Epigenetic dysregulation of transposons in obesity

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Project Summary/Abstract A dramatic increase in the prevalence of obesity and related complications over the last few decades has led to a worldwide epidemic. In the U.S. alone, approximately one in three adults over the age of 20 are obese and are at risk for cardiovascular disease, fatty liver, type 2 diabetes and several types of cancer. Our recent work has demonstrated that diet-induced obesity (DIO), but means of a “western” high fat and high sucrose diet lead to persistent epigenetic modifications in the liver, thereby mediating pervasive changes in transcriptional regulatory programs. Notably, we identified a strong genetic component to these environmentally induced epigenetic modifications with the sites of obesity associated epigenetic modifications being largely specific to individual strains of mice. Strikingly, a large proportion of the epigenetic variation we observed across strains occurred at transposable elements (TEs). These genomic elements constitute approximately half of the human and mouse genomes and have contributed to the evolution of genomes and genomic diversity. While certain classes of TEs are known to be active in early developmental cells, they are generally transcriptionally silenced in later stages of development through mechanisms such as DNA methylation. There is increasing evidence, however, that TEs can be activated somatically and that this dysregulation can contribute to altered gene regulatory programs and disease progression. Our recent work indicates that TEs can be dysregulated in the liver under obesogenic conditions and alter the regulation of genes important for metabolism. Despite the increasing evidence of the importance of TE dysregulation in altering gene regulation and disease progression, the mechanisms responsible for this dysregulation remain poorly understood. According to our hypothesis, obesogenic conditions promote the epigenetic dysregulation of TEs through alterations in DNA methylation profiles and that this can be prevented or reversed therapeutically. Our aims are to: 1) characterize the obesogenic conditions involved in TE dysregulation, 2) determine the role of DNA methylation in mediating obesity associated TE dysregulation and 3) determine if TE dysregulation can be prevented or reversed through dietary supplementation. The results generated from this proposed work will explore a novel molecular mechanism that is associated with the progression of obesity and related complications. These results will furthermore provide a greater understanding of how dysregulation of TEs contribute to other diseases.