Epigenomic Remodeling of Metabolism by Exercise through AP-1

项目概要/摘要 我们要解决体育锻炼如何重塑新陈代谢和改善2型糖尿病。锻炼是 作为2型糖尿病的一线治疗药物，不仅通过消耗能量， 通过基因表达的表观基因组调控引起长期的代谢变化。无偏 介导运动诱导的基因表达变化的关键表观基因组参与者的鉴定还没有被 企图。使用全局核运行（GR 0-seq）和增强子RNA（eRNA）作为功能增强子 标记，我们确定激活蛋白-1（AP-1）作为驱动运动的主要转录因子， 在运动后诱导小鼠骨骼肌增强。功能丧失筛查确定了 AP-1因子JunD在肌肉收缩诱导的应激反应和代谢变化中的关键作用 完全分化的初级肌管。我们将探讨JunD/AP-1在运动介导的心肌细胞凋亡中的体内功能。 使用条件性敲除和过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途径的保守性。 总之，这项工作将提供表观基因组的见解，中间代谢系统，是由 在自然进化过程中的间歇性运动。这将为药物发现计划奠定知识基础 旨在最大限度地提高体育锻炼的代谢效益，特别是考虑到积累 表观基因组修饰药物是可用的，并显示出在治疗癌症和许多其他疾病的承诺， 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.