Epigenetic dysregulation of transposons in obesity

肥胖中转座子的表观遗传失调

• 批准号: 9381644
• 负责人: Dustin Edward Schones
• 金额: $ 43.25万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381644
• 关键词: Adult; Age; Area; Automobile Driving; Binding Sites; Cardiovascular Diseases; Cells; Cytokine Signaling; DNA; DNA Methylation; DNA Transposable Elements; Data; Development; Diet; Dietary Supplementation; Disease; Disease Progression; Elements; Enzymes; Epidemic; Epigenetic Process; Etiology; Evolution; Fatty Liver; Fatty acid glycerol esters; Gene Expression Regulation; Genes; Genetic; Genetic Fingerprintings; Genetic Models; Genetic Transcription; Genome; Genomics; Healthcare Systems; Hepatocyte; Human; Human Genome; Individual; Inflammation; Inflammatory; Insulin Resistance; Investigation; Lead; Lipids; Liver; Mediating; Metabolic Diseases; Metabolism; Modification; Molecular; Mouse Strains; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Omega-3 Fatty Acids; Patients; Play; Prevalence; Publishing; Regulator Genes; Repetitive Sequence; Research; Role; Site; Stimulus; Sucrose; Supplementation; TNFRSF1A gene; Testing; Therapeutic; Tissues; Work; cancer type; cardiovascular disorder risk; cardiovascular risk factor; epigenetic variation; metabolic phenotype; mouse genome; novel; obesogenic; prevent; programs; transcription factor

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.

项目概要/摘要 过去几十年来，肥胖及相关并发症的患病率急剧增加，导致 到世界范围内的流行病。仅在美国，20 岁以上的成年人中就有大约三分之一患有肥胖症 存在患心血管疾病、脂肪肝、2 型糖尿病和多种癌症的风险。我们最近的工作有 证明饮食引起的肥胖（DIO），但“西方”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，我们发现了这些环境诱导的表观遗传的强大遗传成分 与肥胖位点相关的表观遗传修饰很大程度上是针对个体菌株的修饰 的老鼠。引人注目的是，我们观察到的跨菌株表观遗传变异的很大一部分发生在 转座元件（TE）。这些基因组元件构成了人类和小鼠的大约一半 基因组并为基因组的进化和基因组多样性做出了贡献。虽然某些类别的 TE 已知在早期发育细胞中活跃，但它们通常在发育后期被转录沉默。 通过 DNA 甲基化等机制进行发育。然而，越来越多的证据表明，TE 可以 被体细胞激活，这种失调可能导致基因调控程序改变和疾病 进展。我们最近的工作表明，在肥胖条件下，肝脏中的 TE 可能失调，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，其机制 调节失调仍然知之甚少。根据我们的假设，肥胖条件会促进表观遗传 通过改变 DNA 甲基化谱而导致 TE 失调，并且这种情况是可以预防或逆转的 治疗上。我们的目标是：1) 描述 TE 失调所涉及的肥胖状况，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 通过膳食补充剂可以预防或逆转失调。由此产生的结果 拟议的工作将探索与肥胖进展相关的新分子机制 相关并发症。此外，这些结果将有助于更好地理解 TE 的失调是如何发生的。 助长其他疾病。