Epigenetic regulation of lymphatic development

项目摘要/摘要： 淋巴水肿是最常见的淋巴异常，是相当大的发病率的原因，没有 目前有效的治疗方法。从组织中不适当地引流富含蛋白质的渗出液会导致 积聚，导致淋巴水肿。这种情况通常与淋巴瓣缺陷有关。 然而，淋巴瓣形态发生背后的表观遗传学修饰物仍然未知。二 相互对立的组蛋白修饰酶，组蛋白乙酰转移酶(HATS)和组蛋白去乙酰基酶 (HDACs)调节组蛋白的乙酰化状态。HATS的乙酰化通常与 当HDAC介导去乙酰化时，转录激活通常会导致转录抑制。 HDAC缺乏固有的DNA结合域，但通过其信号依赖的方式修饰表观基因组 与染色质修饰物、转录因子和辅因子的相互作用。我们的发现提出了一种新的 HDAC3在小鼠淋巴瓣发育中的作用依赖于染色质，但不依赖于脱乙酰酶。我们 研究发现，HDAC3作为一种基本的流动响应性表观遗传开关，建立了一种特定的 淋巴瓣膜发育的转录程序。我们的数据挑战了长期以来的假设，即 HDAC取代HATS促进组蛋白去乙酰化和转录抑制。这样做的目的是 研究计划是确定HDAC3如何建立和维护特定的转录计划 淋巴瓣发育。此外，拟议的研究将确定不同的 参与信号通路的转录因子、激酶和磷酸酶调节染色质 HDAC3在发育中的淋巴管系统中的募集、磷酸化和功能。尽管紧张 在表观遗传学领域的研究中，人们对表观遗传学和染色质修饰物在 淋巴发育领域。这项提案中概述的一系列实验具有广泛的意义 仅用于了解信号通路如何与染色质修饰物相交来调节淋巴瓣 这种方法不仅适用于先天性心血管疾病的整个领域，而且也适用于整个先天性心血管疾病领域。

Project Summary/Abstract: Lymphedema is the most common lymphatic anomaly and it is responsible for considerable morbidity, with no current effective treatments. Improper drainage of extravasated protein-rich fluid from the tissues causes it to accumulate, resulting in lymphedema. This condition frequently involves defective lymphatic valve development, yet the epigenetic modifiers underlying lymphatic-valve morphogenesis remain unknown. Two opposing classes of histone-modifying enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate the acetylation state of histones. Acetylation by HATs is generally associated with transcriptional activation while HDAC-mediated deacetylation usually results in transcriptional repression. HDACs lack intrinsic DNA-binding domains but modify epigenome in a signal-dependent manner via their interactions with chromatin modifiers, transcription factors, and cofactors. Our findings suggest a novel chromatin dependent, but deacetylase-independent role of Hdac3 in murine lymphatic valve development. We find that Hdac3 functions as an essential flow-responsive epigenetic switch to establish a specific transcriptional program for lymphatic valve development. Our data challenge long-held assumptions that HDACs replace HATs to promote both histone deacetylation and repression of transcription. The goal of this research program is to identify how Hdac3 establishes and maintains a specific transcriptional program for lymphatic valve development. In addition, proposed studies will identify the mechanisms by which different transcription factors, kinases, and phosphatases involved in signaling pathways regulate the chromatin recruitment, phosphorylation, and function of Hdac3 within developing lymphatic vasculature. Despite intense study in the area of epigenetics, very little is known about the role of epigenetic and chromatin modifiers in the field of lymphatic development. The set of experiments outlined in this proposal have broad significance not only for understanding how signaling pathways intersect with chromatin modifiers to regulate lymphatic valve development, but also could be highly applicable to the entire field of congenital cardiovascular diseases.