| First Author | Dalgaard K | Year | 2016 |
| Journal | Cell | Volume | 164 |
| Issue | 3 | Pages | 353-64 |
| PubMed ID | 26824653 | Mgi Jnum | J:230648 |
| Mgi Id | MGI:5763501 | Doi | 10.1016/j.cell.2015.12.025 |
| Citation | Dalgaard K, et al. (2016) Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity. Cell 164(3):353-64 |
| abstractText | 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. VIDEO ABSTRACT. |
