragments of introns sequences can be incorporated into regions of the polynucleotides. In some embodiments, incorporation of one or more intronic sequences may increase protein production and / or polynucleotide levels. Combinations of features can be included in flanking regions and can be contained within other features. For example, an ORF can be flanked by a 5' UTR which can contain a strong Kozak translational initiation signal and / or a 3' UTR which can include an oligo(dT) sequence for templated addition of a poly-A tail.5' UTR can comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and / or different genes such as the 5'UTRs described in U.S. Patent Application Publication No.2010 / 0293625. In some embodiments, a 5'UTR may comprise a sequence as set forth in SEQ ID NO:113. A UTR, or a fragment thereof, can be placed in the same orientation as in the transcript from which it was selected, or can be altered in orientation and / or location. For example, a 5' or 3' UTR can be inverted, shortened, lengthened, or made with one or more other 5' UTRs or 3' UTRs. In some embodiments, a UTR sequence can be changed in some way relative to a reference sequence, e.g., an endogenous UTR. For example, a 3' or 5' UTR can be altered relative to a wild-type or native UTR by a change in orientation or location, by inclusion of additional nucleotides, deletion of nucleotides, or swapping or transposition of nucleotides. In some embodiments, two copies of the same UTR are encoded either in series or substantially in series. In some embodiments, more than two copies of the same UTR are encoded either in series or substantially in series. In some embodiments, flanking regions, e.g., flanking an ORF, can be heterologous. In some embodiments, a 5' untranslated region can be derived from a different species than aFH12877464.1 Attorney Docket: OGY-02925 3' untranslated region. The untranslated region can also include translation enhancer elements (TEE). For example and without limitation, TEEs are described in U.S. Patent Application Publication No.2009 / 0226470. In certain embodiments, a polynucleotide (e.g., an mRNA) encoding an expression activator or an expression activation system further comprises a 3' UTR. A 3'-UTR is the section of mRNA immediately following the translation termination codon. In some embodiments, a 3'-UTR includes regulatory regions that post-transcriptionally influence gene expression. Such regulatory regions within a 3'-UTR can influence polyadenylation, translation efficiency, localization, and / or stability of the mRNA. In some embodiments, a 3'- UTR comprises a binding site for regulatory proteins and / or microRNAs. In some embodiments, the 3'-UTR has a silencer region, which binds to activator proteins and inhibits the expression of the mRNA. In other embodiments, a 3'-UTR comprises an AU-rich element (ARE). Proteins may bind AREs to affect the stability and / or decay rate of mRNA. In some embodiments, a 3'-UTR comprises a sequence SEQ ID NO:114 that directs addition of adenine residues in a poly(A) tail to the end of the mRNA transcript. In some embodiments, a poly(A)tail comprises a sequence as set forth in SEQ ID NO:115. Terminal Modifications In some embodiments, an mRNA described herein comprises one or more terminal modifications, e.g., a 5^Cap structure and / or a poly-A tail (e.g., between 100-200 nucleotides in length). The 5^ cap structure may be selected from the group consisting of CapO, Capl, ARCA, inosine, Nl-methyl-guanosine, 2^fluoro-guanosine, 7-deaza-guanosine, 8-oxo- guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine. In some cases, the modified RNAs also contains a 5^ UTR comprising at least one Kozak sequence, and a 3^ UTR. Such modifications are known and are described, e.g., in WO 2012 / 135805 and WO 2013 / 052523. Additional terminal modifications are described, e.g., in WO 2014 / 164253, WO 2016 / 011306, WO 2012 / 045075, and WO 2014 / 093924. The polynucleotide comprising an mRNA encoding an expression activator or an expression activation system of the present disclosure can further comprise a 5' cap. The 5' cap can bind the mRNA Cap Binding Protein (CBP), thereby increasing mRNA stability. The cap can further assist the removal of 5' proximal introns removal during mRNA splicing. In some embodiments, a polynucleotide comprising an mRNA encoding an expression activator or an expression activation system of the present disclosure comprises a non-hydrolyzable cap structure preventing decapping. In some embodiments, a non-FH12877464.1 Attorney Docket: OGY-02925 hydrolyzable cap structure increases mRNA half-life. Cap structure hydrolysis requires cleavage of 5'-ppp-5' phosphorodiester linkages; thus, modified nucleotides can be used during the capping reaction. Modified guanosine nucleotides may also be suitable for use in the present disclosure, e.g., a-thio-guanosine, a-methyl-phosphonate, and seleno-phosphate nucleotides. In certain embodiments, a 5' cap comprises 2'-0-methylation of the ribose sugars at 5 '-terminal and / or 5'-anteterminal nucleotides at the 2'-hydroxyl group of the sugar ring. In some embodiments, a cap may include cap analogs, i.e., synthetic cap analogs, chemical caps, chemical cap analogs, or structural / functional cap analogs differing from naturally occurring (i.e., endogenous, wild-type, or physiological) 5'-caps in chemical structure. Cap analogs may be chemically (i.e., non-enzymatically) or enzymatically synthesized and / or linked to the polynucleotides of the disclosure. In certain embodiments, an mRNA encoding an expression activator or an expression activation system of the present disclosure can be capped after manufacture (e.g., IVT or chemical synthesis), using enzymes, to generate 5 '-cap structures. In certain embodiments, 5' terminal caps can include endogenous caps or cap analogs. In certain embodiments, a 5' terminal cap can comprise a guanine analog. Suitable guanine analogs include, for example and without limitation, inosine, N1-methyl-guanosine, 2'fluoro- guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2- azido- guanosine. In some embodiments, an mRNA encoding an expression activator or an expression activation system of the present disclosure further comprises a poly-A tail. In some embodiments, one or more terminal groups on the poly-A tail can be incorporated for stabilization. Such poly-A tails can also include structural moieties or 2'-0-methyl modifications, for example, as taught by Li et al. (2005) Current Biology 15: 1501-1507. In some embodiments, a poly-A tail when present is greater than 30 nucleotides in length. In some embodiments, a poly-A tail is greater than 35 nucleotides in length (e.g., at least about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, or 3,000 nucleotides) In some embodiments, a poly-A tail is designed relative to the length of the overall polynucleotide or the length of a particular region of the polynucleotide. For example, this can be based on the length of a coding region, the length of a particular feature or region, or based on the length of the product expressed from the polynucleotide. Accordingly, in someFH12877464.1 Attorney Docket: OGY-02925 embodiments, a poly-A tail can be 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% greater in length than the polynucleotide or fragment thereof. In some embodiments, one or more polynucleotides may be linked together by a Poly- A binding protein (PABP) by the 3'-end of the PABP, using modified nucleotides at the 3'- terminus of a poly-A tail. In some embodiments, an mRNA encoding an expression activator or an expression activator of the present disclosure comprises, consists essentially of, or consists of a 5' terminal cap, a 5' UTR, an open reading frame (ORF), a 3' UTR, and a polyA tail. In some embodiments, a modified mRNA may be cyclized, or concatemerized, to generate a translation competent molecule to assist interactions between poly-A binding proteins and 5^-end binding proteins. The mechanism of cyclization or concatemerization may occur through at least 3 different routes: 1) chemical, 2) enzymatic, and 3) ribozyme catalyzed. The newly formed 5^- / 3^-linkage may be intramolecular or intermolecular. Such modifications are described, e.g., in WO 2013 / 151736. Recombinant Expression Vectors Nucleic acids as described herein or nucleic acids encoding an expression activator or an expression activation system described herein may be incorporated into a vector. Vectors, including those derived from retroviruses such as lentivirus, are suitable tools to achieve long-term gene transfer since they allow long-term, stable integration of a transgene, and its propagation in daughter cells. Examples of suitable vectors include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. In some embodiments, an expression vector may be provided to a cell in the form of a viral vector. Viral vector technology is well known in the art and described in a variety of virology and molecular biology manuals. Viruses that are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers. Expression of natural or synthetic nucleic acids is typically achieved by operably linking a nucleic acid encoding the gene of interest to a promoter and incorporating the construct into an expression vector. Vectors can be suitable for replication and integration in eukaryotes. Typical cloning vectors contain transcription and translation terminators, initiation sequences, and promoters useful for expression of the desired nucleic acidFH12877464.1 Attorney Docket: OGY-02925 sequence. Additional promoter elements, e.g., enhancing sequences, may regulate frequency of transcriptional initiation. Typically, these sequences are located in a region 30-110 bp upstream of a transcription start site, although a number of promoters have recently been shown to contain functional elements downstream of transcription start sites as well. In some embodiments, an expression activator or an expression activation system described herein acts at an enhancing sequence. In some embodiments, the enhancing sequence is an enhancer, a stretch enhancer, a shadow enhancer, a locus control region (LCR), or a super enhancer. In some embodiments, the super enhancer comprises a cluster of enhancers and other regulatory elements. In some embodiments, these sequences are located in a region .2- 2 Mb upstream or downstream of a transcription start site. In some embodiments, the region is a non-coding region. In some embodiments, the region is associated with long-range regulation of a target gene. In some embodiments, the regions are cell-type specific. In some embodiments, a super-enhancer modifies (e.g., increases) target gene expression by recruiting the target gene promoter. In some embodiments, the super enhancer interacts with a target gene promoterthrough an enhancer docking site. In some embodiments, the enhancer docking site is an anchor sequence. In some embodiments, the enhancer docking site is located at least 100 bp, 200 bp, 500 bp, 1000 bp, 1500 bp, 2000 bp, or 3000 bp away from the target gene promoter. In some embodiments, a super enhancer region is at least 100 bp, at least 200 bp, at least 300 bp, at least 500 bp, at least 1 kb, at least 2 kb, at least 3 kb, at least 5 kb, at least 10 kb, at least 15 kb, at least 20 kb, or at least 25 kb long. Spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. For example, in a thymidine kinase (tk) promoter, spacing between promoter elements can be increased to about 50 bp apart before activity begins to decline. Without wishing to be bound by theory, it is hypothesized that depending upon the promoter, individual elements can function either cooperatively or independently to activate transcription. One example of a suitable promoter for use in the present disclosure is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto. In some embodiments, a suitable promoter is Elongation Growth Factor-1a (EF-1a). Alternatively, other constitutive promoter sequences may also be used, including, but not limited to, the simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV)FH12877464.1 Attorney Docket: OGY-02925 long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters including, but not limited to, an actin promoter, a myosin promoter, a hemoglobin promoter, and a creatine kinase promoter. The present disclosure should not be interpreted to be limited to use of any particular promoter or category of promoters (e.g., constitutive promoters). For example, in some embodiments, inducible promoters are contemplated as part of the present disclosure. In some embodiments, use of an inducible promoter provides a molecular switch capable of turning on expression of a polynucleotide sequence to which it is operatively linked, when such expression is desired. In some embodiments, use of an inducible promoter provides a molecular switch capable of turning off expression when expression is not desired. Examples of inducible promoters include, but are not limited to, a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter. In some embodiments, an expression vector to be introduced can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected through viral vectors. In some aspects, a selectable marker may be carried on a separate piece of DNA and used in a co-transfection procedure. Both selectable markers and reporter genes may be flanked with appropriate transcriptional control sequences to enable expression in the host cells. Useful selectable markers may include, for example, antibiotic-resistance genes, such as neomycin, etc. In some embodiments, reporter genes may be used for identifying potentially transfected cells and / or for evaluating the functionality of transcriptional control sequences. In general, a reporter gene is a gene that is not present in or expressed by a recipient source (of a reporter gene) and that encodes a polypeptide whose expression is manifested by some easily detectable property, e.g., enzymatic activity or visualizable fluorescence. Expression of a reporter gene is assayed at a suitable time after the DNA has been introduced into the recipient cells. Suitable reporter genes may include genes encoding luciferase, beta- galactosidase, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or the green fluorescent protein gene (e.g., Ui-Tei et al., 2000 FEBS Letters 479: 79-82). Suitable expression systems are well known and may be prepared using known techniques or obtained commercially. In general, a construct with a minimal 5’ flanking region that shows highest level of expression of reporter gene is identified as a promoter. Such promoter regions mayFH12877464.1 Attorney Docket: OGY-02925 be linked to a reporter gene and used to evaluate agents for ability to modulate promoter- driven transcription. Cells The present disclosure is further directed, in part, to cells comprising an expression activator or expression activation system described herein. Any cell, e.g., cell line, e.g., a cell line suitable for expression of a recombinant polypeptide, known to one of skill in the art is suitable to comprise an expression activator or an expression activation system described herein. In some embodiments, a cell, e.g., cell line, may be used to express an expression activator or an expression activation system, e.g., expression activator(s), described herein. In some embodiments, a cell, e.g., cell line, may be used to express or amplify a nucleic acid, e.g., a vector, encoding an expression activator or an expression activation system, e.g., expression activator(s), described herein. In some embodiments, a cell comprises a nucleic acid encoding an expression activator or an expression activation system, e.g., expression activator(s), described herein. In some embodiments, a cell comprises a first nucleic acid encoding a first component of an expression activation system, e.g., a first expression activator, and a second nucleic acid encoding a second component of the expression activation system, e.g., a second expression activator. In some embodiments, wherein a cell comprises nucleic acid encoding an expression activation system comprising two or more expression activators, the sequences encoding each expression activator are disposed on separate nucleic acid molecules, e.g., on different vectors, e.g., a first vector encoding a first expression activator and a second vector encoding a second expression activator. In some embodiments, the sequences encoding each expression activator are disposed on the same nucleic acid molecule, e.g., on the same vector. In some embodiments, some or all of the nucleic acid encoding the expression activation system is integrated into the genomic DNA of the cell. In some embodiments, the nucleic acid encoding a first expression activator of an expression activation system is integrated into the genomic DNA of a cell, and the nucleic acid encoding a second expression activator of an expression activation system is not integrated into the genomic DNA of a cell (e.g., is situated on a vector). In some embodiments, the nucleic acid(s) encoding a first and a second expression activator of an expression activation system are integrated into the genomic DNA of a cell, e.g., at the same (e.g., adjacent or colocalized) or different sites in the genomic DNA.FH12877464.1 Attorney Docket: OGY-02925 Examples of cells that may comprise and / or express an expression activation system or an expression activator described herein include, but are not limited to, hepatocytes, neuronal cells, endothelial cells, myocytes, and lymphocytes. Methods of Making RNA Methods of making and purifying modified RNAs are known and disclosed in the art. For example and without limitation, modified