Year: 2016
Type: article
Abstract: More than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, "on/off" manner. Trim28(+/D9) mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-"on" state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine.
Source: Cell
Authors: Kevin Dalgaard, Kathrin Landgraf, Steffen Heyne, Adelheid Lempradl, John Longinotto, Klaus Gossens, Marius Ruf, Michael Orthofer, Ruslan Strogantsev, Madhan Selvaraj, Tess Tsai-Hsiu Lu, Eduard Casas, Raffaele Teperino, M. Azim Surani, Ilona Zvetkova, Debra Rimmington, Y.C. Loraine Tung, Brian Lam, Rachel Larder, Giles S.H. Yeo, Stephen O’Rahilly, Tanya Vavouri, Emma Whitelaw, Josef M. Penninger, Thomas Jenuwein, Ching-Lung Cheung, Anne C. Ferguson-Smith, Anthony P. Coll, Antje Körner, J. Andrew Pospisilik
Institutions: Max Planck Institute of Immunobiology and Epigenetics, University Hospital Leipzig, IFB Adiposity Diseases, Leipzig University, Institute of Molecular Biotechnology, Austrian Academy of Sciences, University of Cambridge, Josep Carreras Leukaemia Research Institute, Institute of Predictive and Personalized Medicine of Cancer, Wellcome/MRC Cambridge Stem Cell Institute, The Gurdon Institute, Wellcome/MRC Institute of Metabolic Science, Addenbrooke's Hospital, MRC Metabolic Diseases Unit, La Trobe University, University of Hong Kong
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,552
Funders: Connecticut Department of Energy and Environmental Protection, Wellcome Trust, Institut Français de Bioinformatique, National Institute for Health and Care Research, European Commission, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Max-Planck-Gesellschaft, Medical Research Council, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Boston Area Diabetes Endocrinology Research Center, G1386765427, G1455670351, PARP1 is essential to maintain the epigenetic hallmarks of imprinting control regions, G181390637, Wellcome Trust MRC Cambridge Stem Cell Institute, G2739122216, Genomic imprinting and the epigenetic control of developmental processes, G3191479034, Genomic imprinting and the epigenetic control of genome function., Integriertes Forschungs- und Behandlungszentrum AdipositasErkrankungen, G482351834, NIHR Senior Investigator Award, Beta-cell function in juvenile diabetes and obesity, Insulin Resistance: Lessons from Extreme Phenotypes., Genomic imprinting and the epigenetic control of genome function., G8786631438, G8993529034
OpenAlex ID: W2254116509