Emerin regulation of molecular pathways: implications for muscle disease

内核膜蛋白emerin突变导致肌肉萎缩的机制 疾病仍然未知。Emerin基因突变导致Emery-Dreifuss肌营养不良症 （EDMD），其特征在于进行性骨骼肌萎缩、心律不齐和肌腱断裂。 挛缩骨骼肌表型是由骨骼肌再生失败引起的。骨骼 肌肉干细胞分化需要分化基因的协调的时间表达。 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基因的关联来控制基因的激活或抑制， 或抑制的核结构域。基因组在许多细胞类型的分化过程中进行重组， 控制协调的时间基因表达。这种重组在细胞命运中起着重要作用 在干细胞分化和发育过程中的决定。本文提出的研究将探讨如何 Emerin调节基因组组织和基因表达，以调节协调的时间基因 肌源性分化所需的表达，以及EDMD中这种表达是如何改变的。 该领域缺乏对调节核纤层调控的机制的基本理解， 基因组结构及其对基因表达的影响。核纤层调节基因组的组织 和染色质结构。然而，核纤层蛋白并不是抑制的染色质定位在细胞核中所必需的。 核外围，表明其他核膜蛋白介导它们的关联。我们假设 Emerin是介导受抑制的染色质与细胞核结合的蛋白质之一 信封.支持我们的假设emerin与抑制性染色质机制相互作用， 在分化过程中与生肌分化基因位点相互作用;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（HDAC 3）的相互作用如何建立或 在核膜上保持抑制性染色质。据预测，HDAC 3活性的Emerin调节 调节分化过程中基因组重组和协调的时间表达 分化因此，我们将监测emerin无效的肌源性祖细胞分化过程中的基因表达， 鉴定这些细胞中被破坏的分子途径，这将通过用活化剂处理来证实，或 抑制剂的将使用引起EDMD的Emerin突变体祖细胞来证实这些途径参与了EDMD的发生。 在EDMD中观察到的分化受损。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过程中和肌肉疾病中的转录编程。

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 affect 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.