RNAs are made using in vitro transcription (IVT) enzymatic synthesis. Methods of making IVT polynucleotides are known in the art and are described in WO 2013 / 151666, WO 2013 / 151668, WO 2013 / 151663, WO 2013 / 151669, WO 2013 / 151670, WO 2013 / 151664, WO 2013 / 151665, WO 2013 / 151671, WO 2013 / 151672, WO 2013 / 151667, and WO 2013 / 151736. Methods of purification include purifying an RNA transcript comprising a polyA tail by contacting the sample with a surface linked to a plurality of thymidines or derivatives thereof and / or a plurality of uracils or derivatives thereof (polyT / U) under conditions such that the RNA transcript binds to the surface and eluting the purified RNA transcript from the surface (WO 2014 / 152031); using ion (e.g., anion) exchange chromatography that allows for separation of longer RNAs up to 10,000 nucleotides in length via a scalable method (WO 2014 / 144767); and subjecting a modified RMNA sample to DNAse treatment (WO 2014 / 152030). Modified RNAs encoding proteins in the fields of human disease, antibodies, viruses, and a variety of in vivo settings are known and are disclosed in for example, Table 6 of International Publication Nos. WO 2013 / 151666, WO 2013 / 151668, WO 2013 / 151663, WO 2013 / 151669, WO 2013 / 151670, WO 2013 / 151664, WO 2013 / 151665, WO 2013 / 151736; Tables 6 and 7 International Publication No. WO 2013 / 151672; Tables 6, 178 and 179 of International Publication No. WO 2013 / 151671; and Tables 6, 185 and 186 of International Publication No WO 2013 / 151667. Any of the foregoing may be synthesized as an IVT polynucleotide, chimeric polynucleotide or a circular polynucleotide and linked to the polypeptide described herein, and each may comprise one or more modified nucleotides or terminal modifications. In some embodiments, an expression activator comprises or consists of a protein and may thus be produced by methods of making proteins as known in the art, for example. as provided in the present disclosure. In some embodiments, an expression activation system, e.g., the expression activator(s) of an expression activation system, comprise one or more proteins and may thus be produced by methods of making proteins. As will be appreciated by one of skill in the art, methods of making proteins or polypeptides (which may be included inFH12877464.1 Attorney Docket: OGY-02925 modulating agents as described herein) are routine in the art. See, e.g., Smales & James (Eds.), Therapeutic Proteins: Methods and Protocols (Methods in Molecular Biology), Humana Press (2005); see also Crommelin, Sindelar & Meibohm (Eds.), Pharmaceutical Biotechnology: Fundamentals and Applications, Springer (2013). Delivery Lipid Particles Expression activators or expression activation systems as described herein can be delivered using any biological delivery system / formulation including a particle, for example, a nanoparticle delivery system. Nanoparticles include particles with a dimension (e.g., diameter) between about 1 and about 1000 nanometers, between about 1 and about 500 nanometers in size, between about 1 and about 100 nm, between about 30 nm and about 200 nm, between about 50 nm and about 300 nm, between about 75 nm and about 200 nm, between about 100 nm and about 200 nm, and any range therebetween. A nanoparticle has a composite structure of nanoscale dimensions. In some embodiments, nanoparticles are typically spherical although different morphologies are possible depending on the nanoparticle composition. The portion of the nanoparticle contacting an environment external to the nanoparticle is generally identified as the surface of the nanoparticle. In some embodiments, nanoparticles have a greatest dimension ranging between 25 nm and 200 nm. Nanoparticles as described herein comprise delivery systems that may be provided in any form, including but not limited to solid, semi-solid, emulsion, or colloidal nanoparticles. A nanoparticle delivery system may include but is not limited to lipid-based systems, liposomes, micelles, micro-vesicles, exosomes, or gene gun. In one embodiment, the nanoparticle is a lipid nanoparticle (LNP). In some embodiments, the LNP is a particle that comprises a plurality of lipid molecules physically associated with each other by intermolecular forces. In some embodiments, an LNP may comprise multiple components, e.g., 3-4 components. In one embodiment, the expression activator or a pharmaceutical composition comprising said expression activator (or a nucleic acid encoding the same, or pharmaceutical composition comprising said expression activator nucleic acid) is encapsulated in an LNP. In one embodiment, the expression activation system or a pharmaceutical composition comprising said expression activation system (or a nucleic acid encoding the same, or pharmaceutical composition comprising said expression activation system nucleic acid) is encapsulated in an LNP. In some embodiments, the nucleic acid encoding the first expressionFH12877464.1 Attorney Docket: OGY-02925 activator and the nucleic acid encoding the second expression activator are present in the same LNP. In some embodiments, the nucleic acid encoding the first expression activator and the nucleic acid encoding the second expression activator are present in different LNPs. Preparation of LNPs and the modulating agent encapsulation may be used / and or adapted from Rosin et al, Molecular Therapy, vol.19, no.12, pages 1286-2200, December 2011. In some embodiments, lipid nanoparticle compositions disclosed herein are useful for expression of a protein encoded by mRNA. In some embodiments, nucleic acids, when present in the lipid nanoparticles, are resistant in aqueous solution to degradation with a nuclease. In some embodiments, the LNP formulations may include a CCD lipid, a neutral lipid, and / or a helper lipid. In some embodiments, the LNP formulation comprises an ionizable lipid. In some embodiments, an ionizable lipid may be a cationic lipid, an ionizable cationic lipid, or an amine- containing lipid that can be readily protonated. In some embodiments, the lipid is a cationic lipid that can exist in a positively charged or neutral form depending on pH. In some embodiments, the cationic lipid is a lipid capable of being positively charged, e.g., under physiological conditions. In some embodiments, the lipid particle comprises a cationic lipid in formulation with one or more of neutral lipids, ionizable amine-containing lipids, biodegradable alkyl lipids, steroids, phospholipids including polyunsaturated lipids, structural lipids (e.g., sterols), PEG, cholesterol, and polymer conjugated lipids. In some embodiments, LNP formulation (e.g., MC3 and / or SSOP) includes cholesterol, PEG, and / or a helper lipid. The LNPs may be, e.g., microspheres (including unilamellar and multilamellar vesicles, lamellar phase lipid bilayers that, in some embodiments, are substantially spherical). In some embodiments, the LNP can comprise an aqueous core, e.g., comprising a nucleic acid encoding an expression activator or a system as disclosed herein and referred to herein as “cargo.” In some embodiments of the present disclosure, the cargo for the LNP formulation includes at least one guide RNA. In some embodiments, the cargo, e.g., a nucleic acid encoding an expression activator, or a system as disclosed herein, may be adsorbed to the surface of an LNP, e.g., an LNP comprising a cationic lipid. In some embodiments, the cargo, e.g., a nucleic acid encoding an expression activator, or a system as disclosed herein, may be associated with the LNP. In some embodiments, the cargo, e.g., a nucleic acid encoding an expression activator, or a system as disclosed herein, may be encapsulated, e.g., fully encapsulated and / or partially encapsulated in an LNP.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, an LNP comprising a cargo may be administered for systemic delivery, e.g., delivery of a therapeutically effective dose of cargo that can result in a broad exposure of an active agent within an organism. Systemic delivery of lipid nanoparticles can be by any means known in the art including, for example and without limitation, intravenous, intraarterial, subcutaneous, and intraperitoneal delivery. In some embodiments, systemic delivery of lipid nanoparticles is by intravenous delivery. In some embodiments, an LNP comprising a cargo may be administered for local delivery, e.g., delivery of an active agent directly to a target site within an organism. In some embodiments, an LNP may be locally delivered into a disease site, e.g., a tumor, or other target site, e.g., a site of inflammation, or to a target organ, e.g., the liver, lung, stomach, colon, pancreas, uterus, breast, lymph nodes, and the like. In some embodiments, an LNP as disclosed herein may be locally delivered to a specific cell, e.g., lung, pancreas, and / or epithelial cells. In some embodiments, an LNP as disclosed herein may be locally delivered to a specific site, e.g., a tumor site, e.g., by subcutaneous or orthotopic administration. The LNPs may be formulated as a dispersed phase in an emulsion, micelles, or an internal phase in a suspension. In some embodiments, the LNPs are biodegradable. In some embodiments, the LNPs do not accumulate to cytotoxic levels or cause toxicity in vivo at a therapeutically effective dose. In some embodiments, the LNPs do not accumulate to cytotoxic levels or cause toxicity in vivo after repeat administrations at a therapeutically effective dose. In some embodiments, the LNPs do not cause an innate immune response that leads to a substantially adverse effect at a therapeutically effective dose. In some embodiments, the LNP used comprises the formula (6Z,9Z,28Z,31Z)- heptatriacont-6,9,28,31-tetraene-19-y14-(dimethylamino)butanoate or ssPalm0-phenyl-P4C2 (ssPalmO-Phe, SS-OP). In some embodiments, the LNP formulation comprises the formula, (6Z,9Z,28Z,31Z)-heptatriacont-6,9,28,31-tetraene-19-yl4-(dimethylamino)butanoate(MC3), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), Cholesterol, 1,2-dimyristoyl-rac-glycero- 3-methoxypolyethylene glycol-2000(PEG2k-DMG), e.g., MC3 LNP or ssPalmO-phenyl- P4C2 (ssPalmO-Phe, SS-OP), 1,2-dioleoyl-sn-glycero-3-phosphocholine(DOPC), Cholesterol, 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000(PEG2k-DMG), e.g., SSOP-LNP. Liposomes are spherical vesicle structures composed of a uni- or multilamellar lipid bilayer surrounding internal aqueous compartments and a relatively impermeable outer lipophilic phospholipid bilayer. Liposomes may be anionic, neutral, or cationic. Liposomes are biocompatible, nontoxic, can deliver both hydrophilic and lipophilic drug molecules,FH12877464.1 Attorney Docket: OGY-02925 protect their cargo from degradation by plasma enzymes, and transport their load across biological membranes and the blood brain barrier (BBB) (see, e.g., Spuch and Navarro, Journal of Drug Delivery, vol.2011, Article ID 469679, 12 pages, 2011). Vesicles can be made from several different types of lipids; however, phospholipids are most used to generate liposomes as drug carriers. Vesicles may comprise, for example and without limitation, DOTMA, DOTAP, DOTIM, DDAB, alone or together with cholesterol to yield DOTMA and cholesterol, DOTAP and cholesterol, DOTIM and cholesterol, and DDAB and cholesterol. Methods for preparation of multilamellar vesicle lipids are known in the art (see, for example, U.S. Pat. No.6,693,086, the teachings of which relating to multilamellar vesicle lipid preparation are incorporated herein by reference). Although vesicle formation can be spontaneous when a lipid film is mixed with an aqueous solution, it can also be expedited by applying force in the form of shaking by using a homogenizer, sonicator, or an extrusion apparatus (see, e.g., Spuch and Navarro, Journal of Drug Delivery, vol.2011, Article ID 469679, 12 pages, 2011). Extruded lipids can be prepared by extruding through filters of decreasing size, as described in Templeton et al, Nature Biotech, 15:647-652, 1997, the teachings of which relate to extruded lipid preparation are incorporated herein by reference. Viral Vectors In some embodiments, viral vector systems which can be utilized with the methods and compositions described herein. Suitable viral vector systems for use include, for example and without limitation, (a) adenovirus vectors (e.g., an Ad5 / F35 vector); (b) retrovirus vectors, including but not limited to lentiviral vectors (including integration competent or integration-defective lentiviral vectors), moloney murine leukemia virus, etc.; (c) adeno- associated virus vectors; (d) herpes simplex virus vectors; (e) SV 40 vectors; (f) polyoma virus vectors; (g) papilloma virus vectors; (h) picornavirus vectors; (i) pox virus vectors such as an orthopox, e.g., vaccinia virus vectors or avipox, e.g. canary pox or fowl pox; and (j) a helper-dependent or gutless adenovirus. Replication-defective viruses can also be advantageous. Different vectors will or will not become incorporated into the cells’ genome. The constructs can include viral sequences for transfection, if desired. Alternatively, the construct can be incorporated into vectors capable of episomal replication, e.g., EPV and EBV vectors. See, e.g., U.S. Patent Nos.6,534,261; 6,607,882; 6,824,978; 6,933,113; 6,979,539; 7,013,219; and 7,163,824, the entire contents of each of which is incorporated by reference herein. Vectors, including those derived from retroviruses such as lentivirus, areFH12877464.1 Attorney Docket: OGY-02925 suitable tools to achieve long- term gene transfer since they allow long-term, stable integration of a transgene and its propagation in daughter cells. Examples of vectors include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. In certain embodiments, an expression vector may be provided to a cell in the form of a viral vector. Viral vector technology is known in the art and described in a variety of virology and molecular biology manuals. In some embodiments, a suitable viral vector for use in the present invention is an adeno-associated viral vector, such as a recombinant adeno-associated viral vector. Recombinant adeno-associated virus vectors (rAAV) are gene delivery systems based on the defective and nonpathogenic parvovirus adeno-associated type 2 virus. In some embodiments, the vectors are derived from a plasmid that retains only the AAV 145 bp inverted terminal repeats flanking the transgene expression cassette. Efficient gene transfer and stable transgene delivery due to integration into the genomes of the transduced cell are key features for this vector system. (Wagner et al., Lancet 351:91171702-3 (1998), Kearns et al., Gene Ther.9:748-55 (1996)). AAV serotypes, including AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8 and AAV9, can be used in accordance with the present invention. Replication-deficient recombinant adenoviral vectors (Ad) can be produced at high titer and readily infect a number of different cell types. Most adenovirus vectors are engineered such that a transgene replaces the Ad E1a, E1b, and / or E3 genes; subsequently, the replication defective vector is propagated in a suitable cell system, e.g., HEK293 and variants thereof, that supply deleted gene function in trans. Ad vectors can transduce multiple types of tissues in vivo, including nondividing, differentiated cells, such as those found in liver, kidney, and muscle. Conventional Ad vectors have a large carrying capacity. An example of the use of an Ad vector in a clinical trial involved polynucleotide therapy for antitumor immunization with intramuscular injection (Sterman et al., Hum. Gene Ther.7:1083-9 (1998)). Additional examples of the use of adenovirus vectors for gene transfer in clinical trials include Rosenecker et al., Infection 24:15-10 (1996); Sterman et al., Hum. Gene Ther.9:71083-1089 (1998); Welsh et al., Hum. Gene Ther.2:205-18 (1995); Alvarez et al., Hum. Gene Ther.5:597-613 (1997); Topf et al., Gene Ther.5:507-513 (1998); and Sterman et al., Hum. Gene Ther.7:1083-1089 (1998). Packaging cells are used to form virus particles that are capable of infecting a host cell. Such cells include, for example and without limitation, HEK293 cells, and variants thereof, ^2 cells, and PA317 cells. Viral vectors used in gene therapy are usually generated by a producer cell line that packages a nucleic acid vector into a viral particle. The vectorsFH12877464.1 Attorney Docket: OGY-02925 typically contain the minimal viral sequences required for packaging and subsequent integration into a host (if applicable), other viral sequences being replaced by an expression cassette encoding the protein to be expressed. The missing viral functions are supplied in trans by the packaging cell line. For example, AAV vectors used in gene therapy typically only possess inverted terminal repeat (ITR) sequences from the AAV genome which are required for packaging and integration into the host genome. In some embodiments, viral DNA is packaged in a cell line, which contains a helper plasmid encoding the other AAV genes, namely rep and cap, but lacking ITR sequences. In certain embodiments, the cell line is also infected with adenovirus as a helper. The helper virus promotes replication of the AAV vector and expression of AAV genes from the helper plasmid. In certain embodiments, the helper plasmid is not packaged in significant amounts due to a lack of ITR sequences. In certain embodiments, contamination with adenovirus can be reduced by, e.g., heat treatment to which adenovirus is more sensitive than AAV. Methods of Use Epigenetic Modification In some aspects, the present disclosure provides a method for introducing one or more epigenetic modifications (e.g., DNA demethylation