Endogenous fine-mapping and prioritization of functional regulatory elements in complex genetic loci.

IF 11.1 Q1 CELL BIOLOGY
Ke Zhao, Yao Zhou, Xueqi Wang, Zhao Wang, Xinran Xu, Yichen Chen, Lin Zhao, Chengyue Wu, Jianhua Wang, Hongcheng Yao, Xin Cheng, Wei Wang, Xinlei Chu, Weixin Wang, Xianfu Yi, Yupeng Chen, Miaoxin Li, Wange Lu, Kexin Chen, Pak Chung Sham, Dandan Huang, Jing Zhang, Mulin Jun Li
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引用次数: 0

Abstract

Most genetic loci linked to polygenic traits are in non-coding regions, with complex regulation and linkage disequilibrium (LD), complicating causal variant and gene prioritization. We used multiplexed single-cell CRISPR interference and activation perturbations to investigate cis-regulatory element (CRE) and gene expression relationships within tight LD in the endogenous chromatin context. We demonstrated the prevalence of multiple causality in perfect LD (pLD) for independent expression quantitative trait loci (eQTLs) and uncovered fine-grained genetic effects on gene expression within pLD, which are difficult to decipher using traditional eQTL fine-mapping or existing computational methods. We found that over one-third of the causal CREs lack classical epigenetic markers prior to perturbation, and we functionally validated one of these hidden regulatory mechanisms. Leveraging Multiome single-cell epigenetic and sequence perturbations, we highlighted the regulatory plasticity of the human genome. Our study will guide the exploration of missing causal mechanisms underlying molecular trait regulation and disease development.

复杂基因座中功能调控元件的内源性精细定位和优先排序。
与多基因性状相关的基因位点大多位于非编码区,具有复杂的调控和连锁不平衡(LD),使因果变异和基因优先排序变得复杂。我们使用多重单细胞CRISPR干扰和激活扰动来研究内源性染色质背景下紧密LD内的顺式调控元件(CRE)和基因表达关系。我们证明了独立表达的数量性状位点(eQTL)在完美LD (pLD)中普遍存在多重因果关系,并揭示了pLD内基因表达的细粒度遗传效应,这些效应很难用传统的eQTL精细定位或现有的计算方法来破译。我们发现超过三分之一的因果cre在扰动之前缺乏经典的表观遗传标记,并且我们从功能上验证了这些隐藏的调节机制之一。利用多组单细胞表观遗传学和序列扰动,我们强调了人类基因组的调控可塑性。我们的研究将指导探索分子性状调控和疾病发展背后缺失的因果机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
7.10
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