Direct characterization of cis-regulatory elements and functional dissection of complex genetic associations using HCR-FlowFISH.
Direct characterization of cis-regulatory elements and functional dissection of complex genetic associations using HCR-FlowFISH.
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DOI：
10.1038/s41588-021-00900-4
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发表时间：
2021-08
期刊：
影响因子：
30.8
通讯作者：
Tewhey R
中科院分区：
文献类型：
--
作者：
Reilly SK;Gosai SJ;Gutierrez A;Mackay-Smith A;Ulirsch JC;Kanai M;Mouri K;Berenzy D;Kales S;Butler GM;Gladden-Young A;Bhuiyan RM;Stitzel ML;Finucane HK;Sabeti PC;Tewhey R
基因组功能和遗传变异的有效解释需要从顺式调控元件（克雷斯）的表观遗传作图到内源性功能的表征。我们开发了HCR-FlowFISH，这是一种广泛适用的方法，通过准确定量天然转录物来表征CRISPR干扰的克雷斯，以及CASA（CRISPR活性筛选分析），这是一种量化CRE活性的分层贝叶斯模型。在超过325，000个扰动中，我们提供了克雷斯可以调节多个基因，跳过最近的基因，并可以显示激活和/或沉默效应的证据。在胆固醇水平相关的FADS基因座，我们结合联合收割机内源性屏幕与报告分析，详尽地描述多个全基因组关联信号，功能提名的因果变异，重要的是，确定其靶基因。
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 importantly, identifying their target genes.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
48
作者：
Diao Y;Fang R;Li B;Meng Z;Yu J;Qiu Y;Lin KC;Huang H;Liu T;Marina RJ;Jung I;Shen Y;Guan KL;Ren B
通讯作者：
Ren B
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen