Current estimates place obesity incidence at more than 600 million individuals worldwide. As a prime risk factor for heart disease, stroke, cancer, type 2 diabetes, and neurodegeneration, obesity poses a major socio-economic challenge. Although studies over the last decades have provided a genetic framework for understanding obesity, the contribution of epigenetic regulation remains poorly understood. Now, a study from researchers at the Max Planck Institute has identified a novel epigenetic switch which causes individuals with identical genetic material, such as monozygotic twins, to either be lean or obese. The team state that these new insights fundamentally alter the understanding of how epigenetics influences gene outcomes. The opensource study is published in the journal Cell.
Previous studies show that measurements in monozygotic twins and inbred mouse strains indicate that epigenetic control can have substantial effects on body-mass outcomes. Experiments in multiple model organisms suggest that pre-conceptual and early-life environment contribute to variability by reproducibly shifting offspring phenotype. Also, epidemiological data suggest that similar regulatory mechanisms determine human phenotypic outcomes. However, despite many investigations, little is known about the mechanisms and how these states are reproducibly altered. Earlier studies from group investigated a mouse strain in which only one of two copies of the gene Trim28 was present in the genome. The lab observed that these mice displayed large variations in their body weight despite being genetically identical which suggested the possibility of a purely epigenetic disease. The current study shows that when looking at the weight distribution of genetically identical mice they were either lean or obese, meaning the same genotype can lead to two very different and very stable phenotypes.
The current study compared global gene expression in the two populations to identify a network of so-called ‘imprinted’ genes that was significantly lower expressed in obese animals. The team explain that imprinted genes are a small subset of genes, which are exclusively expressed from either the maternal or paternal gene copy. Results show that the 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, suggesting that it acts like a switch between two distinct phenotypes.
Data findings show that once the switch is triggered, it is a lifelong, epigenetically-driven decision that ends in a stable, either a lean or obese phenotype. Results show that the effect was non-Mendelian, with the effect akin to a light switch, on or off, lean or obese. The researchers note that typically, they usually consider epigenetic control of disease to act much more like a dimmer, shifting phenotypes like body weight up or down gradually.
With the goal of testing whether a comparable switch might exist in humans, the team began analyzing adipose tissue samples from lean and obese children. Results show that 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, where one twin was obese and the other lean, the lab found similar trends that supported evidence of a similar epigenetic effect in humans. The group state that their findings not only help to understand the interaction of genetic and epigenetic factors in obesity and other diseases, they have implications for evolution. They go on to add that an identical genotype can lead to clearly distinguishable phenotypes, known as polyphenism, is most typically seen in honeybees, where either a queen or worker bee may arise from the same DNA.
The team surmise that their study shows for the first time that the genetic machinery to control polyphenisms also exist in mammals, and likely humans. They go on to add that while difficult to prove, an epigenetic switch that can produce distinctly different phenotypes based on the same DNA, could be a selective advantage where one phenotype is not suited for critical environmental conditions for instance. For the future, the researchers state that the idea that phenotypes or diseases might have strong switch-like epigenetic origins suggests that certain disease scenarios are entirely epigenetically driven and therefore that epigenetic therapies might be able to flip such switches off. They go on to conclude that their next goal is to see whether they can turn the disease switch on or off to permanently flip the system back to lean in one shot.
Source: Max-Planck-Gesellschaft, München
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