Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

Cell. 2016 Jan 28;164(3):353-64. doi: 10.1016/j.cell.2015.12.025.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Body Mass Index
  • Child
  • Child, Preschool
  • Epigenesis, Genetic*
  • Haploinsufficiency*
  • Humans
  • Mice
  • Nuclear Proteins / genetics*
  • Nutrition Surveys
  • Obesity / genetics*
  • Polymorphism, Genetic
  • Repressor Proteins / genetics*
  • Thinness / genetics*
  • Tripartite Motif-Containing Protein 28


  • Nuclear Proteins
  • Repressor Proteins
  • TRIM28 protein, human
  • Trim28 protein, mouse
  • Tripartite Motif-Containing Protein 28