Adult skeletal muscle stem cells known as satellite cells are normally maintained in a quiescent state and could activate, differentiate in responding to environmental cues thereby being responsible for muscle integrity and regeneration in the lifetime. Deregulation satellite cell homeostasis has been implicated in the pathology of several human muscle diseases. Satellite cells that are identified by the expression of transcription factor Pax7 (Pax7+) originate from highly proliferative Pax7+/MyoD+ progenitor cells during development. Interestingly it has been demonstrated that satellite cells show a chromatin organization which is different from the corresponding precursors or terminally differentiated progenies suggesting that epigenetic regulators might be causally involved in cell fate determination and cell identity control. In this study I demonstrated that the protein arginine methyltransferase 5 (PRMT5), an epigenetic modifier catalyzes symmetric H3R8 dimethylation (H3R8me2) in nucleosomes, is an essential factor for Pax7+ satellite cell homeostasis in adult skeletal muscle. In contrast, PRMT5 is not required for Pax7+ muscle progenitor cell proliferation and differentiation during development and the function of differentiated myotubes in adult skeletal muscle.In adult resting muscle, PRMT5 is highly expressed in quiescent satellite cells. Induced deletion of PRMT5 in Pax7+ satellite cells does not only lead to a massive decline of the number of muscle stem cells during aging, but also completely abolishes muscle regeneration after acute muscle injury. At the cellular level, PRMT5 is required for satellite cell proliferation, early stage of cell differentiation and cell survival upon differentiation ex vivo. Mechanistically PRMT5 directly binds to the p53 binding site at the locus of cell cycle inhibitor p21 gene and induces epigenetic gene silencing by depositing H3R8me2s. The up-regulation of p21 in Prmt5 mutant satellite cells results in an arrest of satellite cell proliferation. Consistently, genetic loss of p21 partially restores the proliferation defects of PRMT5 deficient satellite cells. Importantly, mice with induced ablation of PRMT5 in Pax7+ satellite cell derived differentiated myocytes regenerate skeletal muscle to the same degree wild type mice, suggesting that PRMT5 is dispensable in differentiated myofibers. Furthermore, ablation of PRMT5 in Pax7+ precursors during embryonic development does not alter the precursor cell proliferation and differentiation, indicating that PRMT5 is dispensable for expansion of skeletal muscle progenitor cells and formation of muscle cells during development. Taken together these findings demonstrate a unique and essential role of PRMT5 in satellite cell homeostasis suggesting distinctgenetic and epigenetic requirements for developmental myogenesis and regenerative myogenesis.In addition, I analyzed the role of PRMT5 in muscle regeneration in a murine model of muscular dystrophy. Induced satellite cell specific deletion of PRMT5 in mdx mice, a model lacking dystrophin expression as that in human Muscular Dystrophy (DMD) patients but showing much less severe and representative muscle phenotypes, results in depletion of the muscle stem cell pool, dramatic loss of muscle mass and increase of muscle fibrosis, recapitulating many pathological features of human DMD patients in only 4 months after PRMT5 ablation. This finding demonstrated that PRMT5 mediated epigenetic regulation of regenerative myogenesis has therapeutic implications for human DMD. Further studies will focus on detailed pathophysiological analyses of PRMT5 and mdx double mutant mice and the role of PRMT5 in human DMD.
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