and / or histone modification) to a site in a region of the genome comprising a target gene in a cell or a population of cells, comprising contacting the cell or the population of cells with a dose of an expression activator described herein or a nucleic acid encoding the expression activator (e.g., an LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the expression activator, wherein the expression activator comprises (i) a DNA-targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein. In some aspects, the present disclosure provides a method for introducing one or more epigenetic modifications (e.g., DNA demethylation and / or histone modification) to a site in a region of the genome comprising a target gene in a cell or a population of cells, comprising contacting the cell or the population of cells with a dose of an expression activation system described herein comprising at least one expression activator (e.g., 1, 2, 3, 4, 5 or more expression activators described herein) or a nucleic acid encoding the at least one expression activator (e.g., an expression activation system comprising at least one LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the at least one expression activator), wherein the at least one expression activator comprises (i) a DNA-targeting moietyFH12877464.1 Attorney Docket: OGY-02925 (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein. In some aspects, the present disclosure provides a method for introducing one or more epigenetic modifications to a site in a region of the genome comprising the target gene in a subject, comprising administering to the subject a dose of an expression activator described herein or a nucleic acid encoding the expression activator (e.g., an LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the expression activator), wherein the expression activator comprises (i) a DNA-targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein. In some aspects, the present disclosure provides a method of introducing one or more epigenetic modifications to a site in a region of the genome comprising the target gene in a subject, comprising administering to the subject a dose of an expression activation system described herein comprising at least one expression activator (e.g., 1, 2, 3, 4, 5 or more expression activators described herein) or a nucleic acid encoding the at least one expression activator (e.g., an expression activation system comprising at least one LNP-formulated expression r activator or an LNP-formulated nucleic acid encoding the at least one expression activator), wherein the at least one expression activator comprises (i) a DNA-targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein. In some embodiments, epigenetic modification at the site is increased as compared to prior to the contacting or as compared to a control cell or control population of cells not contacted with the expression activator or expression activation system. In some embodiments, epigenetic modification at the site is decreased as compared to prior to the contacting or as compared to a control cell or control population of cells not contacted with the expression activator or expression activation system. In some embodiments, the increase or decrease of the epigenetic modification at the site is associated with increased expression of the target gene in the cell or the population of cells. In some embodiments, the epigenetic modification comprises DNA demethylation, wherein an increase in DNA demethylation at the site is associated with increased expression of the target gene in the cell or the population of cells. In some embodiments, the epigenetic modification comprises a histone modification, wherein a decrease in the histone modification at the site is associated with increased expression of the target gene in the cell or the population of cells. In some embodiments, the epigenetic modification comprises a histone modification, wherein an increase in the histoneFH12877464.1 Attorney Docket: OGY-02925 modification at the site is associated with increased expression of the target gene in the cell or the population of cells. In some embodiments, the histone modification comprises histone acetylation, wherein an increase in histone acetylation is associated with increased expression of the target gene in the cell or the population of cells. In some embodiments, the histone modification comprises histone methylation, wherein an increase in histone methylation is associated with increased expression of the target gene in the cell or the population of cells. Methods to measure histone modification are known in the art. As understood by the skilled artisan, methods to detect histone modification of genomic DNA include, but are not limited to, mass spectrometry and genomic approaches based upon chromatin immunoprecipitation (ChIP) in combination with DNA microarray (i.e., ChIP-chip), high- throughput sequencing (i.e., ChIP-seq), or serial analysis of gene expression (ChIP-SAGE). Such methods are described in Kimura, et al (2013) J. Hu. Genetics 58:445. Methods to measure DNA methylation are known in the art, including, but not limited to, mass spectrometry, methylation-specific PCR, sequencing based-assay such as bisulfite sequencing, the Hpall tiny fragment Enrichment by Ligation-mediated PCR (HELP) assay, GLAD-PCR assay, ChIP-on-chip assay, restriction landmark genomic scanning, methylated DNA immunoprecipitation, methyl sensitive southern blotting, high resolution Melt analysis, and methylation sensitive single nucleotide primer extension assay. In some embodiments, the method to measure DNA methylation of a target gene comprises use of a DNA methylation microarray (e.g., an Illumina Methylation Array). Approaches for methylation analysis by microarray are described in Deatherage, et al (2009) Methods Mol Biol 556:117- 139; Schumacher, et al (2006) Nucleic Acids Res 34:528-42; and Willhelm-Benartzi, et al (2013) Br J Cancer 109:1394-1402. In some embodiments, the method comprises a sequencing-based assay, wherein genomic DNA is treated with an agent prior to sequencing that converts cytosine residues to uracil (or another base having distinct hybridization properties from cytosine), but does not affect 5-methylcytosine residues. Exemplary agents are known in the art and include bisulfite, hydrogen sulfite, disulfite, and combinations thereof. Therefore, DNA treated with bisulfite retains the methylated cytosines, but not unmethylated cytosines. The treated DNA is then subjected to sequencing analysis (see, e.g., Campan et al (2009) Methods Mol Biol 507:325-37; Adusumalli, et al (2015) Brief Bioinform 16:369-79). Exemplary methods for sequencing analysis are known in the art and include use of next generation sequencing platforms based on sequencing-by-synthesis or sequencing-by- ligation as employed by Illumina, Life Technologies, and Roche; or based on nanopore sequencing or electronic-detection as employed by Ion Torrent technology. In someFH12877464.1 Attorney Docket: OGY-02925 embodiments, the method to measure DNA methylation comprises enzymatic methyl-seq (EM-seq) (see, e.g., Vaisvila et al (2021) Genome Res 31:1280). In EM-seq, enzymatic reactions (e.g., performed using TET2 and T4-BGT) are used to convert 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (i.e., the oxidation product of 5mC; also referred to as 5hmC) into products resistant to an enzymatic reaction that deaminates unmodified cytosines by converting them to uracils (e.g., performed using APOBEC3A). The enzymatically processed DNA is then amplified by PCR using EM-seq adaptor primers and subjected to sequencing analysis, e.g., using Illumina sequencing. Modulating Gene Expression In another aspect, the present disclosure provides a method of modulating, e.g., increasing, expression of a target gene. In some embodiments, the method comprises providing an expression activator (or a nucleic acid encoding the same, or a pharmaceutical composition comprising said expression activator nucleic acid) or an expression activation system described herein (or a nucleic acid encoding the same, or pharmaceutical composition comprising said expression activation system or nucleic acid), and contacting the target gene, and / or operably linked transcription control element(s) with the expression activator or the expression activation system. In some embodiments, modulating, e.g., increasing expression of a target gene comprises modulation of transcription of a target gene as compared with a reference value, e.g., transcription of a target gene in absence of the expression activator or the expression activation. In some embodiments, the method of modulating, e.g., increasing, expression of a target gene are used ex vivo, e.g., on a cell from a subject, e.g., a mammalian subject, e.g., a human subject. In some embodiments, the methods of modulating, e.g., increasing, expression of a target gene are used in vivo, e.g., on a mammalian subject, e.g., a human subject. In some embodiments, the method of modulating, e.g., increasing, expression of a target gene are used in vitro, e.g., on a cell or cell line as described herein. In some aspects, the present disclosure provides a method of modulating (e.g., increasing) expression of a target gene in a cell or a population of cells, comprising contacting the cell or the population of cells with a dose of an expression activator described herein or a nucleic acid encoding the expression activator (e.g., an LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the expression activator), wherein the expression activator comprises (i) a DNA-targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein.FH12877464.1 Attorney Docket: OGY-02925 In some aspects, the present disclosure provides a method of modulating (e.g., increasing) expression of a target gene in a cell or a population of cells, comprising contacting the cell or the population of cells with a dose of an expression activation system described herein comprising at least one expression activator (e.g., 1, 2, 3, 4, 5 or more expression activators described herein) or a nucleic acid encoding the at least one expression activator (e.g., an expression activation system comprising at least one LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the at least one expression activator), wherein the at least one expression activator comprises (i) a DNA-targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein. In some embodiments, expression of a target gene is increased as compared to prior to the contacting or as compared to a control cell or control population of cells not contacted with the expression activator or the expression activation system. In some embodiments, the contacting is ex vivo. In some embodiments, the contacting is in vivo. In some embodiments, the expression of the target gene is measured by harvesting the cell or population of cells at a time point following the contacting, obtaining the transcriptional or translational product of the target gene in the cell or the population of cells, and quantifying a level of the transcriptional or translation product as compared to a control cell or control population of cells (e.g., a cell or population of cells not contacted with the expression activator or the expression activation system). In some embodiments, expression of the target gene is measured by quantifying the level of mRNA as compared to the control cell or control population of cells. In some embodiments, the level of mRNA is increased by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to the control cell or control population of cells. In some embodiments, the level of mRNA is increased by about 1.1-fold to about 10- fold, by about 1.2-fold to about 10-fold, by about 1.3-fold to about 10-fold, by about 1.4-fold to about 10-fold, by about 1.5-fold to about 10-fold, by about 2-fold to about 10-fold, by about 3-fold to about 10-fold, by about 4-fold to about 10-fold, or by about 5-fold to about 10-fold as compared to the control cell or control population of cells. In some embodiments, expression of the target gene is measured by quantifying the level of polypeptide expressed by the gene as compared to the control cell or control population of cells. In some embodiments, the level of polypeptide is increased by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to the control tissue. In some embodiments, the level of polypeptide is increasedFH12877464.1 Attorney Docket: OGY-02925 by about 1.1-fold to about 10-fold, by about 1.2-fold to about 10-fold, by about 1.3-fold to about 10-fold, by about 1.4-fold to about 10-fold, by about 1.5-fold to about 10-fold, by about 2-fold to about 10-fold, by about 3-fold to about 10-fold, by about 4-fold to about 10-fold, or by about 5-fold to about 10-fold as compared to the control cell or control population of cells. In some aspects, the present disclosure provides a method of modulating (e.g., increasing) expression of a target gene in a target tissue in vivo, comprising administering to a subject a dose of an expression activator described herein or a nucleic acid encoding the expression activator(e.g., an LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the expression activator, wherein the expression activator comprises (i) a DNA-targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein. In some aspects, the present disclosure provides a method of modulating (e.g., increasing) expression of a target gene in a target tissue in vivo, comprising administering to a subject a dose of an expression activation system described herein comprising at least one expression activator (e.g., 1, 2, 3, 4, 5 or more expression activators described herein) or a nucleic acid encoding the at least one expression activator (e.g., an expression activation system comprising at least one LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the at least one expression activator), wherein the at least one expression activator comprises (i) a DNA-targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein. In some embodiments, expression of a target gene is measured by harvesting the target tissue at a time point following the administering, obtaining the transcriptional or translational product of the target gene in the target tissue, and quantifying a level of the transcriptional or translation product as compared to a control tissue (e.g., the same tissue obtained from a subject not administered the expression activator or the expression activation system). In some embodiments, expression of the target gene is measured by quantifying the level of mRNA as compared to the control tissue. In some embodiments, the level of mRNA is increased by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to the control tissue. In some embodiments, the level of mRNA is increased by about 1.1-fold to about 10-fold, by about 1.2-fold to about 10-fold, by about 1.3-fold to about 10-fold, by about 1.4-fold to about 10-fold, by about 1.5-fold to about 10-fold, by about 2-fold to about 10-fold, by about 3-fold to about 10-fold, by about 4-fold to about 10-fold, or by about 5-fold to aboutFH12877464.1 Attorney Docket: OGY-02925 10-fold as compared to the control tissue. In some embodiments, expression of the target gene is measured by quantifying the level of polypeptide encoded by the gene as compared to the control tissue. In some embodiments, the level of polypeptide is increased by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to the control tissue. In some embodiments, the level of polypeptide is increased by about 1.1-fold to about 10-fold, by about 1.2-fold to about 10-fold, by about 1.3-fold to about 10-fold, by about 1.4-fold to about 10-fold, by about 1.5-fold to about 10-fold, by about 2-fold to about 10-fold, by about 3-fold to about 10-fold, by about 4-fold to about 10-fold, or by about 5-fold to about 10-fold as compared to the control tissue. Methods to measure a level of a gene transcriptional or translational product are known in the art. In some embodiments, the method comprises measuring a level of transcriptional product (e.g., mRNA) using any technique known in the art for measuring or quantifying target RNAs in a cell culture or primary cells harvested from a subject, e.g., RNAseq, transcriptome microarrays, and RT-qPCR. In some embodiments, the method comprises measuring a level of polypeptide using any technique known in the art for measuring or quantifying polypeptides in a cell culture or primary cells harvested from a subject, e.g., ELISA, immunoassays (e.g., western blot), and mass spectrometry. In some aspects, the present disclosure provides a method of modulating (e.g., increasing) expression of a target gene in a subject, comprising administering to the subject a dose of an expression activator described herein or a nucleic acid encoding the expression activator (e.g., an LNP- formulated expression activator or an LNP-formulated nucleic acid encoding the expression activator), wherein the expression activator comprises (i) a DNA-targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein. In some aspects, the present disclosure provides a method of modulating (e.g., increasing) expression of a target gene in a subject, comprising administering to the subject a dose of an expression activation system described herein comprising at least one expression activator (e.g., 1, 2, 3, 4, 5 or more expression activators described herein) or a nucleic acid encoding the at least one expression activator (e.g., an expression activation system comprising at least one LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the at least one expression activator), wherein the at least one expression activator comprises (i) a