Epigenomic Remodeling of Metabolism by Exercise through AP-1

项目摘要/摘要 我们想探讨体育锻炼是如何改变新陈代谢和改善2型糖尿病的。锻炼是一种 是治疗2型糖尿病的一线药物，不仅通过燃烧能量发挥其有益的作用，而且还可以 通过表观基因组对基因表达的调节来引起长期的代谢变化。无偏见 介导运动诱导基因表达变化的关键表观基因组成员的鉴定尚未得到 已尝试。利用Gro-Seq和增强子RNA作为功能增强子 标志，我们确定激活蛋白-1(AP-1)是驱动运动的主要转录因子- 运动后小鼠骨骼肌中诱导的增强剂。功能丧失筛查发现 AP-1因子Jund在肌肉收缩应激反应和代谢改变中的关键作用 完全分化的初级肌管。我们将讨论Jund/AP-1在运动介导的体内功能 利用条件性基因敲除和过度表达小鼠模型进行代谢重塑。我们还将描述 激活Jund/AP-1的上游信号决定真正的靶基因和表观基因组变化 由Jund/AP-1控制，并解决人类运动生理学中Jund通路的保守问题。 总而言之，这项工作将提供对中间代谢系统的表观基因组学见解，该系统由 自然进化过程中的间歇性运动。这将为药物发现计划奠定智力基础 旨在最大化体育锻炼对新陈代谢的好处，特别是考虑到积累 表观基因组修饰药物是可用的，并在治疗癌症和许多其他疾病方面显示出希望 临床试验。

Project Summary/Abstract We want to address how physical exercise remodels metabolism and ameliorates type 2 diabetes. Exercise is a first-line treatment for type 2 diabetes, and exerts its beneficial effects not only by burning off energy but also by causing prolonged metabolic changes through epigenomic regulation of gene expression. Nonbiased identification of key epigenomic players that mediate exercise-induced gene expression changes has not been attempted. Using global nuclear-run on (GRO-seq) and enhancer RNA (eRNA) as functional enhancer markers, we identified activation protein-1 (AP-1) as the dominant transcription factors that drive exercise- induced enhancers in mouse skeletal muscles after bouts of exercise. Loss-of-function screening identified the pivotal role of JunD, an AP-1 factor, in muscle contraction-induced stress response and metabolic changes in fully-differentiated primary myotubes. We will address the in vivo function of JunD/AP-1 in exercise-mediated metabolic remodeling using conditional knockout and overexpression mouse models. We will also characterize the upstream signals that activates JunD/AP-1, determine the genuine target genes and epigenomic changes controlled by JunD/AP-1, and address the conservation of the JunD pathway in human exercise physiology. Together, this work will provide epigenomic insights into the intermediary metabolism system that is shaped by intermittent exercise during natural evolution. This will lay intellectual groundwork for drug discovery programs that aim to maximize the metabolic benefit of physical exercise, especially considering that accumulating epigenome-modifying drugs are available and show promises in treating cancer and many other diseases in clinical trials.