The role of nuclear architecture in cardiac development

核结构在心脏发育中的作用

• 批准号: 9258488
• 负责人: Jonathan A. Epstein
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258488
• 关键词: 3-Dimensional; Affect; Architecture; Biological Assay; Cardiac; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Cardiovascular system; Cell Fate Control; Cell Nucleus; Cells; Characteristics; Chromatin; Complex; DNA; DNA Binding; Data; Deacetylase; Development; Dimensions; Disease; Epigenetic Process; Gene Activation; Gene Expression Regulation; Genes; Genome; Heart; Heart Diseases; Heart failure; Heterochromatin; Investigation; Laboratories; Lamins; Lysine; Maps; Membrane Proteins; Modeling; Multipotent Stem Cells; Muscular Dystrophies; Mutation; Nuclear; Nuclear Envelope; Nuclear Lamina; Phenotype; Play; Publishing; Regulation; Role; Signal Transduction; Stem cells; System; Testing; Transcription Factor 3; Work; base; cardiogenesis; cell type; chromatin immunoprecipitation; embryonic stem cell; epigenetic regulation; genome-wide; novel; precursor cell; progenitor; programs; protein complex; public health relevance; theories; transcription factor

 DESCRIPTION (provided by applicant): This proposal outlines a novel theory for the epigenetic regulation of cardiac development that is based upon strong preliminary data and evolving concepts related to the organization of chromatin within cells. Regions of compacted and silenced heterochromatin reside at the periphery of the cell nucleus in association with the inner nuclear lamina. These "lamin associated domains" or "LADs" are dynamic, and change with cellular differentiation. In this proposal, I propose to test whether releasing LADs from the nuclear periphery can result in changes in cardiac differentiation of cardiac precursor cells, and whether tethering of LADs to the nuclear lamina can result in opposing effects. Our preliminary data indicate that Hdac3 plays a non-catalytic role in tethering LADs by functioning in association with Lap2ß (an integral nuclear membrane protein) and cKrox (a DNA-binding transcription factor). Further, our work shows that loss of the tethering function of Hdac3 can modulate LADs and accelerate cardiac differentiation. We will explore the function of LADs in the cardiac lineage commitment and the role of LAD tethering complexes. We will identify specific epigenetic marks characteristic of LAD-tethered chromatin and test the function of these marks. Finally, we will characterize the protein complexes that compose LAD tethers. If successful, this work will open a new field of investigation relating to signal transduction cascades and developmental signals that regulate the orchestrated activation of complex gene programs in the cardiovascular system. The findings may elucidate cardiac disorders including cardiomyopathies related to abnormalities of the nuclear lamina (the "laminopathies") and will provide new avenues for manipulating and evaluating cardiovascular development.

 描述（由应用程序提供）：该提案概述了心脏发育表观遗传调节的新理论，该理论基于与细胞内染色质组织相关的强烈初步数据和不断发展的概念。压实和沉默的异染色质区域与内部核层虫相关的细胞核核心周围。这些“层粘连蛋白相关的结构域”或“ LADS”是动态的，并且随细胞分化而变化。在此提案中，我建议测试从核周围释放小伙子是否会导致心脏前体细胞的心脏分化变化，以及将小伙子束缚在核层中是否会导致相反的影响。我们的初步数据表明HDAC3通过与LAP2ß（积分核膜蛋白）和CKROX（DNA结合转录因子）合作，在绑扎小伙子中起非催化作用。此外，我们的工作表明，HDAC3的束缚功能的损失可以调节小伙子并加速心脏分化。我们将探讨小伙子在心脏谱系承诺中的功能以及小伙子绑扎复合物的作用。我们将确定LAD系列染色质的特定表观遗传标记并测试这些标记的功能。最后，我们将表征构成小伙子系的蛋白质复合物。如果成功的话，这项工作将开放一个新的调查领域，该领域与信号转导级联有关，并开发信号，以调节心血管系统中复杂基因程序的精心策划激活。这些发现可能会阐明心脏病，包括与核椎板异常有关的心肌病（“椎板病”），并将为操纵和评估心血管发育提供新的途径。