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：
10.1038/s41467-023-38439-z
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发表时间：
2023-05-15
影响因子：
16.6
通讯作者：
Scott, William R.
中科院分区：
文献类型：
--
作者：
McAllan, Liam;Baranasic, Damir;Villicana, Sergio;Brown, Scarlett;Zhang, Weihua;Lehne, Benjamin;Adamo, Marco;Jenkinson, Andrew;Elkalaawy, Mohamed;Mohammadi, Borzoueh;Hashemi, Majid;Fernandes, Nadia;Lambie, Nathalie;Williams, Richard;Christiansen, Colette;Yang, Youwen;Zudina, Liudmila;Lagou, Vasiliki;Tan, Sili;Castillo-Fernandez, Juan;King, James W. D.;Soong, Richie;Elliott, Paul;Scott, James;Prokopenko, Inga;Cebola, Ines;Loh, Marie;Lenhard, Boris;Batterham, Rachel L.;Bell, Jordana T.;Chambers, John C.;Kooner, Jaspal S.;Scott, William R.
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起因果作用的证据有限。在这里，我们结合表观基因组范围的关联和整合基因组学来研究脂肪细胞 DNA 甲基化变异对人类肥胖的影响。我们发现与肥胖密切相关的广泛 DNA 甲基化变化（N = 190 个样本，皮下脂肪细胞中有 691 个位点，内脏脂肪细胞中有 173 个位点，P < 1 × 10-7）。我们将肥胖相关的甲基化变异与超过 500 个目标基因的转录组变化联系起来，并确定假定的甲基化-转录因子相互作用。通过孟德尔随机化，我们在 59 个独立位点推断甲基化对肥胖和肥胖引起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发挥因果作用尚不清楚。在此，作者在人类脂肪细胞中进行了一项综合基因组研究，结果表明 DNA 甲基化变异导致肥胖和 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 < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >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.
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影响因子：
12.4
作者：
Chen Q;Shou P;Zheng C;Jiang M;Cao G;Yang Q;Cao J;Xie N;Velletri T;Zhang X;Xu C;Zhang L;Yang H;Hou J;Wang Y;Shi Y
通讯作者：
Shi Y
影响因子：
16.6
作者：
Bacos K;Gillberg L;Volkov P;Olsson AH;Hansen T;Pedersen O;Gjesing AP;Eiberg H;Tuomi T;Almgren P;Groop L;Eliasson L;Vaag A;Dayeh T;Ling C
通讯作者：
Ling C
影响因子：
3.5
作者：
Antonio Perez-Mancera, Pedro;Bermejo-Rodriguez, Camino;Sanchez-Garcia, Isidro
通讯作者：
Sanchez-Garcia, Isidro
DNA甲基化介导了1型糖尿病中HBA1C相关并发症的发展。
影响因子：
20.8
作者：
Chen Z;Miao F;Braffett BH;Lachin JM;Zhang L;Wu X;Roshandel D;Carless M;Li XA;Tompkins JD;Kaddis JS;Riggs AD;Paterson AD;DCCT/EDIC Study Group;Natarajan R
通讯作者：
Natarajan R
DOI：
10.1007/978-1-61779-367-7_14
发表时间：
2012
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Carswell, Kirstin A;Lee, Mi-Jeong;Fried, Susan K
通讯作者：
Fried, Susan K