Emerin regulation of molecular pathways: implications for muscle disease

内核膜蛋白Emerin突变如何导致肌肉的机制(S) 疾病仍然未知。Emerin编码基因突变导致Emery-Dreifuss肌营养不良症 (EDMD)，以进行性骨骼肌萎缩、心律失常和肌腱为特征 痉挛。骨骼肌表型是由于骨骼肌再生失败引起的。骨骼 肌肉干细胞的分化需要分化基因在时间上的协调表达。 分化转录程序的中断会导致分化受损。基因组结构 通过调节基因组与转录活性的关联来控制基因的激活或抑制 或被抑制的核域。基因组在许多细胞类型的分化过程中进行自我重组 控制时间基因的协调表达。这种重组对细胞的命运起着基础性的作用 干细胞分化和发育过程中的决策。这里提出的研究将检验如何 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，以及这在EDMD中是如何改变的。 该领域缺乏对核膜调控机制的基本了解。 基因组结构及其对基因表达的影响。核膜调节基因组组织 和染色质结构。然而，在抑制的染色质定位中，并不需要板层 核周，表明其他核膜蛋白介导了它们之间的联系。我们假设 Emerin是这些蛋白质中的一种，它介导抑制的染色质与核的联系。 信封。支持我们的假设，Emerin与抑制染色质机制相互作用，并动态地 在分化过程中与肌源性分化基因位点相互作用；这种定位是发生蛋白依赖性的。 拟议的研究将测试Emerin与组蛋白脱乙酰基酶3(HDAC3)的相互作用如何建立或 在核膜上维持抑制性染色质。对HDAC3活性的ERIMIN调节被预测为 调控基因组重组和协调分化基因的时间表达 差异化。因此，我们将监测Emerin缺失的肌源性祖细胞分化过程中的基因表达，以 确定在这些细胞中被破坏的分子途径，这将通过激活剂或 抑制剂。将使用导致EDMD的Emerin突变前体细胞来确认这些途径是否参与了 EDMD的分化受损。这些研究将对肌肉疾病产生重大影响 因为他们分析了特定的分子相互作用，介导了核膜上的基因组组织 以及它们的干扰如何在分化和肌肉疾病中改变转录程序。

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.