DNA-targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein.FH12877464.1 Attorney Docket: OGY-02925 In some embodiments, expression of a target gene is increased in the subject (e.g., as measured in a tissue sample or serum obtained from the subject) as compared to prior to the administering or as compared to a control subject who has not received a dose of the expression activator or the expression activation system. In some embodiments, a level of a transcriptional or translation product of the target gene is increased in the subject (e.g., as measured in a tissue sample or serum obtained from the subject) as compared to prior to the administering or as compared to a control subject who has not received a dose of the expression activator or the expression activation system. In some embodiments, expression of the target gene or the level of a transcriptional or translation product thereof is measured in a tissue sample obtained from the subject following administering of the dose of the expression activator or the expression activation system. In some embodiments, the tissue sample is a fresh, frozen, and / or preserved organ, biopsy, and / or aspirate obtained from the subject. In some embodiments, the tissue sample is blood or any blood constituent (e.g., plasma) collected from the subject. In some embodiments, expression of the target gene or the level of a transcriptional or translation product thereof as measured in the tissue sample is compared to expression or a level in a reference tissue sample obtained from the subject prior to the administering or from a control subject. Methods to measure expression of the target gene or the level of a transcriptional or translation product thereof are known in the art and include assays for measuring genomic DNA, mRNA, or cDNA (e.g., RNAseq, RT-PCR, real- time RT-PCR, competitive RT-PCR, northern blotting, nucleic acid microarray) and assays for measuring protein expression (e.g., quantitative immunofluorescence, flow cytometry, western blotting, ELISA, tissue immunostaining, immunoprecipitation, mass spectrometry, immunohistochemistry). In some embodiments, expression of the target gene is measured by harvesting a tissue sample or serum from the subject, obtaining the transcriptional or translational product of the gene in the tissue or serum, and quantifying a level of the transcriptional or translation product as compared to a level in a reference tissue sample obtained from the subject prior to the administering or from a control subject. In some embodiments, expression of the target gene is measured by quantifying the level of mRNA as compared to the reference tissue sample. In some embodiments, the level of mRNA is increased by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to the reference tissue sample. In some embodiments, the level of mRNA is increased by about 1.1-fold to about 10-fold, by about 1.2-fold to about 10-fold, by about 1.3-fold to about 10-fold, by about 1.4-fold to about 10-fold, by about 1.5-fold to aboutFH12877464.1 Attorney Docket: OGY-02925 10-fold, by about 2-fold to about 10-fold, by about 3-fold to about 10-fold, by about 4-fold to about 10-fold, or by about 5-fold to about 10-fold as compared to the reference tissue sample. In some embodiments, expression of the target gene is measured by quantifying the level of polypeptide encoded by the gene as compared to the reference tissue sample. In some embodiments, the level of polypeptide is increased by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to the reference tissue sample. In some embodiments, the level of polypeptide is increased by about 1.1-fold to about 10-fold, by about 1.2-fold to about 10-fold, by about 1.3- fold to about 10-fold, by about 1.4-fold to about 10-fold, by about 1.5-fold to about 10-fold, by about 2-fold to about 10-fold, by about 3-fold to about 10-fold, by about 4-fold to about 10-fold, or by about 5-fold to about 10-fold as compared to the reference tissue sample. In some aspects, the disclosure provides a method of increasing expression of a target gene in a cell or a population of cells, comprising contacting the cell or the population with a dose of an expression activator described herein or a nucleic acid encoding the expression activator (e.g., an LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the expression activator), wherein the expression activator comprises (i) a DNA- targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein. In some aspects, the disclosure provides a method of increasing expression of a target gene in a cell or a population of cells, comprising contacting the cell or the population of cells with a dose of an expression activation system described herein comprising at least one expression activator (e.g., 1, 2, 3, 4, 5 or more expression activators described herein) or a nucleic acid encoding the at least one expression activator (e.g., an expression activation system comprising at least one LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the at least one expression activator), wherein the at least one expression activator comprises (i) a DNA-targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein. In some embodiments, expression of the target gene is increased as compared to prior to the contacting or as compared to a control cell or control population of cells not contacted with the expression activator or the expression activation system. The present disclosure is further directed, in another aspect, to a cell made by a method or process described herein. In some embodiments, the disclosure provides a cell produced by: providing an expression activator or an expression activation system describedFH12877464.1 Attorney Docket: OGY-02925 herein, providing the cell, and contacting the cell with the expression activator (or a nucleic acid encoding the expression activator, or a composition comprising said expression activator or nucleic acid) or the expression activation system (or a nucleic acid encoding the expression activation system, or a composition comprising said expression activation system or nucleic acid). In some embodiments, contacting a cell with an expression activator comprises contacting the cell with a nucleic acid encoding the expression activator under conditions that allow the cell to produce the expression activator. In some embodiments, contacting a cell with an expression activator comprises contacting an organism that comprises the cell with the expression activator or a nucleic acid encoding the expression activator under conditions that allow the cell to produce the expression activator. Methods and compositions as provided herein may treat a condition associated with mis-regulation of a target gene by stably or transiently altering (e.g., increasing) transcription of a target gene. In some embodiments, a method or composition provided herein may increase expression of a target gene in a cell by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% (and optionally up to 100%) relative to expression of the target gene in a cell not contacted by the composition or treated with the method. In some embodiments, the disclosure provides a method of modulating (e.g., increasing) expression of a target gene in a subject having a disorder associated with dysregulation (e.g., mutation) of the target gene in a subject, comprising administering to the subject an expression activator described herein or a nucleic acid encoding the expression activator (e.g., an LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the expression activator), wherein the expression activator comprises (i) a DNA- targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein. In some embodiments, the disclosure provides a method of modulating (e.g., increasing) expression of a target gene in a subject having a disorder associated with dysregulation (e.g., mutation) of the target gene in a subject an expression activation system described herein comprising at least one expression activator (e.g., 1, 2, 3, 4, 5 or more expression activators described herein) or a nucleic acid encoding the at least one expression activator (e.g., an expression activation system comprising at least one LNP-formulated expression activator or an LNP-formulated nucleic acid encoding the at least one expression activator), wherein the at least one expression activator comprises (i) a DNA-targeting moiety (e.g., a TALE, a ZFN, a dCas9 / gRNA) that binds a target sequence described herein, and (ii) an effector domain described herein.FH12877464.1 Attorney Docket: OGY-02925 Methods are described herein to deliver agents, or a composition as disclosed herein, to a subject for treatment of a disorder such that the subject suffers minimal side effects or systemic toxicity in comparison to an alternative, e.g., standard of care, treatment. In some embodiments, the subject does not experience any significant side effects typically associated with standard of care, when treated with the agents and / or compositions described herein. In some embodiments, the subject does not experience a significant side effect including but not limited to alopecia, nausea, vomiting, poor appetite, soreness, neutropenia, anemia, thrombocytopenia, dizziness, fatigue, constipation, oral ulcers, itchy skin, peeling, nerve and muscle damage, auditory changes, weight loss, diarrhea, immunosuppression, bruising, heart damage, bleeding, liver damage, kidney damage, edema, mouth and throat sores, infertility, fibrosis, epilation, moist desquamation, mucosal dryness, vertigo and encephalopathy when treated with the agents and / or compositions described herein. In some embodiments, the subject does not show a significant loss of body weight when treated with the agents and / or compositions described herein. The agents and compositions described herein can be administered to a subject, e.g., a mammal, e.g., in vivo, to treat or prevent a variety of disorders as described herein. Pharmaceutical Compositions The present disclosure is further directed, in part, to pharmaceutical compositions comprising an expression activator or an expression activation system, e.g., expression activator(s), described herein, to pharmaceutical compositions comprising nucleic acids encoding the expression activator or expression activation system, e.g., expression activator(s), described herein, and / or to and / or compositions that deliver an expression activator or expression activation system, e.g., expression activator(s), described herein to a cell, tissue, organ, and / or subject. As used herein, the term “pharmaceutical composition” refers to an active agent (e.g., an expression activator or nucleic acids of the expression activator, e.g., an expression activation system, e.g., expression activator(s) of an expression activation system, or a nucleic acid encoding the same), formulated together with one or more pharmaceutically acceptable carriers (e.g., pharmaceutically acceptable carriers known to those of skill in the art). In some embodiments, an active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, a pharmaceutical composition comprising an expression activator of theFH12877464.1 Attorney Docket: OGY-02925 present disclosure comprises an expression activator or nucleic acid(s) encoding the same. In some embodiments, a pharmaceutical composition comprising an expression activation system of the present disclosure comprises each of the expression activators of the expression activation system or nucleic acid(s) encoding the same (e.g., if an expression activation system comprises a first expression activator and a second expression activator, the pharmaceutical composition comprises the first and second expression activator). In some embodiments, a pharmaceutical composition comprises less than all of the expression activators of an expression activation system comprising a plurality of expression activators. For example, an expression activation system may comprise a first expression activator and a second expression activator, and a first pharmaceutical composition may comprise the first expression activator or nucleic acid encoding the same and a second pharmaceutical composition may comprise the second expression activator or nucleic acid encoding the same. In some embodiments, a pharmaceutical composition may comprise coformulation of one or more expression activators, or nucleic acid(s) encoding the same. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; trans-dermally; or nasally, pulmonary, and / or to other mucosal surfaces. As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the otherFH12877464.1 Attorney Docket: OGY-02925 ingredients of the formulation and not injurious to the patient. In some embodiments, for example, materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, the term “pharmaceutically acceptable salt”, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium,FH12877464.1 Attorney Docket: OGY-02925 calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate, and aryl sulfonate. In various embodiments, the present disclosure provides pharmaceutical compositions described herein with a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipient includes an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non- toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous. Pharmaceutical preparations may be made following conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing, and filling for hard gelatin capsule forms. When a liquid carrier is used, a preparation can be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous solution or suspension. Such a liquid formulation may be administered directly per os. In some embodiments, pharmaceutical compositions may be formulated for delivery to a cell and / or to a subject via any route of administration. Modes of administration to a subject may include injection, infusion, inhalation, intranasal, intraocular, topical delivery, inter-cannular delivery, or ingestion. Injection includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intraventricular, intracapsular, intra-orbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intra-cerebrospinal, and intra-stemal injection and infusion. In some embodiments, administration includes aerosol inhalation, e.g., with nebulization. In some embodiments, administration is systemic (e.g., oral, rectal, nasal, sublingual, buccal, or parenteral), enteral (e.g., system-wide effect, but delivered through the gastrointestinal tract), or local (e.g., local application on the skin, or intravitreal injection). In some embodiments, one or more compositions is administered systemically. In some embodiments, administration is non-parenteral and a therapeutic is a parenteral therapeutic. In some embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, inter-dermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e. g. intrahepatic), mucosal, nasal, oral, rectal,FH12877464.1 Attorney Docket: OGY-02925 subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may be a single dose. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, six, eight, ten, 12, 15 or 20 or more administrations may be given to the subject during one treatment or over a period of time as a treatment regimen. In some embodiments, administrations may be given as needed, e.g., for as long as symptoms associated with the disease, disorder or condition persist. In some embodiments, repeated administrations may be indicated for the remainder of the subject’s life. Treatment periods may vary and could be, e.g., one day, two days, three days, one week, two weeks, one month, two months, three months, six months, a year, or longer. Dosage The dosage of the administered agent or composition can vary based on, e.g., the condition being treated, the severity of the disease, the subject’s individual parameters, including age, physiological condition, size and weight, duration of treatment, the type of treatment to be performed (if any), the particular route of administration and similar factors. Thus, the dose administered of the agents described herein can depend on such various parameters. The dosage of an administered composition may also vary depending upon other factors as the subject’s sex, general medical condition, and severity of the disorder to be treated. It may be desirable to provide the subject with a dosage of a modulatory agent or combination of modulatory agents disclosed herein that is in the range of from about 1 mg / kg to 6 mg / kg as a single intravenous infusion, although a lower or higher dosage also may be administered as circumstances dictate. The dosage may be repeated as needed, for example, once every day (e.g., for 1-30 days), once every 3 days (e.g., for 1-30 days) once every 5 days (e.g., for 1-30 days), once per week (e.g., for 1-6 weeks or for 2-5 weeks). In some embodiments, dosages may include, but are not limited to, 1.0 mg / kg - 6 mg / kg, 1.0 mg / kg - 5 mg / kg, 1.0 mg / kg - 4 mg / kg, 1.0 mg / kg - 3.0 mg / kg, 1.5 mg / kg - 3.0 mg / kg, 1.0 mg / kg - 1.5 mg / kg, 1.5 mg / kg - 3 mg / kg, 3 mg / kg - 4 mg / kg, 4 mg / kg - 5 mg / kg, or 5 mg / kg - 6 mg / kg. The dosage may be administered multiple times, e.g., once, or twice a week, once every 1, or once every 2 weeks. In some embodiments, the subject is provided with a dosage of a modulatory agent or combination of modulatory agents disclosed herein that is in the range ofFH12877464.1 Attorney Docket: OGY-02925 from about 1 mg / kg to 6 mg / kg as multiple intravenous infusions although a lower or higher dosage also may be administered as circumstances dictate. A modulatory agent or a combination of modulatory agents as disclosed herein may be administered as one dosage every 3-5 days, repeated for a