小柯机器人

影响DNA甲基化的遗传变异揭示出调节基因组功能的分子机制
2022-01-05 14:26
来源：小柯机器人

英国伦敦帝国理工学院John C. Chambers等研究人员合作发现，影响DNA甲基化的遗传变异揭示出调节基因组功能的分子机制。这一研究成果与2022年1月3日在线发表在国际学术期刊《自然—遗传学》上。

研究人员利用3,799名欧洲人和3,195名南亚人的血液样本确定了DNA序列变异和DNA甲基化之间的关系。研究人员确定了11,165,559个SNP-CpG关联（甲基化定量性状位点（meQTL），P<10-14），包括467,915个反式操作的meQTL。meQTL富含功能相关的特征，包括共享染色质状态、高通量染色体构象相互作用，以及与基因表达、代谢变异和临床性状的关联。研究人员使用分子相互作用和共定位分析来确定将meQTL位点与表型变异联系起来的多种核调节途径，包括UBASH3B（体重指数）、NFKBIE（类风湿关节炎）、MGA（血压）和COMMD7（白细胞计数）。对于rs6511961，染色质免疫沉淀后测序（ChIP-seq）验证了锌指蛋白（ZNF）333是可能反式作用的效应蛋白。
 
最后，研究人员利用相互作用分析确定了群体和谱系特异的meQTL（包括FADS1的rs174548）对CD8+T细胞的影响最强，从而将脂肪酸代谢与免疫失调和哮喘联系起来。这项研究推进了对将遗传变异与人类表型联系起来的潜在途径的理解。
 
附：英文原文

Title: Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function

Author: Hawe, Johann S., Wilson, Rory, Schmid, Katharina T., Zhou, Li, Lakshmanan, Lakshmi Narayanan, Lehne, Benjamin C., Khnel, Brigitte, Scott, William R., Wielscher, Matthias, Yew, Yik Weng, Baumbach, Clemens, Lee, Dominic P., Marouli, Eirini, Bernard, Manon, Pfeiffer, Liliane, Matas-Garca, Pamela R., Autio, Matias I., Bourgeois, Stephane, Herder, Christian, Karhunen, Ville, Meitinger, Thomas, Prokisch, Holger, Rathmann, Wolfgang, Roden, Michael, Sebert, Sylvain, Shin, Jean, Strauch, Konstantin, Zhang, Weihua, Tan, Wilson L. W., Hauck, Stefanie M., Merl-Pham, Juliane, Grallert, Harald, Barbosa, Eudes G. V., Illig, Thomas, Peters, Annette, Paus, Tomas, Pausova, Zdenka, Deloukas, Panos, Foo, Roger S. Y., Jarvelin, Marjo-Riitta, Kooner, Jaspal S., Loh, Marie, Heinig, Matthias, Gieger, Christian, Waldenberger, Melanie, Chambers, John C.

Issue&Volume: 2022-01-03

Abstract: We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP–CpG associations (methylation quantitative trait loci (meQTL), P<1014), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961, chromatin immunoprecipitation followed by sequencing (ChIP–seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8+ T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.

DOI: 10.1038/s41588-021-00969-x

Source: https://www.nature.com/articles/s41588-021-00969-x

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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