title: Mouse-human experimental epigenetic analysis unmasks dietary targets and genetic liability for diabetic phenotypes.
abstract: 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.
authors.affiliation: 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.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Multhaup
authors.affiliation: 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.
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Seldin
authors.affiliation: Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Jaffe
authors.affiliation: 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.
authors.forename: Xia
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Molecular Medicine and Surgery Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Henriette
authors.initials: H
authors.lastname: Kirchner
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Prosenjit
authors.initials: P
authors.lastname: Mondal
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Varenka
authors.initials: V
authors.lastname: Rodriguez
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drong
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Mehboob
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lindgren
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LI, UK; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Old Road, Headington, Oxford OX3 7LI, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: McCarthy
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, 182 88 Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Näslund
authors.affiliation: Department of Molecular Medicine and Surgery Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
authors.affiliation: 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.
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
authors.affiliation: 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. Electronic address: afeinberg@jhu.edu.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Feinberg
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D059305:Diet, High-Fat; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein