The Dystrophin Glycoprotein Complex Regulates the Epigenetic Activation of Muscle Stem Cell Commitment

• Published in: Cell stem cell Vol. 22; no. 5; pp. 755 - 768.e6
• Main Authors: Chang, Natasha C., Sincennes, Marie-Claude, Chevalier, Fabien P., Brun, Caroline E., Lacaria, Melanie, Segalés, Jessica, Muñoz-Cánoves, Pura, Ming, Hong, Rudnicki, Michael A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.05.2018
• Subjects: Animals; asymmetric division; Carm1; cell polarity; Cells, Cultured; Duchenne muscular dystrophy; Epigenesis, Genetic; Female; Male; Mice; Mice, Inbred Strains; muscle stem cell; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Myogenic Regulatory Factor 5 - genetics; Myogenic Regulatory Factor 5 - metabolism; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; p38γ MAPK; Pax7; PAX7 Transcription Factor - genetics; PAX7 Transcription Factor - metabolism; Protein-Arginine N-Methyltransferases - metabolism; satellite cell; stem cell expansion; Stem Cells - metabolism; β1-syntrophin; β1-syntrophin; satellite cell; asymmetric division; Carm1; Pax7; Duchenne muscular dystrophy; cell polarity; stem cell expansion; p38γ MAPK; muscle stem cell
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2018.03.022

Asymmetrically dividing muscle stem cells in skeletal muscle give rise to committed cells, where the myogenic determination factor Myf5 is transcriptionally activated by Pax7. This activation is dependent on Carm1, which methylates Pax7 on multiple arginine residues, to recruit the ASH2L:MLL1/2:WDR5:RBBP5 histone methyltransferase complex to the proximal promoter of Myf5. Here, we found that Carm1 is a specific substrate of p38γ/MAPK12 and that phosphorylation of Carm1 prevents its nuclear translocation. Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation. The resulting progenitors exhibit reduced Carm1 binding to Pax7, reduced H3K4-methylation of chromatin, and reduced transcription of Myf5 and other Pax7 target genes. Therefore, our experiments suggest that dysregulation of p38γ/Carm1 results in altered epigenetic gene regulation in Duchenne muscular dystrophy. [Display omitted] •p38γ MAPK positively regulates symmetric muscle stem cell expansion•p38γ phosphorylates Carm1 to prevent nuclear localization and interaction with Pax7•p38γ/Carm1 signaling is dysregulated in dystrophin-deficient mdx satellite cells•Carm1-mediated epigenetic induction of Myf5 is impaired in mdx satellite cells Establishment of cell polarity by the dystrophin complex is required for muscle stem cell asymmetric divisions. Chang et al. identify p38γ MAPK as a critical downstream regulator of satellite stem cell commitment, providing a link between dystrophin and epigenetic gene regulation to mediate asymmetric fates of daughter satellite cells.