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: 8656758
• 负责人: Zhi-Ping Liu
• 金额: $ 38.96万
• 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/8656758
• 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 Targeting; 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; deep sequencing; 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.

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以预防、逆转或减缓疾病进展的疾病修饰药物。病理损伤后，心脏会发生一系列组织病理学和结构变化（心脏重塑），包括可进展为心力衰竭的左心室肥厚 (LVH)。新的证据表明，心脏重塑和衰竭与基因表达的重新编程有关，而基因表达的重新编程可能在疾病进展中起因果作用。了解所涉及的机制可以为开发新的介入疗法提供关键。染色质的表观遗传修饰（包括组蛋白甲基化）控制着多种基因组功能，特别是基因转录。组蛋白 3 赖氨酸 9 (H3K9me3) 的三甲基化是一种保守的组蛋白修饰，通常与基因沉默相关，并且发现在小鼠和人类的肥厚和衰竭心脏中发生显着改变。为了了解 H3K9me3 及其特异性去甲基化酶 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。我们对这些转基因小鼠的研究表明，JMJD2A 调节心脏基因表达以响应肥厚刺激，并且是病理性肥厚重塑所必需的。我们提出了两个具体目标来检验这一假设。目的 1. 确定 JMJD2A 在病理性肥厚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标记“胎儿”基因和参与心脏收缩装置的基因的表观遗传特征。 WT 和 JMJD2A KO 小鼠之间观察到的差异基因组 H3-K9/K36-me3 峰将与差异基因表达谱叠加，以鉴定 JMJD2A 的潜在转录靶标。目标 2. 阐明 JMJD2A 调节与心脏肥大和衰竭相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，旨在确定 JMJD2A 调节目标 1 和初步研究中确定的基因转录的分子机制。我们假设 JMJD2A 在肥大重塑过程中被其同源转录因子和/或辅阻遏物招募到靶标，并充当辅激活子或辅阻遏物。启动子分析和生化方法（包括免疫共沉淀和 GST 下拉测定）将用于鉴定可能与 JMJD2A 相互作用的假定转录因子和共阻遏物。我们正在进行的实验表明，JMJD2A 的小分子抑制剂可抑制体外心肌细胞肥大。该提案的成功将为设计利用此类抑制剂对抗未来心脏肥大和衰竭的治疗策略提供机制见解。