Regulation of Cardiac Development by Chromatin Modifying Enzymes

描述(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。一种潜在的病理通常是不正确地区分 心脏发生早期的心脏祖细胞。包括心肌细胞、平滑肌细胞、内皮细胞和特殊传导细胞在内的各种终末期细胞系起源于心脏前体细胞，构成成熟的心脏组织。尽管参与心脏祖细胞分化的转录因子已经被描述，但这一过程中密切相关的染色质修饰物仍然很大程度上未知。组蛋白脱乙酰酶(HDAC)通过改变染色质结构来调节心脏和其他部位的基因表达。我们最近的发现表明，HDAC3在早期心脏发生中扮演了一个新的角色。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，包括房间隔和室间隔缺陷以及心室发育不良。值得注意的是，在分化的心肌细胞中，HDAC3的基因缺失不会导致这些缺陷，这表明HDAC3在心脏前体细胞中具有特定的作用。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。这项建议的总体目标是研究和确定HDAC3在心脏形成早期的心脏前体细胞中的机制功能。在目标1中，我们将描述HDAC3和Tbx5相互作用在早期心脏发生中的功能意义。在目标2中，我们将阐明Fgf8和Bmp4信号在HDAC3功能中的相反作用。在目标3中，我们将确定HDAC3在多潜能心脏前体细胞中的功能。该提案中概述的一系列实验不仅对于理解调节心脏前体细胞多能性和谱系指定的基本机制具有广泛的意义，而且可能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.