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研究发现与启动子相互作用的定量性状基因座丰富了功能性遗传变异
2020-12-22 22:11

美国拉霍亚免疫学研究所Pandurangan Vijayanand和Ferhat Ay小组合作的研究发现,与启动子相互作用的表达定量性状基因座(eQTL)丰富了功能性遗传变异。这一研究成果发表在2020年12月22日出版的国际学术期刊《自然-遗传学》上。

利用对H3K27ac HiChIP的分析,研究人员在五种常见的免疫细胞(免疫细胞表达数据库、表达定量性状基因座和表观基因组顺式相互作用组学(DICE))中,绘制了与其靶基因启动子相互作用激活顺式调控元件与eQTL的重叠情况。这种方法使研究人员能够识别功能上重要的eQTL,并解释其细胞类型限制的机制。

研究人员还设计了一种基于eChTL的发现方法,该方法依赖于HiChIP的启动子相互作用图,并可作为决定测试与基因表达关联SNP结构的框架,并可观察超长距离pieQTL(> 1µm egabase),包括疾病风险变体。研究人员使用报告基因分析、CRISPRi、dCas9-tiling和Cas9介导的碱基编辑器验证了pieQTL的功能。

综上所述,该研究介绍了一种用于功能性eQTL的发现方法,并提供了非编码变体与细胞特异性基因调控和疾病相关性的见解,这些相关性超越了常规eQTL的功能。

据悉,eQTL研究提供了遗传变异与基因表达的关联,但未能准确定位功能上重要的eQTL。

附:英文原文

Title: Promoter-interacting expression quantitative trait loci are enriched for functional genetic variants

Author: Vivek Chandra, Sourya Bhattacharyya, Benjamin J. Schmiedel, Ariel Madrigal, Cristian Gonzalez-Colin, Stephanie Fotsing, Austin Crinklaw, Gregory Seumois, Pejman Mohammadi, Mitchell Kronenberg, Bjoern Peters, Ferhat Ay, Pandurangan Vijayanand

Issue&Volume: 2020-12-21

Abstract: Expression quantitative trait loci (eQTLs) studies provide associations of genetic variants with gene expression but fall short of pinpointing functionally important eQTLs. Here, using H3K27ac HiChIP assays, we mapped eQTLs overlapping active cis-regulatory elements that interact with their target gene promoters (promoter-interacting eQTLs, pieQTLs) in five common immune cell types (Database of Immune Cell Expression, Expression quantitative trait loci and Epigenomics (DICE) cis-interactome project). This approach allowed us to identify functionally important eQTLs and show mechanisms that explain their cell-type restriction. We also devised an approach to eQTL discovery that relies on HiChIP-based promoter interaction maps as a structural framework for deciding which SNPs to test for association with gene expression, and observe ultra-long-distance pieQTLs (>1megabase away), including several disease-risk variants. We validated the functional role of pieQTLs using reporter assays, CRISPRi, dCas9-tiling guides and Cas9-mediated base-pair editing. In this article we present a method for functional eQTL discovery and provide insights into relevance of noncoding variants for cell-specific gene regulation and for disease association beyond conventional eQTL mapping.

DOI: 10.1038/s41588-020-00745-3

Source: https://www.nature.com/articles/s41588-020-00745-3

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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