Regulation of Cardiac Development by Chromatin Modifying Enzymes

项目摘要/摘要： 主动脉瓣疾病是一种日益普遍的发病率和死亡率的原因，目前尚无有效的方法。 药物治疗。潜在的病理通常是瓣膜间质细胞的异常分化。 (VICS)导致细胞外基质(ECM)成分改变和钙化。虽然有各种因素 参与VIC分化的研究已有描述，维持间充质所需的染色质修饰物 受害者的身份在很大程度上仍不清楚。组蛋白脱乙酰酶(HDAC)缺乏固有的DNA结合域，但 通过与转录因子、辅助因子和大分子多蛋白转录的相互作用来修饰染色质 复合体。我们最近发表了在第二心脏区域缺乏HDAC3的小鼠胚胎 祖细胞表现出完全的胚胎致死性和严重的心脏发育缺陷，包括 二尖瓣和增生性主动脉瓣。我们的初步数据表明，HDAC3在人类基因组中扮演了一个新的和意想不到的角色 出生后主动脉瓣动态平衡。HDAC3阴性的主动脉瓣表现为一组离散的 软骨形成基因，这在人类患病的主动脉瓣中经常升高。在小鼠的主动脉瓣中， HDAC3招募多梳抑制复合体2(PRC2)的成分，包括甲基转移酶Ezh2， EED和Suz12富集组蛋白H3(H3K27me3)上lys27的三甲基化，组蛋白H3是一种基因沉默标记，位于 调控成软骨基因座。该研究计划的目标是确定HDAC3如何调节 人和小鼠主动脉瓣间质细胞间充质的特性。此外，拟议的研究 将确定参与信号通路的不同激酶调节 HDAC3的磷酸化、功能和染色质募集。尽管在表观遗传学领域进行了密集的研究， 关于表观遗传学和染色质修饰物在主动脉瓣生物学领域中的作用，人们知之甚少。这个 这一提案中概述的一系列实验不仅对于理解信号如何 与染色质修饰剂相交的通路可以调节主动脉瓣的动态平衡，但也可能高度 适用于整个心血管疾病领域。

Project Summary/Abstract: Aortic valve disease is an increasingly prevalent cause of morbidity and mortality, with no current effective pharmacological treatment. An underlying pathology is often aberrant differentiation of valvular interstitial cells (VICs) leading to altered composition of extracellular matrix (ECM) and calcification. Although various factors involved in VIC differentiation have been described, the chromatin modifiers required to maintain mesenchymal identity of VICs remain largely unknown. Histone deacetylases (Hdacs) lack intrinsic DNA-binding domains but modify chromatin via their interactions with transcription factors, co-factors, and large multiprotein transcriptional complexes. We recently published that mouse embryos lacking Hdac3 within the second heart field cardiac progenitor cells exhibit complete embryonic lethality and severe cardiac developmental defects, including bicuspid and hyperplastic aortic valve. Our preliminary data suggest a novel and unexpected role of Hdac3 in postnatal aortic valve homeostasis. Hdac3-null aortic valves exhibit upregulation of a discrete set of chondrogenic genes, which are frequently elevated in human diseased aortic valves. In murine aortic valves, Hdac3 recruits components of the Polycomb Repressive Complex 2 (PRC2), including methyltransferase Ezh2, Eed, and Suz12 to enrich trimethylation of lys27 on histone H3 (H3K27me3), a gene silencing mark, at the regulatory chondrogenic gene loci. The goal of this research program is to identify how Hdac3 regulates mesenchymal identity of aortic valvular interstitial cells in both humans and mice. In addition, proposed studies will identify the mechanisms by which different kinases involved in signaling pathways regulate the phosphorylation, function, and chromatin recruitment of Hdac3. Despite intense study in the area of epigenetics, very little is known about the role of epigenetic and chromatin modifiers in the field of aortic valve biology. The set of experiments outlined in this proposal have broad significance not only for understanding how signaling pathways intersect with chromatin modifiers to regulate homeostasis of aortic valves, but also could be highly applicable to the entire field of cardiovascular diseases.