小柯机器人

美国麻省理工学院Manolis Kellis研究团队揭示人类大脑、肺、心脏和肌肉中m⁶A甲基化的遗传驱动因素。相关论文于2021年7月1日在线发表在《自然—遗传学》杂志上。

研究人员报告了129个转录组范围的N⁶-甲基腺苷（m⁶A）测序，涵盖来自GTEx/eGTEx的91名个体和4个组织（脑、肺、肌肉和心脏）。研究人员将这些与个体间遗传和表达变异相结合，揭示了8,843个组织特异性和469个组织共享的m⁶A数量性状基因座（QTL）。研究人员将m⁶A QTL与疾病遗传学相结合，鉴定了184个GWAS 共定位的m⁶A QTL，包括潜在的神经质、抑郁、精神分裂症和焦虑症的脑部m⁶A QTL；肺m⁶A QTL是呼气流量和哮喘的基础；肌肉/心脏m⁶A QTL是冠状动脉疾病的基础。

最后，研究人员预测了新的m⁶A调节因子，这些调节因子在m⁶A QTL中显示出优先结合、与已知m⁶A调节因子的蛋白质相互作用，并与其靶标的m⁶A水平的表达相关性。这些研究结果为理解表观转录组修饰的顺式和反式调节、它们的个体间变异及其在人类疾病中的作用提供了重要的见解和资源。

据悉，最普遍的转录后mRNA修饰m⁶A具有多种RNA调节作用，但其在人体组织中的遗传控制仍然未知。

附：英文原文

Author: Xushen Xiong, Lei Hou, Yongjin P. Park, Benoit Molinie, Richard I. Gregory, Manolis Kellis

Issue&Volume: 2021-07-01

Abstract: The most prevalent post-transcriptional mRNA modification, N6-methyladenosine (m6A), plays diverse RNA-regulatory roles, but its genetic control in human tissues remains uncharted. Here we report 129 transcriptome-wide m6A profiles, covering 91 individuals and 4 tissues (brain, lung, muscle and heart) from GTEx/eGTEx. We integrate these with interindividual genetic and expression variation, revealing 8,843 tissue-specific and 469 tissue-shared m6A quantitative trait loci (QTLs), which are modestly enriched in, but mostly orthogonal to, expression QTLs. We integrate m6A QTLs with disease genetics, identifying 184 GWAS-colocalized m6A QTL, including brain m6A QTLs underlying neuroticism, depression, schizophrenia and anxiety; lung m6A QTLs underlying expiratory flow and asthma; and muscle/heart m6A QTLs underlying coronary artery disease. Last, we predict novel m6A regulators that show preferential binding in m6A QTLs, protein interactions with known m6A regulators and expression correlation with the m6A levels of their targets. Our results provide important insights and resources for understanding both cis and trans regulation of epitranscriptomic modifications, their interindividual variation and their roles in human disease. 

DOI: 10.1038/s41588-021-00890-3

Source: https://www.nature.com/articles/s41588-021-00890-3

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
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