研究揭示m6A修飾對人類疾病遺傳力的貢獻
作者：
小柯機器人發布時間：2020/6/30 21:31:04
美國芝加哥大學何川、Xin He、Matthew Stephens等研究人員合作揭示N6-甲基腺苷（m6A）修飾對人類疾病遺傳力的貢獻。這一研究成果於2020年6月29日在線發表於《自然—遺傳學》。
研究人員繪製了60個約魯巴（YRI）淋巴母細胞樣細胞系中m6A峰的定量特徵位點（QTL）。研究人員發現，m6A QTL很大程度上不依賴於表達和剪接QTL，並且富含RNA結合蛋白的結合位點、RNA結構改變變體和轉錄特徵。對m6A的QTL及其相關分子性狀的聯合分析表明，m6A的下遊效應是異質的，且取決於背景。
研究人員鑑定了介導m6A影響翻譯的蛋白質。通過與全基因組關聯研究數據的整合，研究人員發現m6A QTL以與剪接QTL以及表達QTL約一半相當的水平促進了各種免疫和血液相關性狀的遺傳。通過在整個轉錄組關聯研究框架中利用m6A QTL，研究人員鑑定了這些特徵的潛在風險基因。
據了解，N6-甲基腺苷（m6A）在調節信使RNA加工中起重要作用。儘管在該領域取得了快速進展，但對m6A修飾的遺傳決定因素及其在常見疾病中的作用了解甚少。
附：英文原文
Title: Genetic analyses support the contribution of mRNA N 6 -methyladenosine (m 6 A) modification to human disease heritability
Author: Zijie Zhang, Kaixuan Luo, Zhongyu Zou, Maguanyun Qiu, Jiakun Tian, Laura Sieh, Hailing Shi, Yuxin Zou, Gao Wang, Jean Morrison, Allen C. Zhu, Min Qiao, Zhongshan Li, Matthew Stephens, Xin He, Chuan He
Issue&Volume: 2020-06-29
Abstract: N6-methyladenosine (m6A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m6A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m6A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m6A QTLs are largely independent of expression and splicing QTLs and are enriched with binding sites of RNA-binding proteins, RNA structure-changing variants and transcriptional features. Joint analysis of the QTLs of m6A and related molecular traits suggests that the downstream effects of m6A are heterogeneous and context dependent. We identified proteins that mediate m6A effects on translation. Through integration with data from genome-wide association studies, we show that m6A QTLs contribute to the heritability of various immune and blood-related traits at levels comparable to splicing QTLs and roughly half of expression QTLs. By leveraging m6A QTLs in a transcriptome-wide association study framework, we identified putative risk genes of these traits. Quantitative trait locus (QTL) mapping of N6-methyladenosine (m6A) in human cells highlights the role of RNA-binding proteins, RNA secondary structure and context-dependent m6A effects. m6A QTLs are enriched in loci associated with immune and blood-related traits.
DOI: 10.1038/s41588-020-0644-z
Source: https://www.nature.com/articles/s41588-020-0644-z