| The nucleus is separated from the cytosol by the double lipid bilayers of the Outer Nuclear and Inner Nuclear Membranes (ONM and INM). The nuclear envelope has been established as a generally repressive subdomain within the nucleus. Proper establishment of repressed chromatin at the nuclear envelope is essential for lineage specification and differentiation during embryonic development and for tissue repair after injury. Emerin is a highly conserved, ubiquitously expressed protein of the INM. Mutations in emerin cause Emery-Dreifuss muscular dystrophy (EDMD), a disease characterized by skeletal muscle wasting, contracture of major tendons and dilated cardiomyopathy. Emerin has diverse functions, including the regulation of gene expression, cell signaling, nuclear structure, and chromatin architecture. The disruptions to cell signaling linked to emerin mutations are largely unknown. Additionally, the molecular mechanisms behind the initiation and maintenance of repressed chromatin at the nuclear envelope remain poorly understood. This dissertation presents the first studies to interrogate disrupted signaling in cells lacking emerin at the transcriptomic level in an unbiased manner. We identified significant disruptions to the canonical myogenic signaling pathways Wnt, Notch, TGF-beta and IGF in primary myogenic precursor cells. We also demonstrated a novel mechanism by which emerin directly interacts with and stimulates histone deacetylase 3 (HDAC3) activity to regulate the nuclear position and expression of the myogenic loci Pax7, MyoD and Myf5 at the nuclear envelope. Overall, this work supports a model in which emerin facilitates the proper formation of repressed chromatin at the nuclear envelope by activating HDAC3 catalytic activity to regulate the coordinated spatiotemporal expression of genes crucial for cell signaling and myogenic differentiation. |
