Super-Enhancer Constructs for High Gene Expression
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Solution Overview
Problem
Current technologies lack effective methods to modulate the expression of cell type-specific genes required for maintaining cell identity or disease states, such as cancer, due to incomplete understanding of regulatory elements and their mechanisms.
Innovation Solution
The use of super-enhancers, defined as genomic regions occupied by higher concentrations of transcriptional coactivators and chromatin regulators, to drive high expression of specific genes, including those associated with embryonic stem cells or disease states, through nucleic acid constructs and agents that interact with endogenous cellular components.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional enhancers are used to regulate gene expression, then gene expression can be activated, but the expression level is insufficient to maintain cell identity or disease states
Solution Approach 1:
The patent combines multiple enhancer elements into a single super-enhancer construct that integrates several individual enhancers (e.g., CACNA1S enhancer, SCN9A enhancer, ATP2A1 enhancer) to work synergistically. This merging of multiple enhancer functions into one composite element achieves higher gene expression levels and more reliable maintenance of cell identity compared to conventional single enhancers.
2Productivity
If transcriptional coactivators and chromatin regulators are increased at enhancer regions, then gene expression is enhanced, but the complexity of regulatory mechanisms increases
Solution Approach 1:
The super-enhancer construct is segmented into distinct functional modules, each corresponding to a specific enhancer element with defined boundaries and specific gene targets. This segmentation allows for systematic organization of multiple enhancers (e.g., separate CACNA1S, SCN9A, ATP2A1 enhancer regions) while maintaining their individual functions, thereby reducing the overall complexity of understanding and manipulating the regulatory mechanism.
Data Source
Figure 1A~1D
Figure 2A~2D
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AI summary
The present invention relates in some aspects to super-enhancers and related compositions, methods, and agents that are useful for modulating expression of cell type-specific genes that are required for maintenance of cell identity (e.g., embryonic stem cell identity) or maintenance of a disease state (e.g., cancer).