total of at least 3 dosages. Alternatively, a modulatory agent or a combination of modulatory agents as disclosed herein may be administered at 3 mg / kg every 5 days for 25 days. Alternatively, a modulatory agent or a combination of modulatory agents as disclosed herein may be administered at 1.0-5.0 mg / kg every 3-5 days for 1-10 doses. Alternatively, a modulatory agent or a combination of modulatory agents as disclosed herein may be administered at 1.0- 3.0 mg / kg every 5 days for 3 doses then every 3 days for 3 doses. Alternatively, a modulatory agent or a combination of modulatory agents as disclosed herein may be administered at 1.0-3.0 mg / kg every 5 days for 4 doses then every 3 days for 3 doses. Alternatively, a modulatory agent or a combination of modulatory agents as disclosed herein may be administered at 6 mg / kg every 5 days for 1- 10 doses. Alternatively, a modulatory agent or a combination of modulatory agents as disclosed herein may be administered at 3 mg / kg every 5 days for 1-10 doses. Alternatively, a modulatory agent or a combination of modulatory agents as disclosed herein may be administered at 1.5 mg / kg every 5 days for 2 doses, 3 mg / kg every 5 days for 3 doses, 3 mg / kg every 3 days for 1 dose. Alternatively, a modulatory agent or a combination of modulatory agents as disclosed herein may be administered at 6 mg / kg at every 5 days or at 1 .5 mg / kg once a day for 5 days with 2 days off. The dosing schedule can optionally be repeated at other intervals and dosage may be given through various parenteral routes, with appropriate adjustment of the dose and schedule. In some embodiments, the dosing of modulatory agents or a combination of modulatory agents may include a dosage of between 1.0 mg / kg to 6.0 mg / kg, optionally given either weekly, twice per week, or every other week. The person of ordinary skill will realize that a variety of factors, such as age, sex, weight, severity of disorder to be treated may be considered in selecting a dosage of a modulatory agent or a combination of modulatory agents as disclosed herein, and that the dosage and / or frequency of administration may be increased or decreased during the course of therapy. The dosage may be repeated as needed, with evidence of reduction of tumor volume observed after as few as 2 to 8 doses. The dosages and schedules of administration disclosed herein show minimal effect on overall weight of the subject compared to cisplatin, sorafenib, or a small molecule comparator. The subject methods may include use of CT and / or PET / CT, or MRI, to measure tumor response at regular intervals. Blood levels of tumor markers may alsoFH12877464.1 Attorney Docket: OGY-02925 be monitored. Dosages and / or administration schedules may be adjusted as needed, according to the results of imaging and / or marker blood levels. Pharmaceutical compositions according to the present disclosure may be delivered in a therapeutically effective amount. A precise therapeutically effective amount is an amount of a composition that will yield the most effective results in terms of efficacy of treatment in a given subject. This amount will vary depending upon a variety of factors, including but not limited to characteristics of a therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), physiological condition of a subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), nature of a pharmaceutically acceptable carrier or carriers in a formulation, and / or route of administration. Administration In some aspects, the present disclosure provides methods of delivering a therapeutic comprising administering a composition as described herein to a subject, wherein a modulating agent is a therapeutic and / or wherein delivery of a therapeutic causes changes in gene expression relative to gene expression in absence of a therapeutic. Methods as provided in various embodiments herein may be utilized in any some aspects further delineated herein. In some embodiments, one or more compositions, e.g., comprising an expression activator or an expression activation system described herein, is / are targeted to specific cells, or one or more specific tissues. For example, in some embodiments one or more compositions, e.g., comprising an expression activator or an expression activation system described herein, is / are targeted to hepatic, epithelial, connective, muscular, reproductive, and / or nervous tissue or cells. In some embodiments a composition is targeted to a cell or tissue of a particular organ system, e.g., cardiovascular system (heart, vasculature); digestive system (esophagus, stomach, liver, gallbladder, pancreas, intestines, colon, rectum and anus); endocrine system (hypothalamus, pituitary gland, pineal body or pineal gland, thyroid, parathyroids, adrenal glands); excretory system (kidneys, ureters, bladder); lymphatic system (lymph, lymph nodes, lymph vessels, tonsils, adenoids, thymus, spleen); integumentary system (skin, hair, nails); muscular system (e.g., skeletal muscle); nervous system (brain, spinal cord, nerves); reproductive system (ovaries, uterus, mammary glands, testes, vas deferens, seminal vesicles, prostate); respiratory system (pharynx, larynx, trachea, bronchi, lungs, diaphragm); skeletal system (bone, cartilage); and / or combinations thereof. In certain embodiments, an expressionFH12877464.1 Attorney Docket: OGY-02925 activator or an expression activation system described herein is targeted to the liver or liver cells. In some embodiments, a composition of the present disclosure crosses a blood-brain- barrier, a placental membrane, or a blood-testis barrier. In some embodiments, a pharmaceutical composition as provided herein is administered systemically. In some embodiments, administration is non-parenteral and a therapeutic is a parenteral therapeutic. Methods and compositions provided herein, e.g., comprising an expression activator or an expression activation system described herein, may comprise a pharmaceutical composition administered by a regimen sufficient to alleviate a symptom of a disease, disorder, and / or condition. In some aspects, the present disclosure provides methods of delivering a therapeutic by administering compositions as described herein. Pharmaceutical uses of the present disclosure may include compositions (e.g., modulating agents, e.g., disrupting agents) as described herein. In some embodiments, a pharmaceutical composition of the present disclosure has improved PK / PD, e.g., increased pharmacokinetics or pharmacodynamics, such as improved targeting, absorption, or transport (e.g., at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 75%, 80%, 90% improved or more) as compared to an active agent alone. In some embodiments, a pharmaceutical composition has reduced undesirable effects, such as reduced diffusion to a nontarget location, off-target activity, or toxic metabolism, as compared to a therapeutic alone (e.g., at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more reduced) as compared to an active agent alone. In some embodiments, a composition increases efficacy and / or decreases toxicity of a therapeutic (e.g., at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more) as compared to an active agent alone. When the subject to be treated is a mammal such as a human, the composition can be administered by any means known in the art including, but not limited to oral, intraperitoneal, or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal, and intrathecal), intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), nasal, rectal, and topical (including buccal and sublingual) administration. In certain embodiments, the compositions are administered by intravenous infusion or injection. In certain embodiments, the compositions are administered by subcutaneous injection. Kits The present disclosure further provides a kit comprising an expression activator or an expression activation system, e.g., expression activator(s), described herein. In someFH12877464.1 Attorney Docket: OGY-02925 embodiments, a kit comprises an expression activator or an expression activation system (e.g., the expression activator(s) of the expression activation system) and instructions for the use of said expression activator or expression activation system. In some embodiments, a kit comprises a nucleic acid encoding the expression activator or a nucleic acid encoding the expression activation system or a component thereof (e.g., the expression activator(s) of the expression activation system) and instructions for the use of said expression activator (and / or said nucleic acid) and / or said expression activation system (and / or said nucleic acid). In some embodiments, a kit comprises a cell comprising a nucleic acid encoding the expression activator or a nucleic acid encoding the expression activation system or a component thereof (e.g., the expression activator(s) of the expression activation system) and instructions for the use of said cell, nucleic acid, and / or said expression activator or expression activation system. In some embodiments the kit further comprises a set of instructions comprising at least one method for treating a disease or modulating, e.g., increasing the expression of target gene within a cell with said composition. In some embodiments, the kits can optionally include a delivery vehicle for said composition (e.g., a lipid nanoparticle). The reagents may be provided suspended in the excipient and / or delivery vehicle or may be provided as a separate component which can be later combined with the excipient and / or delivery vehicle. In some embodiments, the kits may optionally contain additional therapeutics to be co- administered with the compositions to affect the desired target gene expression. While the instructional materials typically comprise written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated. Such media include but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials. In some embodiments, a kit comprises a unit dosage of an expression activator or an expression activation system, e.g., expression activator(s), described herein, or a unit dosage of a nucleic acid, e.g., a vector, encoding an expression activation system, e.g., expression activator(s), described herein. Definitions As used herein, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. As used herein, the term “agent”, may be used to refer to a compound or entity of any chemical class including, for example, a polypeptide, nucleic acid, saccharide, lipid, smallFH12877464.1 Attorney Docket: OGY-02925 molecule, metal, or combination or complex thereof. As will be clear from context to those skilled in the art, in some embodiments, the term may be utilized to refer to an entity that is or comprises a cell or organism, or a fraction, extract, or component thereof. Alternatively, or additionally, as those skilled in the art will understand in light of context, in some embodiments, the term may be used to refer to a natural product in that it is found in and / or is obtained from nature. In some embodiments, again as will be understood by those skilled in the art in light of context, the term may be used to refer to one or more entities that is man- made in that it is designed, engineered, and / or produced through action of the hand of man and / or is not found in nature. In some embodiments, an agent may be utilized in isolated or pure form; in some embodiments, an agent may be utilized in crude form. In some embodiments, potential agents may be provided as collections or libraries, for example that may be screened to identify or characterize active agents within them. In some embodiments, the term “agent” may refer to a compound or entity that is or comprises a polymer; in some embodiments, the term may refer to a compound or entity that comprises one or more polymeric moieties. In some embodiments, the term “agent” may refer to a compound or entity that is not a polymer and / or is substantially free of any polymer and / or of one or more particular polymeric moieties. In some embodiments, the term may refer to a compound or entity that lacks or is substantially free of any polymeric moiety. The term “anchor sequence” as used herein, refers to a nucleic acid sequence recognized by a nucleating agent that binds sufficiently to form an anchor sequence-mediated conjunction, e.g., a complex. In some embodiments, an anchor sequence comprises one or more CTCF binding motifs. In some embodiments, an anchor sequence is not located within a gene coding region. In some embodiments, an anchor sequence is located within an intergenic region. In some embodiments, an anchor sequence is not located within either of an enhancer or a promoter. In some embodiments, an anchor sequence is located at least 400 bp, at least 450 bp, at least 500 bp, at least 550 bp, at least 600 bp, at least 650 bp, at least 700 bp, at least 750 bp, at least 800 bp, at least 850 bp, at least 900 bp, at least 950 bp, or at least 1 kb away from any transcription start site. In some embodiments, an anchor sequence is located within a region that is not associated with genomic imprinting, monoallelic expression, and / or monoallelic epigenetic marks. In some embodiments, the anchor sequence has one or more functions selected from binding an endogenous nucleating polypeptide (e.g., CTCF), interacting with a second anchor sequence to form an anchor sequence mediated conjunction, or insulating against an enhancer that is outside the anchor sequence mediated conjunction. In some embodiments of the present disclosure, technologies are provided thatFH12877464.1 Attorney Docket: OGY-02925 may specifically target a particular anchor sequence or anchor sequences, without targeting other anchor sequences (e.g., sequences that may contain a nucleating agent (e.g., CTCF) binding motif in a different context); such targeted anchor sequences may be referred to as the “target anchor sequence”. In some embodiments, sequence and / or activity of a target anchor sequence is modulated while sequence and / or activity of one or more other anchor sequences that may be present in the same system (e.g., in the same cell and / or in some embodiments on the same nucleic acid molecule – e.g., the same chromosome) as the targeted anchor sequence is not modulated. In some embodiments, the anchor sequence comprises or is a nucleating polypeptide binding motif. In some embodiments, the anchor sequence is adjacent to a nucleating polypeptide binding motif. The term “anchor sequence-mediated conjunction” as used herein, refers to a DNA structure, in some cases, a complex, that occurs and / or is maintained via physical interaction or binding of at least two anchor sequences in the DNA by one or more polypeptides, such as nucleating polypeptides, or one or more proteins and / or a nucleic acid entity (such as RNA or DNA), that bind the anchor sequences to enable spatial proximity and functional linkage between the anchor sequence. Two events or entities are “associated” with one another, as that term is used herein, if presence, level, form and / or function of one is correlated with that of the other. For example, in some embodiments, a particular entity (e.g., polypeptide, genetic signature, metabolite, microbe, etc.) is considered to be associated with a particular disease, disorder, or condition, if its presence, level, form and / or function correlates with incidence of and / or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and / or remain in physical proximity with one another. