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（由申请人提供）：该提案概述了心脏发育表观遗传调控的新理论，该理论基于强有力的初步数据和与细胞内染色质组织相关的不断发展的概念。致密和沉默的异染色质区域位于细胞核的周边，与内核层相关。这些“核纤层蛋白相关结构域”或“LAD”是动态的，并且随着细胞分化而变化。在这个建议中，我建议测试是否从核周边释放LADs可以导致心脏前体细胞的心脏分化的变化，以及是否将LADs拴系到核层可以导致相反的效果。我们的初步数据表明，Hdac3通过与Lap2 α（一种完整的核膜蛋白）和cKrox（一种DNA结合转录因子）一起发挥作用，在束缚LAD中发挥非催化作用。此外，我们的工作表明，Hdac 3的束缚功能的丧失可以调节LAD并加速心脏分化。我们将探讨左前降支在心脏谱系定型中的作用以及左前降支栓系复合物的作用。我们将确定特定的表观遗传标记特征的LAD系留染色质和测试这些标记的功能。最后，我们将表征组成LAD系链的蛋白质复合物。如果成功，这项工作将开辟一个新的研究领域，涉及信号转导级联和发育信号，调节心血管系统中复杂基因程序的协调激活。这些发现可能阐明心脏疾病，包括与核纤层异常相关的心肌病（“核纤层病”），并将为操纵和评估心血管发育提供新的途径。