Multhaup Michael L, Seldin Marcus M, Jaffe Andrew E, Lei Xia, Kirchner Henriette, Mondal Prosenjit, Li Yuanyuan, Rodriguez Varenka, Drong Alexander, Hussain Mehboob, Lindgren Cecilia, McCarthy Mark, Näslund Erik, Zierath Juleen R, Wong G William, Feinberg Andrew P
Department of Medicine, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA; Center for Epigenetics, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
Department of Physiology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
Cell Metab. 2015 Jan 6;21(1):138-49. doi: 10.1016/j.cmet.2014.12.014.
Using a functional approach to investigate the epigenetics of type 2 diabetes (T2D), we combine three lines of evidence-diet-induced epigenetic dysregulation in mouse, epigenetic conservation in humans, and T2D clinical risk evidence-to identify genes implicated in T2D pathogenesis through epigenetic mechanisms related to obesity. Beginning with dietary manipulation of genetically homogeneous mice, we identify differentially DNA-methylated genomic regions. We then replicate these results in adipose samples from lean and obese patients pre- and post-Roux-en-Y gastric bypass, identifying regions where both the location and direction of methylation change are conserved. These regions overlap with 27 genetic T2D risk loci, only one of which was deemed significant by GWAS alone. Functional analysis of genes associated with these regions revealed four genes with roles in insulin resistance, demonstrating the potential general utility of this approach for complementing conventional human genetic studies by integrating cross-species epigenomics and clinical genetic risk.
我们采用功能方法研究2型糖尿病（T2D）的表观遗传学，整合了三条证据线索——小鼠饮食诱导的表观遗传失调、人类表观遗传保守性以及T2D临床风险证据——以通过与肥胖相关的表观遗传机制识别与T2D发病机制相关的基因。从对基因同质小鼠进行饮食操纵开始，我们识别出差异DNA甲基化基因组区域。然后，我们在接受Roux-en-Y胃旁路手术前后的瘦人和肥胖患者的脂肪样本中重复这些结果，识别出甲基化变化的位置和方向均保守的区域。这些区域与27个T2D遗传风险位点重叠，其中仅一个位点通过全基因组关联研究（GWAS）被认为具有显著性。对与这些区域相关基因的功能分析揭示了四个在胰岛素抵抗中起作用的基因，证明了这种方法通过整合跨物种表观基因组学和临床遗传风险来补充传统人类遗传学研究的潜在普遍效用。
