Regulation of Cardiac Development by Chromatin Modifying Enzymes

染色质修饰酶对心脏发育的调节

• 批准号: 9251882
• 负责人: Chinmay M Trivedi
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251882
• 关键词: Binding Sites; Cardiac; Cardiac Myocytes; Cardiac development; Cell Differentiation process; Cells; Chromatin; Chromatin Structure; Complex; Congenital Abnormality; Congenital Heart Defects; DNA; Defect; Development; Embryo; Embryonic Heart; Endothelial Cells; Enhancers; Enzymes; Fibroblast Growth Factor 8; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Heart; Heart Atrium; Histone Deacetylase; Human; Mus; Pathology; Phenotype; Phosphorylation; Process; Regenerative Medicine; Regulation; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stem cells; Structure; TBX5 protein; Testing; Tissues; Transcript; United States; Ventricular Septal Defects; base; bone morphogenic protein; cardiogenesis; congenital heart disorder; experimental study; novel; pluripotency; precursor cell; prevent; public health relevance; transcription factor

DESCRIPTION (provided by applicant): Congenital heart defects are the most common type of birth defects in the United States. An underlying pathology is often improper differentiation of cardiac progenitor cells during early cardiogenesis. Various committed endpoint lineages including cardiomyocytes, smooth muscle cells, endothelial cells, and specialized conduction cells, arise from cardiac progenitor cells to compose the mature heart tissue. Although transcription factors involved in cardiac progenitor cell differentiation have been described, the closely associated chromatin modifiers of this process remain largely unknown. Histone deacetylases (Hdacs) modify chromatin structure to regulate gene expression in the heart and elsewhere. Our recent findings suggest a novel role of Hdac3 during early cardiogenesis. We find that deletion of Hdac3 in cardiac precursor cells in mice results in complete embryonic lethality and severe cardiac developmental defects, including atrial and ventricular septal defects and hypoplastic ventricles. Strikingly, genetic deletion of Hdac3 in differentiated cardiomyocytes did not cause these defects, suggesting a specific role for Hdac3 in cardiac precursor cells. We have further found that Hdac3-deficient cardiac precursor cells precociously and preferentially differentiate into the cardiomyocyte lineage. The overall goal of this proposal is to investigate and define mechanistic functions of Hdac3 in cardiac progenitor cells during early cardiogenesis. In Aim 1, we will characterize the functional significance of Hdac3 and Tbx5 interaction during early cardiogenesis. In Aim 2, we will elucidate opposing roles of Fgf8 and Bmp4 signaling on Hdac3 function. In Aim 3, we will define the function of Hdac3 in multipotent cardiac progenitor cells. The set of experiments outlined in this proposal have broad significance not only for understanding the fundamental mechanisms that regulate pluripotency and lineage specification of cardiac progenitor cells, but also could be highly applicable to the entire field of regenerative medicine.

描述（由申请人提供）：先天性心脏病是美国最常见的出生缺陷类型。潜在的病理学通常是不正确的分化 早期心脏发生过程中的心脏祖细胞。各种定向终点谱系，包括心肌细胞、平滑肌细胞、内皮细胞和特化传导细胞，由心脏祖细胞产生，组成成熟的心脏组织。尽管已经描述了参与心脏祖细胞分化的转录因子，但与该过程密切相关的染色质修饰剂仍然很大程度上未知。组蛋白脱乙酰酶 (Hdacs) 修饰染色质结构以调节心脏和其他部位的基因表达。我们最近的研究结果表明 Hdac3 在早期心脏发生过程中发挥着新的作用。我们发现，小鼠心脏前体细胞中 Hdac3 的缺失会导致胚胎完全死亡和严重的心脏发育缺陷，包括心房和心室间隔缺陷以及心室发育不全。引人注目的是，分化心肌细胞中 Hdac3 的基因缺失并没有导致这些缺陷，这表明 Hdac3 在心脏前体细胞中具有特定作用。我们进一步发现Hdac3缺陷的心脏前体细胞提前并优先分化为心肌细胞谱系。该提案的总体目标是研究和定义早期心脏发生过程中心脏祖细胞中 Hdac3 的机制功能。在目标 1 中，我们将描述 Hdac3 和 Tbx5 相互作用在早期心脏发生过程中的功能意义。在目标 2 中，我们将阐明 Fgf8 和 Bmp4 信号传导对 Hdac3 功能的相反作用。在目标 3 中，我们将定义 Hdac3 在多能心脏祖细胞中的功能。该提案中概述的一组实验不仅对于理解调节心脏祖细胞多能性和谱系规范的基本机制具有广泛的意义，而且可以高度适用于整个再生医学领域。