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Cell. 2016 Jan 28;164(3):353-64. doi: 10.1016/j.cell.2015.12.025.

Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity.

Author information

1
Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
2
Department of Women's and Child Health, Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, University of Leipzig, 04103 Leipzig, Germany; Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, 04103 Leipzig, Germany.
3
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,1030 Vienna, Austria.
4
Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
5
Institute for Predictive and Personalized Medicine of Cancer (IMPPC) and Josep Carreras Leukaemia Research Institute, Can Ruti Campus, Ctra de Can Rutí, Cami de les Escoles s/n, Badalona 08916, Barcelona, Spain.
6
Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK; Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 3EG, UK.
7
University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Welcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
8
Department of Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, VIC 3086, Australia.
9
Department of Pharmacology and Pharmacy, Centre for Genomic Sciences, The University of Hong Kong, Hong Kong.
10
Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany. Electronic address: pospisilik@ie-freiburg.mpg.de.

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.

Comment in

PMID:
26824653
PMCID:
PMC4735019
DOI:
10.1016/j.cell.2015.12.025
[Indexed for MEDLINE]
Free PMC Article

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