Epigenomic Remodeling of Metabolism by Exercise through AP-1

AP-1 对运动代谢的表观基因组重塑

• 批准号: 9765305
• 负责人: Zheng Sun
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765305
• 关键词: Address; Binding Sites; Blood; Clinical; Clinical Trials; Data; Diabetes Mellitus; Diet; Disease; Dominant-Negative Mutation; Economic Burden; Enhancers; Enzymes; Epigenetic Process; Evolution; Exercise; Exercise Physiology; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genome; Glucose; Glucose Clamp; Glucose Intolerance; Health; Hormones; Human; In Vitro; Knock-out; Knockout Mice; Knowledge; Lipids; Malignant Neoplasms; Measurement; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Molecular Analysis; Mus; Muscle; Muscle Contraction; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Oxidation-Reduction; Pathway interactions; Pharmaceutical Preparations; Physical Exercise; Play; Public Health; RNA; Reactive Oxygen Species; Role; Running; Signal Transduction; Skeletal Muscle; System; Testing; Work; biological adaptation to stress; drug discovery; epigenome; epigenomics; glucose metabolism; glucose tolerance; glucose uptake; histone modification; in vivo; insight; insulin sensitizing drugs; insulin signaling; insulin tolerance; loss of function; mouse model; mutant; overexpression; pandemic disease; programs; protein activation; recruit; screening; transcription factor; transcriptome sequencing; uptake

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.

项目概要/摘要 我们想要解决体育锻炼如何重塑新陈代谢并改善 2 型糖尿病的问题。运动是 2 型糖尿病的一线治疗方法，不仅通过燃烧能量发挥其有益作用，还通过 通过基因表达的表观基因组调控引起长期的代谢变化。无偏见 介导运动引起的基因表达变化的关键表观基因组参与者的鉴定尚未得到证实 尝试过。使用全局核运行 (GRO-seq) 和增强子 RNA (eRNA) 作为功能增强子 标记物，我们确定激活蛋白-1 (AP-1) 是驱动运动的主要转录因子 - 运动后在小鼠骨骼肌中诱导增强剂。功能丧失筛查确定了 JunD（一种 AP-1 因子）在肌肉收缩引起的应激反应和代谢变化中发挥着关键作用 完全分化的初级肌管。我们将探讨 JunD/AP-1 在运动介导中的体内功能 使用条件敲除和过度表达小鼠模型进行代谢重塑。我们还将表征 激活JunD/AP-1的上游信号，确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。 总之，这项工作将为中间代谢系统提供表观基因组学见解，该系统是由 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已经上市，并有望治疗癌症和许多其他疾病 临床试验。