Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

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

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)353-364
Number of pages12
JournalCell
Volume164
Issue number3
DOIs
StatePublished - Jan 28 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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