Epigenetic regulation of lymphatic development

淋巴管发育的表观遗传调控

• 批准号: 10192805
• 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: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192805
• 关键词: Ablation; Acetylation; Area; Blood; Chromatin; Chromatin Remodeling Factor; Chylothorax; Complex; Congenital Cardiovascular Abnormality; Cues; DNA; DNA Binding Domain; Data; Deacetylase; Deacetylation; Development; Disease; Drainage procedure; Elements; Enhancers; Enzymes; Epigenetic Process; Exhibits; Genetic Transcription; Goals; Histone Acetylation; Histone Deacetylase; Histone Deacetylation; Histone H3; Histones; Human; Liquid substance; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphedema; MAPK1 gene; Mediating; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Mutant Strains Mice; Mutate; Mutation; Neonatal; Noonan Syndrome; PTPN11 gene; Pathologic; Pathology; Patients; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Proteins; Ras/Raf; Research; Role; Signal Pathway; Signal Transduction; Structure; Syndrome; Testing; Tissues; Transcriptional Activation; base; cofactor; effective therapy; epigenetic regulation; epigenome; experimental study; extracellular; gain of function; gain of function mutation; gene repression; histone acetyltransferase; loss of function; lymphatic development; lymphatic drainage; lymphatic malformations; lymphatic valve; lymphatic vasculature; lymphatic vessel; novel; programs; recruit; response; shear stress; transcription factor

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.

项目概要/摘要： 淋巴水肿是最常见的淋巴异常，它是相当大的发病率，没有 目前有效的治疗方法。从组织中渗出的富含蛋白质的液体的不适当引流导致其 积累，导致水肿。这种情况往往涉及淋巴阀缺陷 发育，但表观遗传修饰剂的基础瓣形态仍然未知。两 组蛋白修饰酶、组蛋白乙酰基转移酶（HAT）和组蛋白脱乙酰基酶 （HDAC）调节组蛋白的乙酰化状态。通过HAT的乙酰化通常与 HDAC介导的去乙酰化通常导致转录激活，而HDAC介导的去乙酰化通常导致转录抑制。 HDAC缺乏内在的DNA结合结构域，但通过其信号依赖性方式修饰表观基因组。 与染色质修饰剂、转录因子和辅因子的相互作用。我们的发现表明 Hdac 3在小鼠淋巴管瓣发育中的染色质依赖性，但脱乙酰酶独立性作用。我们 发现Hdac 3作为一个重要的流动响应表观遗传开关，以建立一个特定的 淋巴管瓣发育的转录程序。我们的数据挑战了长期以来的假设， HDAC取代HAT以促进组蛋白去乙酰化和转录抑制。这个目标 研究计划是确定Hdac 3如何建立和维持一个特定的转录程序， 淋巴瓣发育此外，拟议的研究将确定不同的机制， 参与信号通路的转录因子、激酶和磷酸酶调节染色质 Hdac 3在发育中的淋巴管系统中的募集、磷酸化和功能。尽管激烈 在表观遗传学领域的研究中，很少有人知道表观遗传和染色质修饰剂在细胞凋亡中的作用。 淋巴发育领域。该提案中概述的一系列实验具有广泛的意义， 只是为了了解信号通路如何与染色质修饰剂交叉，以调节淋巴阀 开发，而且还可以高度适用于整个先天性心血管疾病领域。