Grant: Operating Grant

In adult skeletal muscle, satellite cells are specialized cells whose job is to replenish muscle tissue lost through damage or disease. At the molecular level, the behavior of the satellite cells and their descendants in carrying out this role is regulated by a variety of factors. These include Pax3, Pax7 and the MyoD family of transcription factors, which act to switch on or off target genes, and factors such as HATs, HDACs and CTCF, which alter the conformation of the DNA itself, thereby affecting target genes. In Duchenne Muscular Dystrophy (DMD), the activity levels and targets of these factors become altered, resulting in a dysregulation of satellite cell function that exacerbates the disease. However, the extent and nature of these alterations in the regulatory network are not well understood. In this proposal, we outline an experimental program designed to clarify the normal and DMD-altered roles of the major regulators of myogenesis. Our study will be based primarily on high-throughput genome-scale measurements of the DNA-binding sites of the various regulatory factors, of DNA packaging and conformation, and of target gene expression under various conditions. These experiments will provide important new insights into the regulation of myogenesis, and will facilitate the development of new therapeutic strategies for many muscle diseases, including muscular dystrophy.