AI Article Synopsis
- Effective interpretation of genome function now requires understanding the actual roles of cis-regulatory elements (CREs) beyond just mapping them.
- We developed a new technique called HCR-FlowFISH that uses flow cytometry to assess the effects of CRISPR on these CREs by measuring native RNA levels.
- In our study of over 325,000 genetic changes, we discovered that CREs can influence multiple genes simultaneously, bypass nearby genes, and exhibit both activation and silencing roles.
Article Abstract
Effective interpretation of genome function and genetic variation requires a shift from epigenetic mapping of cis-regulatory elements (CREs) to characterization of endogenous function. We developed hybridization chain reaction fluorescence in situ hybridization coupled with flow cytometry (HCR-FlowFISH), a broadly applicable approach to characterize CRISPR-perturbed CREs via accurate quantification of native transcripts, alongside CRISPR activity screen analysis (CASA), a hierarchical Bayesian model to quantify CRE activity. Across >325,000 perturbations, we provide evidence that CREs can regulate multiple genes, skip over the nearest gene and display activating and/or silencing effects. At the cholesterol-level-associated FADS locus, we combine endogenous screens with reporter assays to exhaustively characterize multiple genome-wide association signals, functionally nominate causal variants and, importantly, identify their target genes.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8925018 | PMC |
| http://dx.doi.org/10.1038/s41588-021-00900-4 | DOI Listing |
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