Epigenetic dysregulation of transposons in obesity

项目总结/摘要 在过去的几十年里，肥胖症和相关并发症的患病率急剧增加， 一种全球性的流行病。仅在美国，大约三分之一的20岁以上的成年人肥胖， 有患心血管疾病、脂肪肝、2型糖尿病和几种癌症的风险。我们最近的工作 表明饮食诱导的肥胖症（DIO），但“西方”高脂肪和高糖饮食的手段导致 肝脏中持续的表观遗传修饰，从而介导转录调控的普遍变化， 程序.值得注意的是，我们确定了一个强大的遗传成分，这些环境诱导的表观遗传 与肥胖相关的表观遗传修饰位点的修饰在很大程度上对个体菌株具有特异性 对小鼠引人注目的是，我们在不同菌株间观察到的大部分表观遗传变异发生在 转座因子（TE）。这些基因组元件构成了人类和小鼠基因组的大约一半。 基因组，并有助于基因组和基因组多样性的进化。虽然某些类别的TE 已知它们在早期发育细胞中有活性，但在发育后期通常转录沉默。 通过DNA甲基化等机制进行发育。然而，越来越多的证据表明， 在体细胞上被激活，这种失调可能导致基因调控程序的改变和疾病 进展我们最近的研究表明，在致肥胖条件下，肝脏中的TE可能失调， 改变对新陈代谢重要的基因的调节。尽管越来越多的证据表明， 在改变基因调节和疾病进展中的调节异常， 对失调仍知之甚少。根据我们的假设，肥胖条件促进表观遗传 通过DNA甲基化谱的改变导致TE失调，并且这可以被预防或逆转。 治疗上我们的目的是：1）描述TE失调中涉及的致肥胖条件，2） 确定DNA甲基化在介导肥胖相关TE失调中的作用，以及3）确定TE是否 可以通过膳食补充来预防或逆转失调。由此产生的结果 拟议的工作将探索一种新的分子机制，与肥胖的进展， 相关并发症。这些结果将进一步提供一个更好的了解如何失调的TE 有助于其他疾病。

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.