Emerin regulation of molecular pathways: implications for muscle disease

 描述（由申请人提供）：Emerin（一种内核被膜蛋白）突变导致肌肉疾病的潜在机制仍不清楚。编码Emerin的基因突变会导致Emery-Dreifuss肌营养不良症（EDMD），其特征是进行性骨骼肌萎缩、心律不齐和肌腱挛缩。骨骼肌表型是由骨骼肌再生失败引起的。骨骼肌干细胞分化需要分化基因的协调时间表达。分化转录程序的破坏导致分化受损。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激活或抑制。基因组在许多细胞类型的分化过程中进行重组，以控制协调的时间基因表达。这种重组在干细胞分化过程中的细胞命运决定中起着重要作用 在发展中。本文提出的研究将研究emerin如何调节基因组组织和基因表达，以调节肌源性分化所需的协调时间基因表达，以及这在EDMD中如何改变。该领域缺乏对基因组结构的核纤层调控机制及其对基因表达的影响的基本理解。核纤层调控基因组的组织和染色质的结构。然而，核纤层蛋白不需要抑制染色质定位在核周围，这表明其他核膜蛋白介导它们的协会。我们假设emerin是这些蛋白质之一，介导的协会被压抑的染色质与核膜。支持我们的假设emerin与抑制性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依赖的。拟议的研究将测试emerin与组蛋白脱乙酰基酶3（HDAC 3）的相互作用如何在核膜上建立或维持抑制性染色质。HDAC 3活性的Emerin调节被预测为在分化期间调节基因组重组和分化基因的协调时间表达。因此，我们将监测emerin空肌原性祖细胞分化过程中的基因表达，以确定这些细胞中被破坏的分子通路，这将通过用激活剂或抑制剂治疗来证实。将使用引起EDMD的emerin突变体祖细胞来确认这些途径参与EDMD中观察到的受损分化。这些研究将对肌肉疾病产生重大影响，因为它们分析了在核膜上介导基因组组织的特定分子相互作用，以及它们的破坏如何改变分化和肌肉疾病期间的转录编程。

 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.