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non- covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof. In some embodiments, a DNA sequence is “associated with” a target genomic or transcription complex when the nucleic acid is at least partially within the target genomic or transcription complex, and expression of a gene in the DNA sequence is affected by formation or disruption of the target genomic or transcription complex.FH12877464.1 Attorney Docket: OGY-02925 As used herein, the term “domain” refers to a section or portion of an entity. In some embodiments, a “domain” is associated with a particular structural and / or functional feature of the entity so that, when the domain is physically separated from the rest of its parent entity, it substantially or entirely retains the particular structural and / or functional feature. Alternatively or additionally, in some embodiments, a domain may be or include a portion of an entity that, when separated from that (parent) entity and linked with a different (recipient) entity, substantially retains and / or imparts on the recipient entity one or more structural and / or functional features that characterized it in the parent entity. In some embodiments, a domain is or comprises a section or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, polypeptide, etc.). In some embodiments, a domain is or comprises a section of a polypeptide. In some such embodiments, a domain is characterized by a particular structural element (e.g., a particular amino acid sequence or sequence motif, alpha-helix character, beta-sheet character, coiled-coil character, random coil character, etc.), and / or by a particular functional feature (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.). As used herein, the term “CpG sequence,” also called “CpG site” or “CpG dyad,” are regions of DNA having 5^ to 3^ a cytosine nucleoside linked to a guanine nucleoside by a phosphate group (i.e., 5^-C-phosphate linkage-G-3^). As used herein, the term “CpG islands,” also called “CG islands,” are regions of the genome comprising a high frequency of CpG sequences. GpG islands and criteria for identifying CpG islands are known in the art and described in, for example, Bird et al, (1985) Cell 40:91-99). One definition of a CpG island is a region of (1) at least 200 bp in length, (2) a GC percentage greater than 50%, and (3) an observed-to-expected CpG ratio greater than 60%. The observed-to-expected CpG ratio may be calculated in multiple ways. Two methods of calculating the observed-to-expected CpG ratio are as follows: (a) (number of C * number of G) / length of sequence (b) ((number of C + number of G) / length of sequence)2See, e.g., Gardiner-Garden M, Frommer M (1987). "CpG islands in vertebrate genomes". Journal of Molecular Biology.196 (2): 261–282. doi:10.1016 / 0022- 2836(87)90689-9. PMID 3656447; Saxonov S, Berg P, Brutlag DL (2006). "A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters". Proc Natl Acad Sci USA.103 (5): 1412–1417. Bibcode:2006, PNAS.103.1412S. doi:10.1073 / pnas.0510310103. PMC 1345710. PMID 16432200. Sources for identification of CpG islands in mammalian genomes (e.g., the hg19 (GRCh37) or hg38 (GRch38) humanFH12877464.1 Attorney Docket: OGY-02925 reference genomes) are known in the art, and include, for example, the UCSC Genome Browser (world wide web: genome.ucsc.edu / cgi-bin / hgTrackUi?g=cpgIslandExt). CpG islands often occur near transcription start sites and promote regions. Indeed, many gene promoters reside within or near CpG islands (see, e.g., Saxonov et al (2006) PNAS 103:1412- 17). As used herein, the term “DNA-targeting moiety” refers to an agent or entity that specifically targets, e.g., binds, a target sequence in genomic DNA (e.g., a transcriptional control element or an anchor sequence). As used herein, the term “effector domain” refers to a domain capable of altering the expression of a target gene when localized to an appropriate site in the nucleus of a cell. As used herein, the term “expression activator” refers to an agent or entity with one or more functionalities that increases expression of a target gene in a cell and that specifically binds to a DNA sequence (e.g., a DNA sequence associated with a target gene or a transcription control element operably linked to a target gene). An expression activator comprises at least one targeting moiety and optionally one effector domain. As used herein, the term “genomic complex” is a complex that brings together two genomic sequence elements that are spaced apart from one another on one or more chromosomes, via interactions between and among a plurality of protein and / or other components (potentially including, the genomic sequence elements). In some embodiments, a genomic sequence element may be or comprise a CTCF binding motif, a promoter and / or an enhancer. In some embodiments, a genomic sequence element includes at least one or both of a promoter and / or regulatory site (e.g., an enhancer). In some embodiments, complex formation is nucleated at the genomic sequence element(s) and / or by binding of one or more of the protein component(s) to the genomic sequence element(s). As will be understood by those skilled in the art, in some embodiments, co-localization (e.g., conjunction) of the genomic sites via formation of the complex alters DNA topology at or near the genomic sequence element(s), including, in some embodiments, between them. In some embodiments, a genomic complex comprises an anchor sequence-mediated conjunction, which comprises one or more loops. In some embodiments, a genomic complex as described herein is nucleated by a nucleating polypeptide such as, for example, CTCF and / or Cohesin. In some embodiments, a genomic complex as described herein may include, for example, one or more of CTCF, Cohesin, non-coding RNA (e.g., eRNA), transcriptional machinery proteins (e.g., RNA polymerase, one or more transcription factors, for example selected from the group consisting of TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH, etc.), transcriptional regulatorsFH12877464.1 Attorney Docket: OGY-02925 (e.g., Mediator, P300, enhancer-binding proteins, repressor-binding proteins, histone modifiers, etc.), etc. In some embodiments, a genomic complex as described herein includes one or more polypeptide components and / or one or more nucleic acid components (e.g., one or more RNA components), which may, in some embodiments, be interacting with one another and / or with one or more genomic sequence elements (e.g., anchor sequences, promoter sequences, regulatory sequences (e.g., enhancer sequences)) so as to constrain a stretch of genomic DNA into a topological configuration (e.g., a loop) that it does not adopt when the complex is not formed. As used herein, the term “moiety” refers to a defined chemical group or entity with a particular structure and / or or activity, as described herein. As used herein, the term “modulating agent” refers to an agent comprising one or more targeting moieties and one or more effector moieties that is capable of altering (e.g., increasing or decreasing) expression of a target gene. As used herein, in its broadest sense, the term “nucleic acid” refers to any compound and / or substance that is or can be incorporated into an oligonucleotide chain. In some embodiments, a nucleic acid is a compound and / or substance that is or can be incorporated into an oligonucleotide chain via a phosphodiester linkage. As will be clear from context, in some embodiments, "nucleic acid" refers to an individual nucleic acid residue (e.g., a nucleotide and / or nucleoside); in some embodiments, "nucleic acid" refers to an oligonucleotide chain comprising individual nucleic acid residues. In some embodiments, a "nucleic acid" is or comprises RNA; in some embodiments, a "nucleic acid" is or comprises DNA. In some embodiments, a nucleic acid is, comprises, or consists of one or more natural nucleic acid residues. In some embodiments, a nucleic acid is, comprises, or consists of one or more nucleic acid analogs. In some embodiments, a nucleic acid analog differs from a nucleic acid in that it does not utilize a phosphodiester backbone. For example, in some embodiments, a nucleic acid is, comprises, or consists of one or more "peptide nucleic acids", which are known in the art and have peptide bonds instead of phosphodiester bonds in the backbone, are considered within the scope of the present disclosure. Alternatively or additionally, in some embodiments, a nucleic acid has one or more phosphorothioate and / or 5'-N-phosphoramidite linkages rather than phosphodiester bonds. In some embodiments, a nucleic acid is, comprises, or consists of one or more natural nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxy guanosine, and deoxycytidine). In some embodiments, a nucleic acid is, comprises, or consists of one or more nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-FH12877464.1 Attorney Docket: OGY-02925 pyrimidine, 3 -methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl- uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5- propynyl-uridine, C5 -propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7- deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, 2- thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, a nucleic acid comprises one or more modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) as compared with those in natural nucleic acids. In some embodiments, a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or protein. In some embodiments, a nucleic acid includes one or more introns. In some embodiments, nucleic acids are prepared by one or more of isolation from a natural source, enzymatic synthesis by polymerization based on a complementary template (in vivo or in vitro), reproduction in a recombinant cell or system, and chemical synthesis. In some embodiments, a nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 or more residues long. In some embodiments, a nucleic acid is partly or wholly single stranded; in some embodiments, a nucleic acid is partly or wholly double stranded. In some embodiments a nucleic acid has a nucleotide sequence comprising at least one element that encodes, or is the complement of a sequence that encodes, a polypeptide. In some embodiments, a nucleic acid has enzymatic activity. As used herein, the term “nucleating polypeptide” or “conjunction nucleating polypeptide” as used herein, refers to a protein that associates with an anchor sequence directly or indirectly and may interact with one or more conjunction nucleating polypeptides (that may interact with an anchor sequence or other nucleic acids) to form a dimer (or higher order structure) comprised of two or more such conjunction nucleating polypeptides, which may or may not be identical to one another. When conjunction nucleating polypeptides associated with different anchor sequences associate with each other so that the different anchor sequences are maintained in physical proximity with one another, the structure generated thereby is an anchor-sequence-mediated conjunction. That is, the close physical proximity of a nucleating polypeptide-anchor sequence interacting with another nucleating polypeptide-anchor sequence generates an anchor sequence-mediated conjunction (e.g., in some cases, a DNA loop), that begins and ends at the anchor sequence. As those skilled in the art, reading the present specification will immediately appreciate, terms such asFH12877464.1 Attorney Docket: OGY-02925 “nucleating polypeptide”, “nucleating molecule”, “nucleating protein”, “conjunction nucleating protein”, may sometimes be used to refer to a conjunction nucleating polypeptide. As will similarly be immediately appreciated by those skilled in the art reading the present specification, an assembles collection of two or more conjunction nucleating polypeptides (which may, in some embodiments, include multiple copies of the same agent and / or in some embodiments one or more of each of a plurality of different agents) may be referred to as a “complex”, a “dimer” a “multimer”, etc. As used herein, the phrase “operably linked” refers to a juxtaposition wherein the components described are in a relationship permitting them to function in their intended manner. A transcription control element "operably linked" to a functional element, e.g., gene, is associated in such a way that expression and / or activity of the functional element, e.g., gene, is achieved under conditions compatible with the transcription control element. In some embodiments, "operably linked" transcription control elements are contiguous (e.g., covalently linked) with coding elements, e.g., genes, of interest; in some embodiments, operably linked transcription control elements act in trans to or otherwise at a distance from the functional element, e.g., gene, of interest. In some embodiments, operably linked means two nucleic acid sequences are comprised on the same nucleic acid molecule. In a further embodiment, operably linked may further mean that the two nucleic acid sequences are proximal to one another on the same nucleic acid molecule, e.g., within 1,000, 500, 100, 50, or 10 base pairs of each other or directly adjacent to each other. As used herein, the terms “peptide,” “polypeptide,” and “protein” refer to a compound comprised of amino acid residues covalently linked by peptide bonds, or by means other than peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds or by means other than peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. As used herein, the term “proximal” refers to the location of a first site and a second site in the genome that occur sufficiently close (e.g., occurring within a span of bases of up to 2,000 bases) for a function directed to the first site results in a desired functional outcome at the second site or vice versa. For example, in some embodiments, the first site is a target sequence described herein and the second site is a site for epigenetic modulation (e.g., a CpGFH12877464.1 Attorney Docket: OGY-02925 island), wherein the first site and the second site are sufficiently close that an expression activator targeting the first site via its DNA-targeting moiety results in a desired epigenetic modulation at the second site via its effector domain. In some embodiments, the first site is a site for epigenetic modulation (e.g., a CpG island) and the second site is a transcriptional control element (e.g., a promoter) operably linked to a target gene, wherein the first site and the second site are sufficiently close that an expression activator that introduces an epigenetic modulation at the first site via its effector domain results in altered transcriptional regulation at the second site (e.g., transcriptional regulation resulting in increased expression of the target gene). In some embodiments, the location of the first site and the location of the second site occur within or overlapping a span of about 300 bases to about 2,000 bases. In some embodiments, the location of the first site and the location of the second site occur within or overlapping a span of about 500 bases to about 1,500 bases. In some embodiments, the location of the first site and the location of the second site occur within or overlapping a span of about 500 bases to about 1,000 bases. As used herein, the term “pharmaceutical composition” refers to an active agent (e.g., a modulating agent, e.g., an expression activator or expression activation system of the present disclosure), formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, an active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; trans-dermally; or nasally, pulmonary, and / or to other mucosal surfaces. As used herein, “proximal” refers to a closeness of two sites, e.g., nucleic acid sites, such that binding of an expression activator at the first site and / or modification of the first site by an expression activator will produce the same or substantially the same effect as binding and / or modification of the other site. For example, a targeting moiety may bind to a first siteFH12877464.1 Attorney Docket: OGY-02925 that is proximal to an enhancer (the second site), and the effector moiety associated with said targeting moiety may epigenetically modify the first site such that the enhancer’s effect on expression of a target gene is modified, substantially the same as if the second site (the enhancer sequence) had been bound and / or modified. In some embodiments, a site proximal to a target gene (e.g., an exon, intron, or splice site within the target gene), proximal to a transcription control element operably linked to the target gene, or proximal to an anchor sequence is less than 5,000, 4,000, 3,000, 2,000, 1,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50, or 25 base pairs from the target gene (e.g., an exon, intron, or splice site within the target gene), transcription control element, or anchor sequence (and optionally at least 20, 25, 50, 100, 200, or 300 base pairs from the target gene (e.g., an exon, intron, or splice site within the target gene), transcription control element, or anchor sequence). As used herein, the term “specific”, referring to an agent having an activity, is understood by those skilled in the art to mean that the agent discriminates between potential target entities or states. For example, an in some embodiments, an agent is said to bind “specifically” to its target if it binds preferentially with that target in the presence of one or more competing alternative targets. In some embodiments, specific interaction is dependent upon the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to that of a reference specific binding agent. In some embodiments, specificity is evaluated relative to that of a reference non-specific binding agent. In some embodiments, the agent or entity does not detectably bind to the competing alternative target under conditions of binding to its target entity. In some embodiments, binding agent binds with higher on-rate, lower off-rate, increased affinity, decreased dissociation, and / or increased stability to its target entity as compared with the competing alternative target(s). As used herein, the term “specific binding” refers to an ability to discriminate between possible binding partners in the environment in which binding is to occur. In some embodiments, a binding agent that interacts with one particular target when other potential targets are present is said to "bind specifically" to the target with which it interacts. In some embodiments, specific binding is assessed by detecting or determining degree of association between the binding agent and its partner; in some embodiments, specific binding is assessed by detecting or determining degree of dissociation of a binding agent-partner complex. In some embodiments, specific binding is assessed by detecting or determining ability of theFH12877464.1 Attorney Docket: OGY-02925 binding agent to compete with an alternative interaction between its partner and another entity. In some embodiments, specific binding is assessed by performing such detections or determinations across a range of concentrations. As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the art will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” may therefore be used in some embodiments herein to capture potential lack of completeness inherent in many biological and chemical phenomena. An agent or entity is considered to “target” another agent or entity, in accordance with the present disclosure, if it binds specifically to the targeted agent or entity under conditions in which they come into contact with one another. In some embodiments, for example, an antibody (or antigen-binding fragment thereof) targets its cognate epitope or antigen. In some embodiments, a nucleic acid having a particular sequence targets a nucleic acid of substantially complementary