Epigenetic dysregulation of transposons in obesity

项目摘要/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上升，导致 一场世界性的流行病。仅在美国，20岁以上的成年人中约有1/3患有肥胖症 有患心血管疾病、脂肪肝、2型糖尿病和多种癌症的风险。我们最近的工作是 证明了饮食诱导的肥胖(DIO)，但西方的高脂肪和高蔗糖饮食会导致 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，我们确定了这些环境诱导的表观遗传的一个强烈的遗传成分 肥胖相关表观遗传修饰主要针对个别菌株的修饰 老鼠的世界。引人注目的是，我们观察到的跨品系表观遗传变异的很大一部分发生在 转座元件(TES)。这些基因组成分约占人类和小鼠的一半 并对基因组的进化和基因组多样性作出了贡献。而某些类别的TES是 已知它们在早期发育细胞中活跃，通常在晚期转录水平上沉默。 通过DNA甲基化等机制发育。然而，越来越多的证据表明，TES可以 躯体被激活，这种失调可能导致基因调控程序改变和疾病 进步。我们最近的工作表明，在肥胖条件下，TES可以在肝脏中失调，并且 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TE的重要性 改变基因调控和疾病进展的失调，导致这一现象的机制 人们对监管失调仍知之甚少。根据我们的假设，肥胖条件促进了表观遗传学 DNA甲基化谱的改变导致TES的失调，这是可以预防或逆转的 从治疗上讲。我们的目标是：1)描述与TE失调有关的肥胖条件；2) 确定DNA甲基化在介导肥胖相关的TE失调中的作用，以及3)确定TE 饮食补充剂可以预防或扭转调节失调。由此产生的结果 拟议的工作将探索一种新的分子机制，它与肥胖的进展和 相关并发症。这些结果将进一步提供对TES失调的更好的理解 会导致其他疾病。

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.