Epigenetic regulation in cardiac development

项目摘要/摘要 心脏发育是一个复杂的发展过程，需要精确协调的空间。 以及基因转录的时间调节。表观遗传因素，如Ten-11易位(Tet) 催化5-甲基胞嘧啶(5mC)氧化的双加氧酶家族，在协调 正常心脏发育过程中的心脏转录网络。其他人也表现出了Tet的枯竭 美国将在体外阻止胚胎干细胞向心脏祖细胞分化。该团队已经进一步 证实心脏特异性Tet缺失可导致非致密性心肌病(NCC)，原因是 染色质可及性调节失调和长程增强子-启动子环受损 转录对心脏发育至关重要的基因。最近，该团队进一步发现，Tet 缺陷的胚胎心脏组织表现出对脂肪代谢重要的基因的异常表达， 这也可能是在心脏特异性Tet缺陷小鼠模型中观察到的发育缺陷。 尽管从这些研究中获得了知识，但仍有两个悬而未决的问题尚未解决：(I)Tet如何 蛋白质获得它们的专一性，以精确地调控谱系特异性增强子；以及(Ii)是否以及如何 孕期母体代谢应激源影响Tet相关表观遗传途径及心脏 后代的发育。在这个研究项目中，PI将使用两种独特的转基因小鼠 模型和人类胚胎干细胞向心脏谱系分化以解决这些问题。 在项目1中，该团队将调查新发现的TET2的致病机制 先天性心脏病(CHD)患者基因突变损害心脏发育和心脏谱系 规格。在项目2中，该团队将解开支持Tet介导的增强子的分子机制 心脏发育过程中的识别特异性。在项目3中，研究小组将阐明产前产妇的高 脂肪饮食作为应激源，影响Tet介导的表观遗传调节，从而扰乱心脏发育。从一个 从翻译的角度来看，我们将测试维生素C的使用情况，以促进Tet的活性并降低 与母亲高脂饮食暴露有关的发育缺陷。建议的基础研究包括 促进心脏健康发育和阐明以前被低估的机制所必需的 是冠心病和心血管疾病的基础。这项提案还将使我们深入了解外部 代谢物影响心脏发育过程中的表观遗传景观以及代谢因素如何 用于纠正表观遗传异常，以恢复正常的心脏发育。

Project Summary/ Abstract The development of heart is a complicated developmental process that requires precise and coordinated spatial and temporal regulation in gene transcription. Epigenetic factors, such as the Ten-eleven Translocation (TET) family of dioxygenase that catalyzes 5-methyocytosine (5mC) oxidation, play indispensable roles in orchestrating the cardiac transcription network during normal heart development. Tet depletion has been shown by others and us to block the differentiation of embryonic stem cells toward cardiac progenitor ex vivo. The team has further established that cardiac specific Tet deletion could result in noncompaction cardiomyopathy (NCC) due to dysregulation of chromatin accessibility and impaired long-range enhancer-promoter looping that disrupts the transcription of genes important for cardiac development. More recently, the team further discovered that Tet deficient embryonic heart tissues exhibited abnormal expression of genes that are important for lipid metabolism, which might also count for developmental defects observed in cardiac specific Tet-deficient mouse models. Despite the knowledges obtained from these studies, two outstanding questions remain unresolved: (i) how Tet proteins acquire their specificity to precisely regulate lineage-specific enhancers; and (ii) whether and how prenatal maternal metabolic stressors influence TET-related epigenetic pathways and impact cardiac development in the progeny. In this research program, the PI will use both unique genetically modified mouse models and human embryonic stem cells differentiated toward the cardiac lineage to address these questions. In project 1, the team will investigate the pathogenic mechanisms regarding how newly discovered TET2 mutations in patients with congenital heart diseases (CHD) impair heart development and cardiac lineage specification. In project 2, the team will unravel molecular mechanisms undergirding TET-mediated enhancer recognition specificity during heart development. In project 3, the team will illuminate how prenatal maternal high fat diet as a stressor effects Tet mediated epigenetic regulation to perturb cardiac development. From a translational perspective, we will test the use of vitamin C to boost Tet activity and reduce the risk of developmental defects related to maternal high fat-diet exposure. The proposed fundamental studies are necessary to promote healthy cardiac development and illuminate previously underappreciated mechanisms underpinning CHDs and cardiovascular diseases. This proposal will also lend insight into how external metabolites influence epigenetic landscapes during heart development and how metabolic factors can be harnessed to rectify epigenetic abnormalities to restore normal cardiac development.