TY - JOUR
T1 - Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity
AU - Dalgaard, Kevin
AU - Landgraf, Kathrin
AU - Heyne, Steffen
AU - Lempradl, Adelheid
AU - Longinotto, John
AU - Gossens, Klaus
AU - Ruf, Marius
AU - Orthofer, Michael
AU - Strogantsev, Ruslan
AU - Selvaraj, Madhan
AU - Lu, Tess Tsai Hsiu
AU - Casas, Eduard
AU - Teperino, Raffaele
AU - Surani, M. Azim
AU - Zvetkova, Ilona
AU - Rimmington, Debra
AU - Tung, Y. C.Loraine
AU - Lam, Brian
AU - Larder, Rachel
AU - Yeo, Giles S.H.
AU - O'Rahilly, Stephen
AU - Vavouri, Tanya
AU - Whitelaw, Emma
AU - Penninger, Josef M.
AU - Jenuwein, Thomas
AU - Cheung, Ching Lung
AU - Ferguson-Smith, Anne C.
AU - Coll, Anthony P.
AU - Körner, Antje
AU - Pospisilik, J. Andrew
N1 - Publisher Copyright:
© 2016 The Authors.
PY - 2016/1/28
Y1 - 2016/1/28
N2 - Summary 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.
AB - Summary 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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U2 - 10.1016/j.cell.2015.12.025
DO - 10.1016/j.cell.2015.12.025
M3 - Article
C2 - 26824653
AN - SCOPUS:84955611443
SN - 0092-8674
VL - 164
SP - 353
EP - 364
JO - Cell
JF - Cell
IS - 3
ER -