Thursday, November 21, 2024
11/21/2024
X-linked Emery-Dreifuss muscular dystrophy (EDMD1) is an inherited disorder characterized by progressive skeletal muscle wasting, irregular heart rhythms, and major tendon contractures. EDMD1 is caused by mutations in emerin, an inner nuclear envelope protein, but the molecular mechanisms for the pathogenesis remains unknown. We do know that the skeletal muscle pathogenesis in EDMD1 is related to impaired muscle regeneration due to compromised muscle stem cell differentiation. During differentiation, the genome in muscle stem cells is dynamically reorganized to coordinate the temporal expression of the differentiation transcriptional program. Our previous data showed the functional interaction between emerin and histone deacetylase 3 (HDAC3) contributes to regulating this genomic reorganization. Our working hypothesis is that the dynamic interaction between emerin and HDAC3 regulates the genomic reorganization necessary for differentiation. We further predict abrogation of this interaction by EDMD1-causing emerin mutations disrupt this genomic reorganization to block transcriptional reprogramming. To test this hypothesis, we will: Aim 1. Determine how emerin binding to HDAC3 organizes repressed myogenic loci at the nuclear envelope (NE); Aim 2. Evaluate the dynamic organization of myogenic loci at the NE during differentiation and its dysfunction in EDMD1; and Aim 3. Test if shifting H4K5 acetylation dynamics by treatment with histone acetyltransferase (HAT) inhibitors or HDAC3 activators rescues EDMD1 differentiation. Completion of these studies will provide mechanistic insight into the impaired muscle regeneration underlying the skeletal muscle pathogenesis of EDMD1. These studies will also significantly impact other neuromuscular diseases because muscle regeneration is important in many of these diseases. Completion of these studies will also have a broader impact because repairing tissue damage throughout the body uses resident stem cells that require the coordinated temporal expression of differentiation genes, which is dictated by dynamic genomic reorganization.
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