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Journal Article

Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

MPS-Authors

Dalgaard,  Kevin
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;
Nord Nordisk A/S;

Heyne,  Steffen
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lempradl,  Adelheid
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Longinotto,  John
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Gossens,  Klaus
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Ruf,  Marius
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Selvaraj,  Madhan
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lu,  Tess Tsai-Hsiu
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Teperino,  Raffaele
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;
Institute of Experimental Genetics, Helmholtz Zentrum Muenchen and German Center for Diabetes Research /DZD);

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Jenuwein,  Thomas
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons198873

Pospisilik,  John Andrew
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Dalgaard, K., Landgraf, K., Heyne, S., Lempradl, A., Longinotto, J., Gossens, K., et al. (2016). Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity. Cell, 164, 353-364. doi:10.1016/j.cell.2015.12.025.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002C-AF2F-C
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.