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.

项目摘要/摘要： 淋巴水肿是最常见的淋巴异常，它导致相当大的发病率，但没有 目前有效的治疗方法。组织中外渗的富含蛋白质的液体不正确排出会导致其 积聚，导致淋巴水肿。这种情况通常涉及淋巴瓣膜缺陷 然而，淋巴瓣形态发生背后的表观遗传修饰因素仍然未知。二 相反类别的组蛋白修饰酶、组蛋白乙酰转移酶 (HAT) 和组蛋白脱乙酰酶 (HDAC) 调节组蛋白的乙酰化状态。 HAT 的乙酰化通常与 转录激活，而 HDAC 介导的去乙酰化通常会导致转录抑制。 HDAC 缺乏内在的 DNA 结合域，但通过其信号依赖性方式修改表观基因组。 与染色质修饰剂、转录因子和辅因子的相互作用。我们的发现表明了一部小说 Hdac3 在小鼠淋巴瓣发育中的染色质依赖但脱乙酰酶独立的作用。我们 发现 Hdac3 作为一个重要的流响应表观遗传开关来建立特定的 淋巴瓣发育的转录程序。我们的数据挑战了长期以来的假设： HDAC 取代 HAT 促进组蛋白脱乙酰化和转录抑制。此举的目标 研究计划的目的是确定 Hdac3 如何建立和维护特定的转录程序 淋巴瓣发育。此外，拟议的研究将确定不同的机制 参与信号通路调节染色质的转录因子、激酶和磷酸酶 Hdac3 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，人们对表观遗传学和染色质修饰剂在表观遗传学中的作用知之甚少。 淋巴管发育领域。该提案中概述的一组实验具有广泛的意义，但不 仅用于了解信号通路如何与染色质修饰剂相交叉来调节淋巴瓣膜 的发展，而且也可以高度适用于先天性心血管疾病的整个领域。