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Trim28 haploinsufficiency triggers bi-stable epigenetic obesity.

Cell 164, 353-364 (2016)
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Position-effect Variegation; Imprinted Gene; C. Elegans; Transgenerational Inheritance; Insulin-resistance; Metabolic Disease; Mouse; Mice; Expression; Germline
Reviewing status