Regulation of Cardiac Development by Chromatin Modifying Enzymes

描述（由申请人提供）：先天性心脏缺陷是美国最常见的出生缺陷类型。一个潜在的病理往往是不正确的分化， 在早期心脏发生过程中的心脏祖细胞。各种定向的终点谱系，包括心肌细胞、平滑肌细胞、内皮细胞和特化传导细胞，由心脏祖细胞产生以组成成熟的心脏组织。虽然参与心脏祖细胞分化的转录因子已被描述，但这一过程中密切相关的染色质修饰剂仍在很大程度上未知。组蛋白去乙酰化酶（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的新作用。我们发现，小鼠心脏前体细胞中Hdac3的缺失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损和发育不良的心室。引人注目的是，在分化的心肌细胞中Hdac3的基因缺失并没有导致这些缺陷，这表明Hdac3在心脏前体细胞中的特定作用。我们进一步发现，Hdac3缺陷的心脏前体细胞早熟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Hdac3在早期心脏发生过程中心脏祖细胞中的机制功能。在目的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信号对Hdac3功能的相反作用。在目标3中，我们将定义Hdac 3在多能心脏祖细胞中的功能。本提案中概述的一组实验不仅对理解调节心脏祖细胞多能性和谱系特异性的基本机制具有广泛意义，而且也可以高度适用于整个再生医学领域。

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.