sequence. As used herein, the term “target gene” means a gene that is targeted for modulation, e.g., of expression. In some embodiments, a target gene is part of a targeted genomic complex (e.g., a gene that has at least part of its genomic sequence as part of a target genomic complex, e.g., inside an anchor sequence-mediated conjunction), which genomic complex is targeted by one or more modulating agents as described herein. In some embodiments, modulation comprises inhibition of expression of the target gene. In some embodiments, a target gene is modulated by contacting the target gene or a transcription control element operably linked to the target gene with an expression activation system, e.g., expression activator(s), described herein. In some embodiments, a target gene is aberrantly expressed (e.g., over-expressed) in a cell, e.g., a cell in a subject (e.g., patient). As used herein, the term “targeting moiety” means an agent or entity that specifically targets, e.g., binds, a genomic sequence element (e.g., an expression control sequence or anchor sequence). In some embodiments, the genomic sequence element is proximal to and / or operably linked to a target gene. As used herein, the phrase “therapeutic agent” refers to an agent that, when administered to a subject, has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / orFH12877464.1 Attorney Docket: OGY-02925 condition. In some embodiments, a therapeutic agent comprises an expression activation system, e.g., an expression activator, described herein. In some embodiments, a therapeutic agent comprises a nucleic acid encoding an expression activation system, e.g., an expression activator, described herein. In some embodiments, a therapeutic agent comprises a pharmaceutical composition described herein. As used herein, the term “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, an effective amount of a substance may vary depending on such factors as desired biological endpoint(s), substance to be delivered, target cell(s) or tissue(s), etc. For example, in some embodiments, an effective amount of compound in a formulation to treat a disease, disorder, and / or condition is an amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. Other Embodiments In some aspects, the disclosure relates to the following embodiments. Throughout this section, the term “embodiment” is abbreviated as “E” followed by an ordinal. For example, E1 is equivalent to Embodiment 1. E1. An expression activator for increasing expression of a target gene comprising: (i) a DNA-targeting moiety that binds to a target sequence of 15-20 nucleotides in or near the target gene; and (ii) an effector domain comprising an epigenetic activating domain encoded by a fragment of a gene selected from MYBL1, DUX4, MYB, CEPBPD, ATF4, NCOA2, TP53, FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2 and STB3. E2. The expression activator of Embodiment 1, wherein the DNA-targeting moiety comprises a zinc finger (ZF) domain.FH12877464.1 Attorney Docket: OGY-02925 E3. The expression activator of Embodiment 1, wherein the DNA-targeting moiety comprises a transcription activator-like effector (TALE) domain. E4. The expression activator of Embodiment 1, wherein the DNA-targeting moiety comprises a nuclease inactive polypeptide and a gRNA comprising a sequence complementary to the target sequence. E5. The expression activator of Embodiment 4, wherein the nuclease inactive polypeptide is a nuclease inactive Cas (dCas) polypeptide. E6. The expression activator of Embodiment 4 or 5, wherein the nuclease inactive polypeptide is operably linked to at least one GCN4 peptide, and wherein the effector domain is operably linked to an antibody or antibody fragment specific for the at least one GCN4 peptide. E7. The expression activator of Embodiment 6, wherein the antibody or antibody fragment is a scFv. E8. The expression activator of any one of Embodiments 1-7, wherein the effector domain comprises an amino acid sequence having at least 90% identity to an amino acid sequence selected from SEQ ID Nos: 1-35. E9. The expression activator of any one of Embodiments 1-7, wherein the effector domain comprises an amino acid sequence selected from SEQ ID Nos: 1-35. E10. The expression activator of any one of Embodiments 1-9, wherein the target sequence is in or near a promoter region of the gene. E11. The expression activator of any one of Embodiments 1-9, wherein the target sequence is in or near an enhancer region of the gene. E12. The expression activator of any one of Embodiments 1-11, wherein the effector domain demethylates a CpG island, methylates a histone, adds an acetyl group to a histone, binds to a methylated CpG island, binds to a protein to form heterochromatin, and / or binds a GATA sequence in DNA. E13. The expression activator of any one of Embodiments 1-12, wherein the DNA- targeting moiety and the effector domain do not naturally occur in the same gene product. E14. The expression activator of any one of Embodiments 1-13, wherein the DNA binding moiety comprises a first polypeptide and the effector domain comprises a second polypeptide that is not covalently linked to the first polypeptide. E15. The expression activator of any one of Embodiments 1-13, wherein the DNA binding moiety and the effector domain comprise a single polypeptide.FH12877464.1 Attorney Docket: OGY-02925 E16. A method of increasing expression of a target gene in a cell, comprising contacting the cell with the expression activator of any one of Embodiments 1-15. E17. A nucleic acid encoding the expression activator of any one of Embodiments 1-15. E18. A recombinant expression vector comprising the nucleic acid of Embodiment 17. E19. A messenger RNA (mRNA) encoding the expression activator of any one of Embodiments 1-15. E20. A lipid nanoparticle (LNP) comprising the expression activator of any one of Embodiments 1-15, the nucleic acid of Embodiment 17, the recombinant expression vector of Embodiment 18, or the mRNA of Embodiments 19. E21. A pharmaceutical composition comprising the expression activator of any one of Embodiments 1-15, the nucleic acid of Embodiment 17, the recombinant expression vector of Embodiment 18, the mRNA of Embodiment 19, or the LNP of Embodiment 20, and a pharmaceutically acceptable carrier. E22. A method of altering expression of a target gene in a cell, comprising contacting the cell with the expression activator of any one of Embodiment 1-15, the nucleic acid of Embodiment 17, the recombinant expression vector of Embodiment 18, the mRNA of Embodiment 19, the LNP of Embodiment 20, or the pharmaceutical composition of Embodiment 21. E23. The method of Embodiment 22, wherein expression of the target gene is increased. EXAMPLES The disclosure now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure, and are not intended to limit the scope of the disclosure in any way. Example 1: Development and Validation of Epigenetic Activators for Upregulation of Target Genes Described in this Example are methods to generate and validate fusion proteins composed of an epigenetic activator to upregulate expression of target genes, which may occur by demethylation of CpG sequences in a transcriptional regulatory element (e.g., promoter). Epigenetic regulators having activating domains encoded by fragments of a selected gene are generated and utilized in a three component system. The system includes i) a dCas9 fused to 5 GCN4 peptides (e.g., dCas9-SunTag), ii) a fusion protein having an scFv fused to 104FH12877464.1 Attorney Docket: OGY-02925 the activating domain, where the scFv is specific for a GCN4 peptide of the dCas9-SunTag, and iii) a guide RNA (gRNA) designed to direct the dCas9 and fusion protein to a target DNA sequence. Epigenetic regulators are validated for their ability to upregulate gene regulation. Specifically, a target gene is scanned using a bioinformatics tool to identify regions predicted to increase gene expression, for example, upon decreased methylation of CpG residues within the region. In one approach, a database is used that contains the human genome annotated with potential regions that are CpG islands. UCSC Genome Browser is an exemplary database that provides the human genome annotated with potential CpG islands characterized by a minimum length of about 200 bases, a GC content of 50% or greater, and a ratio greater than 0.6 of observed number of CpG residues to the expected number based on the number of guanine and cytosine nucleotides in the segment. The promoter region of a target gene is evaluated to identify potential CpG islands using this approach. Target sequences within this region are selected for experimental evaluation based upon criteria such as low likelihood of off-target binding. In one approach, a gRNA comprising a nucleic acid sequence complementary to the selected target sequence is designed to be used with an mRNA encoding a dCas9 linked to 5 GCN4 peptides, e.g., by linker, and an mRNA encoding an scFv specific for a GCN4 peptide and fused to an epigenetic activator, e.g., by a linker. In another approach, mRNA encoding a a TALE domain or a zinc-finger (ZF) domain fused to an epigenetic activator is designed. A TALE domain that binds the selected target sequence is designed by modifying the repeat array in a Xanthomonas TALE to have RVDs that correspond to each nucleotide in the target sequence (e.g., NI for A; HD for C; NN or NK for G; and NG for T). A ZF domain that binds the selected target sequence is designed by modifying the one or more Zn fingers or fragments thereof. In either approach, the mRNA molecules are constructed with a 5^Cap 1 structure, a polyA tail, and fully-modified with N1-methyl-pseudouridine. The mRNAs and optionally gRNA are formulated together or separately in a lipid nanoparticle, such as a SSOP LNP containing 45% MC3, 44% cholesterol, 9% DSPC, 2% DMG-PEG2000 (N:P=3). The effect on target gene expression is measured in vitro. In an exemplary method to measure gene expression, cells (e.g., Hepa1-6 cells, HEP3B cells, or K562 cells) are transfected with LNP-formulated mRNA encoding the dCas9-SunTag, and scFv fusion protein. Negative control cells are untreated. At different timepoints (cells are harvested and RNA is isolated using a Qiagen RNeasy®Plus 96 kit in accordance with the manufacturer’s instructions. RNA is reverse-transcribed to cDNA and analyzed by multiplexed qPCR usingFH12877464.1 Attorney Docket: OGY-02925 TaqMan®primer probes specific to either ACTB or GAPDH (housekeeper control) and a target gene. Relative target gene mRNA expression is determined through the comparative ^^Ct method. An increase in target gene mRNA expressed relative to untreated cells indicates the LNP-formulated mRNA functioned for upregulation of the target gene. The effect on methylation at the targeted region of a target gene is measured using amplicon enzymatic methyl-seq (EM-Seq). In one exemplary approach, genomic DNA is isolated from cells samples at the indicated time points following treatment with LNP- formulated mRNA encoding dCas9-SunTag and mRNA encoding an scFv-effector fusion protein. Negative control cells are untreated. Genomic DNA is sheared, e.g., by sonication. Fragmented DNA was purified using SPRI beads (1× SPRISelect, Beckman-Coulter®Cat #B23319) and subjected to EM-conversion using a NEB®EM-seq Conversion Kit (Cat #E7125) according to the manufacturer’s instructions. Purified, converted DNA is PCR amplified at the target gene locus. The amplicon is transposase-labeled with Illumina®sequencing adapters. Libraries are dual-indexed (combinatorial) via PCR (see, e.g., Mezger A, et al. Nature Comm.2018 (PMID: 30194434)). Final libraries are purified using SPRI beads and sequenced on a MiSeq (Illumina®). The EM-Seq data is assessed for alignment quality using FastQC, adapter-trimmed and quality filtered using TrimGalore, and aligned to the mm10 reference genome using Bismark. Fragment-level methylation calls are made using the "Bismark Methylation Extractor" tool for each sample and aggregated into strand-specific CpG, CHG, and CHH context files. CpG context is the measure of interest while CHG and CHG files are used to assess conversion efficiency. Fragments are flagged if there is any sign of incomplete conversion in CHG and CHH contexts, and these fragment IDs are used to filter the CpG context files prior to quantifying methylation levels. CpG methylation is determined by the ratio of methylated read coverage to total read coverage for each CpG. Amplicon-wide and CpG-specific mean methylation values are calculated at the level of technical replicates, biological replicates, and experimental groups and summarized in box / dot plots. A decrease in amplicon-wide CpG methylation relative to untreated cells indicates the LNP-formulated mRNA functioned for epigenetic regulation at the targeted region. In some instances, the effect on target gene expression and / or DNA methylation with a dCas9-SunTag and scFv-effector fusion protein as described is not appreciably altered relative to a negative control (e.g., target gene expression is not appreciably increased and / or DNA methylation is not appreciably decreased, each relative to untreated control cells), attributable, at least in part and without being bound by theory, to factors such as insufficient binding affinity of the particular DNA binding domain to the target sequence, insufficientFH12877464.1 Attorney Docket: OGY-02925 loading of mRNA encoding the construct into the LNP (e.g., as a result of the particular mRNA sequence tested), and / or insufficient expression of the mRNA upon introducing the LNP-formulated mRNA encoding the construct to cells. It is within the skill of the ordinary artisan to optimize an scFv-effector fusion protein directed to a target sequence, e.g., by codon optimization of the mRNA sequence, selection of RVDs in the TALE approach that enhance binding affinity to the target sequence, and selection of alternate lipid formulations to improve LNP packaging. Example 2: Targeted Modification Results in Upregulation of Target Gene mRNA This example describes editing target genes with (i) a fusion of a catalytically inactive Cas9 (dCas9) to 5 GCN4 peptides, (ii) an scFv specific for GCN4 peptide fused to an epigenetic activating domain encoded by a fragment of a selected gene, and (iii) gRNA to target sequences within a target gene (e.g., Target Gene 1, Target Gene 2, Target Gene 3, Target Gene 4, Target Gene 5, Target Gene 6, Target Gene 7, Target Gene 8, or Target Gene 9) to upregulate target gene expression. gRNAs were designed to target sequences near or within the promoter or enhancer region CpG-island of a target gene (i.e., Target Gene 1, Target Gene 2, Target Gene 3, Target Gene 4, Target Gene 5, Target Gene 6, Target Gene 7, Target Gene 8, or Target Gene 9) and were assessed for target gene upregulation. Effectors designed and generated are provided in Table 3. The mRNA sequence of dCas9-SunTag is provided in SEQ ID NO: 36, and the DNA sequence of dCas9-SunTag is provided in SEQ ID NO: 72. Table 3. Epigenetic Regulator Sequences FH12877464.1 Attorney Docket: OGY-02925 FH12877464.1 Attorney Docket: OGY-02925 Assaying for target gene upregulation in vitro From a stock concentration of 100 µg / ml mRNA, dCas9-SunTag, scFv-sfGFP- effectors, and a pool of gRNAs were formulated into MC3 LNPs (45% MC3, 44% cholesterol, 9% DSPC, 2% DMG-PEG2000; N:P=3) at a 1:1:1 ratio. K-562 cells (ATCC CCL-243) or HEP3B were treated with 0.625 µg / ml of the indicated mRNA in lipid. Hepa1-6 cells were treated with 1.0 µg / ml of the indicated mRNA in lipid. Control cells were untreated. For target gene expression analysis, at the times indicated in FIGs.1A-10 post- treatment, RNA was isolated using the Qiagen RNeasy®Plus 96 kit in accordance with the manufacturer’s instructions. RNA was then reverse-transcribed to cDNA and analyzed by multiplexed qPCR using TaqMan®primer probes specific to either ACTB or 36b4 (housekeeper control) and the target gene. Relative target gene mRNA expression was determined through the comparative ^^Ct method. As shown in FIGs.1A-1B, expression activators having epigenetic activating domains encoded by a fragment of gene VPR, VP64, NC0A1, LEUTX, E2F2, KLF15,FH12877464.1 Attorney Docket: OGY-02925 INO80D, FOXO6, or TP53 and used in combination with gRNAs targeting the distal or proximal promoter resulted in significantly increased Target Gene 1 expression compared to untreated control cells. As shown in FIGs.2A-2B, expression activators having epigenetic activating domains encoded by a fragment of gene VPR, VP16, VP64, NCOA2, MYBL1, LEUTX, CREB3L1, E2F2, or KLF15 and used in combination with gRNAs targeting the enhancer, the promoter, or the enhancer / promoter resulted in significantly increased Target Gene 2 expression compared to untreated control cells. As shown in FIGs.3A-3B, expression activators having epigenetic activating domains encoded by a fragment of gene VPR, VP64, VP16, NCOA2, MYBL1, LEUTX, CREB3L1, E2F2, KLF15, UBN1, INO80D, FOXO6, or TP53 and used in combination with gRNAs targeting the enhancer, promoter, or enhancer / promoter resulted in significantly increased Target Gene 3 expression compared to untreated control cells. As shown in FIGs.4A-4B, expression activators having epigenetic activating domains encoded by a fragment of gene MYBL1, E2F2, NCOA2, LEUTX, or CREB3L1 and used in combination with gRNAs targeting Site 1, Site 2, Site 3, Site 4, or Site 5 of Target Gene 4 in Hepa1-6 cells resulted in significantly increased Target Gene 4 expression compared to untreated control cells. Expression activators with epigenetic activating domains encoded by a fragment of NCOA2 or LEUTX showed the highest activity at d...

