Emerin regulation of molecular pathways: implications for muscle disease

艾默林对分子途径的调节：对肌肉疾病的影响

基本信息

批准号：
9098125
负责人：
JAMES Michael HOLASKA
金额：
$ 24.14万
依托单位：
UNIVERSITY OF THE SCIENCES PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098125
关键词：
Affect Architecture Binding Cells Chromatin Chromosome Mapping Complex Contracture Data Deacetylation Defect Development Disease Down-Regulation Emery-Dreifuss Muscular Dystrophy Epigenetic Process Failure Gene Activation Gene Expression Gene Expression Profiling Genes Genetic Transcription Genome Genomics Goals HDAC3 gene Inborn Genetic Diseases Injury Lamins Mediating Molecular Monitor Muscle satellite cell Muscular Dystrophies Mutation Myopathy Natural regeneration Nuclear Nuclear Envelope Nuclear Lamina Null Lymphocytes Pathology Pathway interactions Pharmaceutical Preparations Phenotype Physiological Play Proteins Regulation Research Research Design Role Skeletal Muscle Tendon structure Testing X-linked Emery-Dreifuss muscular dystrophy base cell type design emerin env Gene Products gene repression genome-wide heart rhythm in vitro activity in vivo inhibitor/antagonist muscle regeneration mutant progenitor programs public health relevance skeletal muscle wasting small molecule stem cell differentiation therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The mechanism(s) underlying how mutations in emerin, an inner nuclear envelope protein, cause muscle disease remain unknown. Mutations in the gene encoding emerin cause Emery-Dreifuss Muscular Dystrophy (EDMD), characterized by progressive skeletal muscle wasting, irregular heart rhythms and tendon contractures. The skeletal muscle phenotype is caused by the failure to regenerate skeletal muscle. Skeletal muscle stem cell differentiation requires the coordinated temporal expression of differentiation genes. Disruption of the differentiation transcriptional program causes impaired differentiation. Genomic architecture controls gene activation or repression by regulating the association of the genome with transcriptionally active or repressed nuclear domains. The genome reorganizes itself during differentiation of many cell types to control coordinated temporal gene expression. This reorganization plays fundamental roles in cell fate decisions during stem cell differentiation and in development. The research proposed here will examine how emerin regulates genomic organization and gene expression to regulate the coordinated temporal gene expression required for myogenic differentiation and how this is altered in EDMD. The field lacks a fundamental understanding of the mechanisms regulating nuclear lamina regulation of genomic architecture and its effect on gene expression. The nuclear lamina regulates genomic organization and chromatin architecture. However, the lamins are not required for repressed chromatin localization at the nuclear periphery, suggesting other nuclear envelope proteins mediate their association. We hypothesize emerin is one of these proteins that mediates the association of repressed chromatin with the nuclear envelope. Supporting our hypothesis emerin interacts with repressive chromatin machinery and dynamically interacts with myogenic differentiation gene loci during differentiation; this localization is emerin-dependent. The proposed studies will test how the interaction of emerin with histone deacetylase 3 (HDAC3) establishes or maintains repressive chromatin at the nuclear envelope. Emerin regulation of HDAC3 activity is predicted to regulate genomic reorganization and coordinated temporal expression of differentiation genes during differentiation. Thus we will monitor gene expression during emerin-null myogenic progenitor differentiation to identify molecular pathways disrupted in these cells, which will be confirmed by treatment with activators or inhibitors. EDMD-causing emerin mutant progenitors will be used to confirm these pathways are involved in the impaired differentiation seen in EDMD. These studies will have a significant impact on muscle disease because they analyze specific molecular interactions mediating genomic organization at the nuclear envelope and how their disruption alters transcriptional programing during differentiation and in muscle disease.

描述（由申请人提供）：emerin（一种内核包膜蛋白）的突变如何导致肌肉疾病的机制仍然未知。编码 emerin 的基因突变导致 Emery-Dreifuss 肌营养不良症（EDMD），其特征是进行性骨骼肌营养不良。肌肉萎缩、心律失常和肌腱挛缩是由骨骼肌干细胞分化再生失败引起的。需要分化基因的协调时间表达，从而导致分化受损。基因组结构通过调节基因组与转录活性或抑制的核结构域的关联来控制基因的激活或抑制。这种重组在干细胞分化过程中的细胞命运决定中发挥着重要作用。这里提出的研究将研究 emerin 如何调节基因组组织和基因表达，以调节肌原性分化所需的协调时间基因表达，以及 EDMD 中如何改变这一点。该领域缺乏对调节核纤层调节机制的基本了解。核纤层调节基因组组织和染色质结构，然而，核纤层蛋白并不是抑制染色质定位于核外围所必需的，这表明还有其他核膜蛋白。我们先驱 emerin 是介导抑制染色质与核膜关联的蛋白质之一，支持我们的假设，emerin 与抑制染色质机制相互作用，并在分化过程中与肌源性分化基因位点动态相互作用；这种定位是 emerin 依赖性的。拟议的研究将测试 emerin 与组蛋白脱乙酰酶 3 (HDAC3) 的相互作用如何在核内建立或维持抑制性染色质Emerin 对 HDAC3 活性的调节预计会在分化过程中调节基因组重组和协调分化基因的时间表达，因此我们将监测 Emerin 缺失的肌原性祖细胞分化过程中的基因表达，以鉴定这些细胞中被破坏的分子途径。引起 EDMD 的 emerin 突变祖细胞的治疗将用于确认这些途径参与 EDMD 中观察到的分化受损，因为它们分析了特定的肌肉疾病。介导核膜基因组组织的分子相互作用，以及它们的破坏如何改变分化过程中和肌肉疾病中的转录编程。