Epigenetic regulation of lymphatic development

淋巴管发育的表观遗传调控

基本信息

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
项目类别：
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

项目摘要

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，它是造成相当大的发病率的，没有当前的有效治疗。来自组织的富含蛋白质的液体的排水不当会导致其引流积累，导致淋巴水肿。这种情况经常涉及缺陷的淋巴瓣开发，然而，淋巴阀形态发生的基础遗传修饰剂仍然未知。二相反的组蛋白改良酶，组蛋白乙酰转移酶（HATS）和组蛋白脱乙酰基酶（HDAC）调节组蛋白的乙酰化状态。帽子的乙酰化通常与转录激活而HDAC介导的脱乙酰化通常会导致转录抑制。 HDAC缺乏固有的DNA结合结构域，但通过信号依赖性的方式修饰表观基因组与染色质修饰符，转录因子和辅因子的相互作用。我们的发现暗示了一本小说染色质依赖性，但HDAC3在鼠淋巴瓣发育中的脱乙酰基酶独立的作用。我们发现HDAC3是必不可少的流响应表观遗传开关，以建立特定淋巴瓣发育的转录程序。我们的数据挑战长期以来的假设 HDAC取代帽子以促进组蛋白脱乙酰基和转录的抑制。目标的目标研究计划是为了确定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的转录因子，激酶和磷酸酶调节染色质 HDAC3在发育的淋巴管系统中的募集，磷酸化和功能。尽管强烈在表观遗传学领域的研究，对表观遗传和染色质修饰剂在淋巴发育领域。本提案中概述的一组实验没有广泛的意义仅用于了解信号通路如何与染色质修饰剂相交以调节淋巴瓣发展，但也可能非常适用于整个先天性心血管疾病的领域。