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Dalgaard, K.* ; Landgraf, K.* ; Heyne, S.* ; Lempradl, A.* ; Longinotto, J.* ; Gossens, K.* ; Ruf, M.* ; Orthofer, M.* ; Strogantsev, R.* ; Selvaraj, M.* ; Lu, T.T.* ; Casas, E.* ; Teperino, R. ; Surani, M.A.* ; Zvetkova, I.* ; Rimmington, D.* ; Tung, Y.C.L.* ; Lam, B.* ; Larder, R.* ; Yeo, G.S.H.* ; O'Rahilly, S.* ; Vavouri, T.* ; Whitelaw, E.* ; Penninger, J.M.* ; Jenuwein, T.* ; Cheung, C.* ; Ferguson-Smith, A.C.* ; Coll, A.P.* ; Koerner, A.* ; Pospisilik, J.A.*

Trim28 haploinsufficiency triggers bi-stable epigenetic obesity.

Cell 164, 353-364 (2016)
Verlagsversion DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Position-effect Variegation; Imprinted Gene; C. Elegans; Transgenerational Inheritance; Insulin-resistance; Metabolic Disease; Mouse; Mice; Expression; Germline
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Zeitschrift Cell
Quellenangaben Band: 164, Heft: 3, Seiten: 353-364 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Mass.
Begutachtungsstatus Peer reviewed