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Twin Study Reveals Epigenetic 'On/Off' Switch for Obesity

NEW YORK (GenomeWeb) – A team of international researchers has found that differences in gene expression play a key role in determining a person's predisposition to obesity, and that epigenetic marks can alter the activity of genes related to weight control.

As they reported in Cell today, the team conducted a study of genetically identical mice and human twin pairs to determine what makes one person more likely than another to become obese. What they found suggests that there's an epigenetic "on/off" switch that can trigger obesity in certain individuals.

"We're interested in the mechanisms that can make identical twins come out not so identical, and how these mechanisms contribute to disease," senior author and Max Planck Institute of Immunobiology and Epigenetics researcher Andrew Pospisilik said in a statement. "If twins can come out substantially different from one another, it means that each of us could have come out differently than how we did."

The team started by looking at a 2010 Genome Biology study that showed genetically identical mice can have highly variable body masses because of a mutation in a protein called Trim28, suggesting that this protein could epigenetically contribute to obesity.

For this study, the researchers started by generating large populations of genetically identical Trim28-deficient mice that shared the same environmental conditions. They found that the mice exhibited a bi-modal body-weight distribution, with some animals randomly emerging at a normal weight and others randomly becoming obese. There were also a few mice in the middle of the two extremes.

In further examining the mice, the team found that the obese animals exhibited an obese "on" state characterized by an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1. "Independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype," Pospisilik and his colleagues wrote.

Further, transcriptome analyses of adipose tissue in children indicated that humans also cluster into distinct sub-populations 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," the team wrote.

Such epigenetic changes could allow a species to adapt to extreme conditions, such as starvation, particularly as they can be modified by environmental factors. "A switch-like mechanism to produce individuals with different traits without changing DNA provides a selective advantage at the population level," Pospisilik said in the statement. "Polyphenism allows an emergency or plan B version that gets the species through transient selective pressures."

Pospisilik also plans to examine the broader role of Trim28 in behavior and disease — deficiency of this protein can also increase the risk of cancer and anxiety in mice, the researchers note.

As such, these findings could also have clinical implications. "Our study shows that [epigenetic] shifts may not only occur along a continuum, but may also have areas of high stability," Pospisilik added. "This suggests the possibility that we may be able to switch physiology to produce a state that is inherently stable to stay lean or obese."