Reilly, StevenGosai, Sager J.Gutierrez, AlanMackay-Smith, AvaUlirsch, JacobKanai, MasahiroMouri, KousukeBerenzy, DanielKales, SusanButler, Gina M.Gladden-Young, AdrianneBhuiyan, Redwan M.Stitzel, Michael L.Finucane, Hilary K.Sabeti, PardisTewhey, Ryan2023-02-092021-07-29Reilly, Steven K, Sager J Gosai, Alan Gutierrez, Ava Mackay-Smith, Jacob C Ulirsch, Masahiro Kanai, Kousuke Mouri, et al. 2021. “Direct Characterization of Cis-Regulatory Elements and Functional Dissection of Complex Genetic Associations Using HCR-FlowFISH.” Nature Genetics 53 (8): 1166–76.1061-40361546-1718https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37374309Abstract: 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 HCR-FlowFISH, a broadly applicable approach to characterize CRISPR-perturbed CREs via accurate quantification of native transcripts, alongside CASA (CRISPR Activity Screen Analysis), 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 can 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 nominating causal variants and identifying their target genes.en-USGeneticsJournal Article2023-02-0910.1038/s41588-021-00900-4