Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

Dalgaard, Kevin; Landgraf, Kathrin; Heyne, Steffen; Lempradl, Adelheid; Longinotto, John; Gossens, Klaus; Ruf, Marius; Orthofer, Michael; Strogantsev, Ruslan; Selvaraj, Madhan; Lu, Tess Tsai-Hsiu; Casas, Eduard; Teperino, Raffaele; Surani, M. Azim; Zvetkova, Ilona; Rimmington, Debra; Tung, Y.C. Loraine; Lam, Brian; Larder, Rachel; Yeo, Giles S.H.; O’Rahilly, Stephen; Vavouri, Tanya; Whitelaw, Emma; Penninger, Josef M.; Jenuwein, Thomas; Cheung, Ching-Lung; Ferguson-Smith, Anne C.; Coll, Anthony P.; Körner, Antje; Pospisilik, John Andrew

doi:10.1016/j.cell.2015.12.025

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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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https://www.cell.com/fulltext/S0092-8674(15)01689-X
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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: https://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.