Mouse-human experimental epigenetic analysis unmasks dietary targets and genetic liability for diabetic phenotypes

Michael L Multhaup; Marcus M Seldin; Andrew E Jaffe; Xia Lei; Henriette Kirchner; Prosenjit Mondal; Yuanyuan Li; Varenka Rodriguez; Alexander Drong; Mehboob Hussain; Cecilia Lindgren; Mark McCarthy; Erik Näslund; Juleen R Zierath; G William Wong; Andrew P Feinberg

doi:10.1016/j.cmet.2014.12.014

Mouse-human experimental epigenetic analysis unmasks dietary targets and genetic liability for diabetic phenotypes

Cell Metab. 2015 Jan 6;21(1):138-49. doi: 10.1016/j.cmet.2014.12.014.

Authors

Michael L Multhaup¹, Marcus M Seldin², Andrew E Jaffe³, Xia Lei², Henriette Kirchner⁴, Prosenjit Mondal⁵, Yuanyuan Li⁵, Varenka Rodriguez¹, Alexander Drong⁶, Mehboob Hussain⁵, Cecilia Lindgren⁶, Mark McCarthy⁷, Erik Näslund⁸, Juleen R Zierath⁴, G William Wong², Andrew P Feinberg⁹

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Molecular Medicine and Surgery Karolinska Institutet, 171 77 Stockholm, Sweden.
⁵ Department of Pediatrics, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
⁶ Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
⁷ 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.
⁸ Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, 182 88 Stockholm, Sweden.
⁹ 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.

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.

MeSH terms

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

Substances

RNA, Small Interfering
TCF7L2 protein, human
Transcription Factor 7-Like 2 Protein

Abstract

MeSH terms

Substances

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