Cell · 2016
Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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 J Andrew
Аннотация
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.