Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Following muscle injury or strength training exercise, satellite cells residing in the muscle proliferate and fuse, renewing or increasing the size and strength of the muscle. The number of satellite cells and the regenerative capacity of muscle decrease during aging and in diseases such as muscular dystrophy. During development and in the adult, the transcription factor Pax7 regulates genes necessary for the maintenance and proliferation of satellite cells and is required for the survival of these cells. This project aims to build a better understanding of the requirement for Pax7 and how it functions. We have found that to activate genes, Pax7 recruits MLL, a histone methyltransferase, which relaxes DNA packing, facilitating access for transcription. Previous studies have found that MLL is required for expression of developmental regulators that are necessary to maintain other types of adult stem cells. We are developing a genetically modified mouse in which MLL is removed from muscle satellite cells. In cultured muscle progenitor cells lacking MLL (MLL KO), expression of Pax7 is weakly reduced, but expression of Pax7 targets is lost, as is proliferation. Over-expression of Pax7 overcomes the MLL KO defect and Pax7 target gene expression and proliferation are recovered. In this study, we aim to determine; 1) the effect of the loss of MLL on the accessibility and expression of Pax7 target genes, 2) the effect of the loss of MLL on muscle regeneration in-vivo, 3) the mechanism by which Pax7 can activate genes without MLL, and 4) whether MLL is required for expression of other myogenic developmental regulators. Determining how over-expressed Pax7 is able to overcome DNA packing based gene expression restrictions, and identification of new developmental regulators important for muscle will be informative for devising new strategies to save satellite cells in diseased muscle and for generation of satellite cells from non-muscle tissue for cell replacement therapy.