研究發現與啟動子相互作用的定量性狀基因座豐富了功能性遺傳變異
作者：
小柯機器人發布時間：2020/12/22 22:11:15
美國拉霍亞免疫學研究所Pandurangan Vijayanand和Ferhat Ay小組合作的研究發現，與啟動子相互作用的表達定量性狀基因座（eQTL）豐富了功能性遺傳變異。這一研究成果發表在2020年12月22日出版的國際學術期刊《自然-遺傳學》上。
利用對H3K27ac HiChIP的分析，研究人員在五種常見的免疫細胞（免疫細胞表達資料庫、表達定量性狀基因座和表觀基因組順式相互作用組學（DICE））中，繪製了與其靶基因啟動子相互作用激活順式調控元件與eQTL的重疊情況。這種方法使研究人員能夠識別功能上重要的eQTL，並解釋其細胞類型限制的機制。
研究人員還設計了一種基於eChTL的發現方法，該方法依賴於HiChIP的啟動子相互作用圖，並可作為決定測試與基因表達關聯SNP結構的框架，並可觀察超長距離pieQTL（> 1µm egabase），包括疾病風險變體。研究人員使用報告基因分析、CRISPRi、dCas9-tiling和Cas9介導的鹼基編輯器驗證了pieQTL的功能。
綜上所述，該研究介紹了一種用於功能性eQTL的發現方法，並提供了非編碼變體與細胞特異性基因調控和疾病相關性的見解，這些相關性超越了常規eQTL的功能。
據悉，eQTL研究提供了遺傳變異與基因表達的關聯，但未能準確定位功能上重要的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