CRISPR Screening of Gene Regulatory Elements for Leukemia
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Solution Overview
Problem
Current methods for understanding and targeting human gene regulatory elements are limited, making it difficult to establish their contributions to traits and diseases, particularly in leukemia, due to sparse functional understanding of millions of predicted regulatory elements.
Innovation Solution
A composition comprising a Cas9 protein or fusion protein with specific guide RNA targeting specific gene regulatory elements, including SCD, LDB1, and others, to modulate their expression and affect cell viability or fitness in leukemia cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If genome-wide assays and CRISPR-based perturbation screens are used to measure regulatory element activity, then the ability to identify and characterize gene regulatory elements is improved, but the functional understanding remains sparse due to the sheer number of millions of predicted elements
Solution Approach 1:
The patent segments the genome into specific loci of interest, focusing CRISPR-based perturbation screens on targeted regions rather than attempting to screen all millions of regulatory elements simultaneously. This segmentation allows for deeper functional characterization of selected elements while managing the complexity of genome-wide analysis.
Solution Approach 2:
The patent changes the scale and scope parameters of regulatory element analysis by transitioning from comprehensive genome-wide screening to focused loci-specific screening. This parameter change enables more detailed functional assessment of individual elements and their contributions to cell fitness, overcoming the information loss that occurs when attempting to analyze all elements at once.
2Device complexity
If CRISPR-based perturbation screens are limited to small regions or oncogene loci, then the complexity and resource requirements are reduced, but the functional understanding of the broader genome remains incomplete
Solution Approach 1:
The patent creates a universal CRISPR-based screening platform that can be applied to both focused loci and expanded genomic regions. The system's multi-functionality allows it to adapt to different screening scopes, enabling comprehensive functional assessment without proportionally increasing complexity. The same core technology serves both targeted and broader genomic analysis needs.
3Productivity
If high-throughput technologies are used to measure regulatory element activity across the genome, then the quantity of identified elements increases, but the biological importance and functional contribution of individual elements becomes harder to establish
Solution Approach 1:
The patent applies preliminary action by first identifying regulatory elements through high-throughput genome-wide assays, then systematically prioritizing and characterizing the most promising candidates through focused CRISPR perturbation screens. This staged approach maintains high productivity in element discovery while ensuring precise functional assessment of selected elements before committing extensive resources to their characterization.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The approach provides a method to target and modify gene regulatory elements, potentially treating leukemia by altering cell fitness, growth rates, and viability, offering a comprehensive understanding of regulatory elements' functions and their role in diseases.
Implementation Method 1
at least one guide RNA (gRNA) that targets the Cas9 protein to a regulatory element of a target gene
Data Source
AI summary
Disclosed herein am compositions and methods for targeting a novel regulatory element of agene. The compositions may be used in methods of modifying growth of a cell, decreasing cell fitness, increasing cell fitness, and/or treating cancer such as leukemia.