Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes
Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes
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DOI：
10.1101/2021.12.20.21266893
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发表时间：
2021-12
影响因子：
16.6
通讯作者：
Liam McAllan;Damir Baranasic;Sergio Villicaña;Scarlett Brown;Weihua Zhang;B. Lehne;M. Adamo;A. Jenkinson;M. Elkalaawy;B. Mohammadi;M. Hashemi;Nadia Fernandes;Nathalie Lambie;Richard Williams;Colette Christiansen;Youwen Yang;L. Zudina;V. Lagou;Sili Tan;J. Castillo-Fernandez;James W D King;R. Soong;P. Elliott;J. Scott;I. Prokopenko;Inês Cebola;M. Loh;B. Lenhard;R. Batterham;J. Bell;J. Chambers;J. Kooner;W. Scott
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文献类型：
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作者：
Liam McAllan;Damir Baranasic;Sergio Villicaña;Scarlett Brown;Weihua Zhang;B. Lehne;M. Adamo;A. Jenkinson;M. Elkalaawy;B. Mohammadi;M. Hashemi;Nadia Fernandes;Nathalie Lambie;Richard Williams;Colette Christiansen;Youwen Yang;L. Zudina;V. Lagou;Sili Tan;J. Castillo-Fernandez;James W D King;R. Soong;P. Elliott;J. Scott;I. Prokopenko;Inês Cebola;M. Loh;B. Lenhard;R. Batterham;J. Bell;J. Chambers;J. Kooner;W. Scott
DNA甲基化变异在人类肥胖中普遍存在，但在疾病发病机制中的致病作用的证据有限。在这里，我们结合联合收割机表观全基因组关联和整合基因组学研究脂肪细胞DNA甲基化变异在人类肥胖中的影响。我们发现了广泛的DNA甲基化变化，这些变化与肥胖密切相关（N = 190个样本，皮下脂肪细胞中691个位点，内脏脂肪细胞中173个位点，P500靶基因，并确定了假定的甲基化-转录因子相互作用。通过孟德尔随机化，我们推断了59个独立位点的甲基化对肥胖和肥胖诱导的代谢紊乱的因果影响。脂肪细胞中的靶向甲基化测序、CRISPR激活和基因沉默进一步鉴定了区域甲基化变异、潜在的调控元件和新的细胞代谢效应。我们的研究结果表明DNA甲基化是人类肥胖及其代谢并发症的重要决定因素，并揭示了甲基化改变可能影响脂肪细胞功能的机制。DNA甲基化变异与人类肥胖有关，但它是否在疾病发病机制中起因果作用尚不清楚。在这里，作者在人类脂肪细胞中进行了一项综合基因组研究，以表明DNA甲基化变异有助于肥胖和2型糖尿病易感性，揭示了潜在的基因组和分子机制。
DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P 500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions. DNA methylation variation is associated with human obesity but a whether it plays a causal role in disease pathogenesis is unclear. Here, the authors perfom an integrative genomic study in human adipocytes to show that DNA methylation variations contribute to obesity and type 2 diabetes susceptibility, revealing underlying genomic and molecular mechanisms.