Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity.
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.
This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.cell.2015.12.025
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (095515/Z/11/Z)
Medical Research Council (MR/J001597/1)
Wellcome Trust (100574/Z/12/Z)
Medical Research Council (MC_PC_12009)
Medical Research Council (G0600717)
Medical Research Council (MC_UU_12012/5/B)
Wellcome Trust (095606/Z/11/Z)
Medical Research Council (G0900554)