Claims

Attorney Docket: OGY-02925 CLAIMS 1. An expression activator for increasing expression of a target gene comprising: (i) a DNA-targeting moiety that binds to a target sequence of 15-20 nucleotides in or near the target gene; and (ii) an effector domain comprising an epigenetic activating domain encoded by a fragment of a gene selected from MYBL1, DUX4, MYB, CEPBPD, ATF4, NCOA2, TP53, FOXO1, NFE2, E2F2, UBN1, CREB3L1, FOXO3, KLF15, MLXIPL, LEUTX, INO80D, CR3L1, ATF6A, CSN9, FOXO6, CACTIN, C1QBP, KLF4, MYC, NUTM1, VP16, VP64, YLR278C, PIP2, PA.v1b, and STB3. . The expression activator of claim 1, wherein the DNA-targeting moiety comprises a zinc finger (ZF) domain.

3. The expression activator of claim 1, wherein the DNA-targeting moiety comprises a transcription activator-like effector (TALE) domain.

4. The expression activator of claim 1, wherein the DNA-targeting moiety comprises a nuclease inactive polypeptide and a gRNA comprising a sequence complementary to the target sequence.

5. The expression activator of claim 4, wherein the nuclease inactive polypeptide is a nuclease inactive Cas (dCas) polypeptide.

6. The expression activator of claim 4 or 5, wherein the nuclease inactive polypeptide is operably linked to at least one GCN4 peptide, and wherein the effector domain is operably linked to an antibody or antibody fragment specific for the at least one GCN4 peptide. . The expression activator of claim 6, wherein the antibody or antibody fragment is a scFv.

8. The expression activator of any one of claims 1-7, wherein the effector domain comprises an amino acid sequence having at least 90% identity to an amino acid sequence selected from SEQ ID Nos: 1-35 and 116.FH12877464.1Attorney Docket: OGY-02925 9. The expression activator of any one of claims 1-7, wherein the effector domain comprises an amino acid sequence selected from SEQ ID Nos: 1-35 and 116.

10. The expression activator of any one of claims 1-9, wherein the target sequence is in or near a promoter region of the gene.

11. The expression activator of any one of claims 1-9, wherein the target sequence is in or near an enhancer region of the gene.

12. The expression activator of any one of claims 1-11, wherein the effector domain demethylates a CpG island, methylates a histone, adds an acetyl group to a histone, binds to a methylated CpG island, binds to a protein to form heterochromatin, and / or binds a GATA sequence in DNA.

13. The expression activator of any one of claims 1-12, wherein the DNA-targeting moiety and the effector domain do not naturally occur in the same gene product.

14. The expression activator of any one of claims 1-13, wherein the DNA binding moiety comprises a first polypeptide and the effector domain comprises a second polypeptide that is not covalently linked to the first polypeptide.

15. The expression activator of any one of claims 1-13, wherein the DNA binding moiety and the effector domain comprise a single polypeptide.

16. A method of increasing expression of a target gene in a cell, comprising contacting the cell with the expression activator of any one of claims 1-15.

17. A nucleic acid encoding the expression activator of any one of claims 1-15.

18. A recombinant expression vector comprising the nucleic acid of claim 17.

19. A messenger RNA (mRNA) encoding the expression activator of any one of claims 1-FH12877464.1Attorney Docket: OGY-02925 20. A lipid nanoparticle (LNP) comprising the expression activator of any one of claims 1-15, the nucleic acid of claim 17, the recombinant expression vector of claim 18, or the mRNA of claim 19.

21. A pharmaceutical composition comprising the expression activator of any one of claims 1-15, the nucleic acid of claim 17, the recombinant expression vector of claim 18, the mRNA of claim 19, or the LNP of claim 20, and a pharmaceutically acceptable carrier. . A method of altering expression of a target gene in a cell, comprising contacting the cell with the expression activator of any one of claims 1-15, the nucleic acid of claim 17, the recombinant expression vector of claim 18, the mRNA of claim 19, the LNP of claim 20, or the pharmaceutical composition of claim 21.

23. The method of claim 22, wherein expression of the target gene is increased.FH12877464.1

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