Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

Area of Science:

• Genetics
• Developmental Biology
• Metabolic Disorders

Background:

• Obesity affects over half a billion people globally, with significant heritability remaining unexplained by traditional Mendelian genetics.
• Understanding the genetic underpinnings of obesity is crucial for developing effective interventions.

Purpose of the Study:

• To identify novel genetic networks involved in obesity heritability.
• To investigate the role of Trim28 in regulating body weight and gene expression.
• To explore the potential for polyphenism in obesity in both mice and humans.

Main Methods:

• Utilized Trim28(+/D9) mutant mice to study body weight distribution and gene expression.
• Analyzed the expression of an imprinted gene network (Nnat, Peg3, Cdkn1c, Plagl1) in obese and normal mice.
• Performed adipose tissue transcriptome analyses in human children.

Main Results:

• Trim28(+/D9) mutant mice displayed a bimodal body weight distribution, indicating a stochastic obesity phenotype.
• The obese state correlated with reduced expression of specific imprinted genes.
• Human children showed distinct subpopulations based on Trim28 expression and imprinted gene dysregulation, mirroring the mouse phenotype.

Conclusions:

• Identified a Trim28-dependent network that triggers obesity in a non-Mendelian, "on/off" fashion.
• Provided evidence for discrete polyphenism in obesity in both mice and humans.
• Highlighted the implications for complex trait genetics, evolution, and medicine.