Epigenetic switch for obesity

Epigenetic switch for obesity

It is well known that a predisposition to adiposity lies in our genes. A new study by researchers shows that it is also crucial how these genes are regulated. The scientists led by Andrew Pospisilik discovered a novel regulatory, epigenetic switch, which causes individuals with identical genetic material, such as monozygotic twins, to either be lean or obese. Interestingly, much like a classical light switch there are only two discrete outcomes -- ON and OFF, or rather obese and not obese -- not continuous increments as with a dimmer. These new insights fundamentally alter our understanding of how epigenetics influences gene outcomes.

When looking at the weight distribution of large cohorts of genetically identical mice, the Max Planck researchers noticed something odd. The body weight of the animals wasn't random, they came in two flavors, either lean or obese. 

By comparing global gene expression in the two populations, the team discovered a network of so-called 'imprinted' genes that was significantly lower expressed in obese animals. Imprinted genes are a small subset of genes, which are exclusively expressed from either the maternal or paternal gene copy. 

The authors showed that loss of one copy of these imprinted genes also resulted in a 'bi-stable' distribution of either lean or obese animals. This confirmed the functional importance of the imprinted network and suggested that it acts like a switch between two distinct phenotypes.

"Once the switch is triggered, it is a lifelong, epigenetically-driven decision that ends in a stable, either a lean or obese phenotype" says the author and adds "Such clearly separated phenotypes have a genetic cause; here, though we found that the effect was non-Mendelian. The effect is akin to a light switch -- on or off, lean or obese. Typically, we usually consider epigenetic control of disease to act much more like a dimmer, shifting phenotypes like body weight up or down gradually."

Researchers began analyzing adipose tissue samples from lean and obese children. The results were intriguing. A subset of overweight children, about half of cohort, showed altered expression levels of TRIM28 and the network of imprinted genes, a signature that paralleled their observations in the mice. Exploring published data from identical twins discordant for obesity (i.e. where one twin was obese and the other lean), they found similar trends that supported existence of a similar epigenetic effect in humans.

Authors 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

The study of the researchers shows for the first time that the genetic machinery to control polyphenisms also exist in mammals, and likely humans. While difficult to prove, an epigenetic switch that can produce distinctly different phenotypes based on the same DNA, could be a selective advantage.