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.