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RNA编辑是常见炎症性疾病遗传风险的基础
2022-08-07 19:47
来源：小柯机器人

美国斯坦福大学Jin Billy Li课题组发现，RNA编辑是常见炎症性疾病的遗传风险基础。2022年8月3日，《自然》杂志在线发表了这项成果。

研究人员发现，ADAR介导的腺苷-肌苷RNA编辑，是对抑制细胞双链RNA（dsRNA）介导的先天免疫干扰素反应至关重要的转录后事件，并且是与常见炎症性疾病相关的遗传变异的重要潜在机制。研究人员在49个人体组织中鉴定并描述了30,319个顺式RNA编辑定量性状位点（edQTL）。这些edQTL在自身免疫和免疫介导的疾病的全基因组关联研究信号中显著富集。edQTL与疾病风险位点的共定位分析进一步确定了倒置重复Alu元件形成的关键免疫原性dsRNA，以及意外的、高比例的顺式自然反义转录本。此外，炎症性疾病风险变异体，总的来说，与附近dsRNA的编辑减少有关，并在炎症性疾病中诱发干扰素反应。这种独特的定向效应与既定的机制一致，即ADAR1缺乏RNA编辑导致dsRNA传感器MDA5的特异性激活和随后的干扰素反应和炎症。这些研究结果表明，细胞dsRNA编辑和感应是以前未被重视的常见炎症性疾病的一个机制。
 
据悉，人类遗传学的一个主要挑战是确定性状相关和疾病相关变体的分子机制。为了实现这一目标，对具有中间分子表型（如基因表达和拼接）的遗传变体进行定量性状位点（QTL）测绘已被广泛采用。然而，尽管取得了成功，但相当一部分性状相关和疾病相关变体的分子基础仍不清楚。
 
附：英文原文
 
Title: RNA editing underlies genetic risk of common inflammatory diseases

Author: Li, Qin, Gloudemans, Michael J., Geisinger, Jonathan M., Fan, Boming, Aguet, Franois, Sun, Tao, Ramaswami, Gokul, Li, Yang I., Ma, Jin-Biao, Pritchard, Jonathan K., Montgomery, Stephen B., Li, Jin Billy

Issue&Volume: 2022-08-03

Abstract: A major challenge in human genetics is to identify the molecular mechanisms of trait-associated and disease-associated variants. To achieve this, quantitative trait locus (QTL) mapping of genetic variants with intermediate molecular phenotypes such as gene expression and splicing have been widely adopted1,2. However, despite successes, the molecular basis for a considerable fraction of trait-associated and disease-associated variants remains unclear3,4. Here we show that ADAR-mediated adenosine-to-inosine RNA editing, a post-transcriptional event vital for suppressing cellular double-stranded RNA (dsRNA)-mediated innate immune interferon responses5,6,7,8,9,10,11, is an important potential mechanism underlying genetic variants associated with common inflammatory diseases. We identified and characterized 30,319 cis-RNA editing QTLs (edQTLs) across 49 human tissues. These edQTLs were significantly enriched in genome-wide association study signals for autoimmune and immune-mediated diseases. Colocalization analysis of edQTLs with disease risk loci further pinpointed key, putatively immunogenic dsRNAs formed by expected inverted repeat Alu elements as well as unexpected, highly over-represented cis-natural antisense transcripts. Furthermore, inflammatory disease risk variants, in aggregate, were associated with reduced editing of nearby dsRNAs and induced interferon responses in inflammatory diseases. This unique directional effect agrees with the established mechanism that lack of RNA editing by ADAR1 leads to the specific activation of the dsRNA sensor MDA5 and subsequent interferon responses and inflammation7,8,9. Our findings implicate cellular dsRNA editing and sensing as a previously underappreciated mechanism of common inflammatory diseases.

DOI: 10.1038/s41586-022-05052-x

Source: https://www.nature.com/articles/s41586-022-05052-x

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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