Epigenetic Regulation of Cardiac Hypertrophy and Heart Failure

心脏肥大和心力衰竭的表观遗传调控

• 批准号: 8371213
• 负责人: Zhi-Ping Liu
• 金额: $ 39.73万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371213
• 关键词: Acute; Adult; Area; Biochemical; Biological; Biological Assay; Biology; Candidate Disease Gene; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; ChIP-seq; Chromatin; Clinical Trials; Co-Immunoprecipitations; Complement; Complex; Development; Developmental Gene; Disease; Disease Progression; Drug Delivery Systems; Enzymes; Epigenetic Process; Event; Excision; Failure; Future; Gene Expression; Gene Expression Alteration; Gene Silencing; Genes; Genetic Transcription; Genomics; Heart; Heart Hypertrophy; Heart failure; Histone Deacetylase Inhibitor; Histones; Human; Hypertrophic Cardiomyopathy; Hypertrophy; In Vitro; Investigation; Journals; Knock-out; Knockout Mice; Lead; Left Ventricular Hypertrophy; Lysine; Medical; Methods; Methylation; Molecular; Molecular Profiling; Mus; Muscle Cells; Outcome; Patients; Performance; Pharmaceutical Preparations; Physiological; Play; Public Health; Publishing; RNA Polymerase II; Recruitment Activity; Regulation; Research; Role; Series; Stimulus; Stress; Technology; Testing; Therapeutic; Tissue-Specific Gene Expression; Transferase; Transgenic Mice; Transgenic Organisms; United States; base; cancer therapy; chromatin immunoprecipitation; chromatin modification; clinical application; combat; constriction; design; fetal; histone modification; inhibitor/antagonist; innovation; insight; malignant neurologic neoplasms; mortality; myocardin; prevent; programs; promoter; research study; response; small molecule; stressor; success; transcription factor

DESCRIPTION (provided by applicant): One of the major challenges in managing and treating heart failure patients is to develop disease modifying drugs that can prevent, reverse, or slow down the disease progression. Upon pathological insults, the heart undergoes a series of histopathological and structural changes (cardiac remodeling), including left ventricular hypertrophy (LVH) that can progress to heart failure. Emerging evidence indicates that cardiac remodeling and failure are associated with reprogramming of gene expression that may have a causative role in the disease progression. Understanding mechanisms involved could provide a key to develop new interventional therapeutics. Epigenetic modification of chromatin, including histone methylation, governs a multitude of genomic functions, in particular gene transcription. Trimethylation of histone 3 lysine 9 (H3K9me3) is a conserved histone modification normally associated with gene silencing, and was found to be dramatically altered in hypertrophic and failing hearts in mouse and humans. To understand the role of H3K9me3 and its specific demethylase JMJD2A in the reprogramming of gene expression, we generated JMJD2A transgenic and knockout (KO) mouse lines. Our studies with these genetically modified mice suggest that JMJD2A regulates cardiac gene expression in response to hypertrophic stimuli and is required for pathological hypertrophic remodeling. We propose two specific aims to test this hypothesis. Aim 1. To identify the epigenetic mechanisms by which JMJD2A regulates cardiac gene expression during pathological hypertrophic remodeling. We will generate the genomic landscapes of H3-K4/K9/K27/K36-me3 using ChIP-seq technology. Our objective is to identify the epigenetic signatures that mark the "fetal" genes and genes involved in the cardiac contractile apparatus under both physiological and pathological conditions. The observed differential genomic H3-K9/K36-me3 peaks between WT and JMJD2A KO mice will be superimposed with differential gene expression profiles to identify potential transcriptional targets of JMJD2A. Aim 2. To unravel the molecular mechanism(s) by which JMJD2A regulates the expression of genes involved in cardiac hypertrophy and failure. The genomic approach will be complemented with classic molecular and biochemical methods in this aim to identify the molecular mechanisms by which JMJD2A regulates the transcription of genes identified in aim 1 and those identified in the preliminary studies. We postulate that JMJD2A is recruited to the target by its cognate transcription factor, and/or co-repressor during hypertrophic remodeling, and functions as either a co-activator or a co-repressor. Promoter analysis and biochemical methods including co-immunoprecipitation and GST-pull down assays will be used to identify putative transcription factors and co-repressors that may interact with JMJD2A. Our ongoing experiments indicated that small molecule inhibitors of JMJD2A inhibited myocyte hypertrophy in vitro. The success of the proposal will provide mechanistic insights to design therapeutic strategies of utilizing this class of inhibitors to combat cardiac hypertrophy and failure in the future. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the success of the proposal could help us in the future to design disease modifying drugs to prevent, reverse, or slow down the progression of cardiac hypertrophy and heart failure.

描述（由申请人提供）：管理和治疗心力衰竭患者的主要挑战之一是开发可预防，逆转或减慢疾病进展的疾病。在病理侮辱下，心脏会经历一系列的组织病理学和结构变化（心脏重塑），包括可以发展为心力衰竭的左心室肥大（LVH）。新兴的证据表明，心脏重塑和衰竭与可能在疾病进展中具有致病作用的基因表达的重编程有关。了解所涉及的机制可以为开发新的介入治疗剂提供关键。染色质的表观遗传学修饰，包括组蛋白甲基化，特别是基因组转录。组蛋白3赖氨酸9（H3K9ME3）的三甲基化是一种通常与基因沉默相关的保守组蛋白修饰，并且发现在小鼠和人类的肥厚性心脏和失败的心脏中被发现急剧改变。为了了解H3K9Me3及其特定脱甲基酶JMJD2A在基因表达重编程中的作用，我们生成了JMJD2A转基因和敲除（KO）小鼠系。我们对这些遗传改性小鼠的研究表明，JMJD2A对肥大性刺激的响应调节心脏基因的表达，并且是病理性肥大重塑所必需的。我们提出了两个特定的目的来检验这一假设。目的1。确定JMJD2A在病理肥厚性重塑过程中调节心脏基因表达的表观遗传机制。我们将使用CHIP-SEQ技术生成H3-K4/K9/K27/K36-ME3的基因组景观。我们的目标是确定在生理和病理条件下都标志着心脏收缩仪的“胎儿”基因和基因的表观遗传特征。观察到的差异基因组H3-K9/K36-ME3 WT和JMJD2A KO小鼠之间的峰将与差异基因表达谱叠加，以识别JMJD2A的潜在转录靶标。目的2。阐明JMJD2A调节与心脏肥大和衰竭有关的基因表达的分子机制。基因组方法将与经典的分子和生化方法相辅相成，目的是确定JMJD2A调节AIM 1中鉴定的基因的转录以及在初步研究中鉴定的基因的转录。我们假设JMJD2A是通过其同源转录因子和/或共抑制剂在肥厚性重塑期间募集到靶标的，并用作共激活因子或共抑制剂。启动子分析和生化方法（包括共免疫沉淀和GST-pull降低测定法）将用于识别可能与JMJD2A相互作用的推定转录因子和共抑制剂。我们正在进行的实验表明，JMJD2A的小分子抑制剂在体外抑制了肌细胞肥大。该提案的成功将为设计治疗策略提供机械见解，以利用这类抑制剂来打击心脏肥大和未来的失败。 公共卫生相关性：拟议的研究与公共卫生有关，因为该提案的成功可能会帮助我们在未来设计疾病，以预防，逆转或减慢心脏肥大和心力衰竭的进展。