Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

Kevin Dalgaard(Max Planck Institute of Immunobiology and Epigenetics), Kathrin Landgraf(University Hospital Leipzig), Steffen Heyne(Max Planck Institute of Immunobiology and Epigenetics), Adelheid Lempradl(Max Planck Institute of Immunobiology and Epigenetics), John Longinotto(Max Planck Institute of Immunobiology and Epigenetics), Klaus Gossens(Max Planck Institute of Immunobiology and Epigenetics), Marius Ruf(Max Planck Institute of Immunobiology and Epigenetics), Michael Orthofer(Institute of Molecular Biotechnology), Ruslan Strogantsev(University of Cambridge), Madhan Selvaraj(Max Planck Institute of Immunobiology and Epigenetics), Tess Tsai-Hsiu Lu(Max Planck Institute of Immunobiology and Epigenetics), Eduard Casas(Josep Carreras Leukaemia Research Institute), Raffaele Teperino(Max Planck Institute of Immunobiology and Epigenetics), M. Azim Surani(Wellcome/MRC Cambridge Stem Cell Institute), Ilona Zvetkova(University of Cambridge), Debra Rimmington(University of Cambridge), Y.C. Loraine Tung(University of Cambridge), Brian Lam(University of Cambridge), Rachel Larder(University of Cambridge), Giles S.H. Yeo(University of Cambridge), Stephen O’Rahilly(University of Cambridge), Tanya Vavouri(Josep Carreras Leukaemia Research Institute), Emma Whitelaw(La Trobe University), Josef Penninger(Institute of Molecular Biotechnology), Thomas Jenuwein(Max Planck Institute of Immunobiology and Epigenetics), Ching‐Lung Cheung(Chinese University of Hong Kong), Anne C. Ferguson‐Smith(University of Cambridge), Anthony P. Coll(University of Cambridge), Antje Körner(University Hospital Leipzig), J. Andrew Pospisilik(Max Planck Institute of Immunobiology and Epigenetics)
Cell
January 1, 2016
10.1016/j.cell.2015.12.025
Cited by 197Open Access
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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.

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