Harnessing Functional Genomics to Identify Mechanisms of Stem Cell Dependent Tissue Regeneration

Skeletal muscle stem cells (MuSC), also called satellite cells,are indispensable for maintenance and regeneration of adultskeletal muscles. Yet, a comprehensive picture of the regulatoryeventscontrolling the fate of MuSC during regeneration is missing.We have integrated functional genomic approaches includinggenetic high-throughput loss-of-function screening to identifymechanisms regulating MuSC self-renewal and differentiationduring skeletal muscle regeneration. In depth in vivo analysisrevealed that MuSC-specific inactivation of epigenetic modifiersincluding the histonemethyl transferase prmt۵ and theNuRD deacetylation complex prevents expansion of MuSCs,abolishes long-term SC maintenance and abrogates skeletalmuscle regeneration by direct epigenetic regulation of discretecell fate determinants.