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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.

Original publication

DOI

10.1016/j.cmet.2014.12.014

Type

Journal article

Journal

Cell metabolism

Publication Date

01/2015

Volume

21

Pages

138 - 149

Addresses

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.

Keywords

Cells, Cultured, Adipocytes, Animals, Mice, Inbred C57BL, Humans, Mice, Diabetes Mellitus, Type 2, RNA, Small Interfering, Glucose Tolerance Test, DNA Methylation, Gene Expression Regulation, Epigenesis, Genetic, Polymorphism, Single Nucleotide, Male, Genome-Wide Association Study, Genetic Loci, Transcription Factor 7-Like 2 Protein, Diet, High-Fat