The dystrophin glycoprotein complex regulates the epigenetic activation of muscle stem cell commitment

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• dc.contributor.author Chang, Natasha C.
• dc.contributor.author Sincennes, Marie-Claude
• dc.contributor.author Chevalier, Fabien P.
• dc.contributor.author Brun, Caroline E.
• dc.contributor.author Lacaria, Melanie
• dc.contributor.author Segalés Dalmau, Jessica
• dc.contributor.author Muñoz Cánoves, Pura, 1962-
• dc.contributor.author Ming, Hong
• dc.contributor.author Rudnicki, Michael A.
• dc.date.accessioned 2023-04-21T06:15:24Z
• dc.date.available 2023-04-21T06:15:24Z
• dc.date.issued 2018
• dc.description.abstract 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.
• dc.description.sponsorship We thank Drs. Jeffrey Dilworth and Lynn Megeney for careful reading of the manuscript. We also thank Jennifer Ritchie for animal husbandry, Dr. Lawrence Puente for mass spectrometry analysis, Dr. Chloë van Oostende for microscopy and imaging analysis, Paul Oleynik for FACS, and Fan Xiao, Natasha Mercier, and David Wilson for technical assistance. N.C.C. is a recipient of the Centre for Neuromuscular Disease Scholarship in Translational Research Award from the University of Ottawa Brain and Mind Research Institute and was supported by Postdoctoral fellowships from the Canadian Institutes of Health Research (CIHR) and the Ontario Institute for Regenerative Medicine (OIRM). F.P.C. was supported by a Postdoctoral fellowship from the French Muscular Dystrophy Association (AFM)-Téléthon (380782). C.E.B. is supported by a Postdoctoral fellowship from OIRM. M.L. was supported by a Postdoctoral fellowship from CIHR. P.M.-C. acknowledges support from ERC-2016-AdG-741966 (STEM-AGING) and SAF2015-67369-R. M.A.R. holds the Canada Research Chair in Molecular Genetics. These studies were carried out with support of grants to M.A.R. from the US NIH (R01AR044031), the Canadian Institutes of Health Research (FDN-148387), the Muscular Dystrophy Association (USA), E-Rare-2: Canadian Institutes of Health Research/Muscular Dystrophy Canada (ERA-132935), and the Stem Cell Network.
• dc.format.mimetype application/pdf
• dc.identifier.citation Chang NC, Sincennes MC, Chevalier FP, Brun CE, Lacaria M, Segalés J, Muñoz-Cánoves P, Ming H, Rudnicki MA. The dystrophin glycoprotein complex regulates the epigenetic activation of muscle stem cell commitment. Cell Stem Cell. 2018 May 3;22(5):755-768.e6. DOI: 10.1016/j.stem.2018.03.022
• dc.identifier.doi http://dx.doi.org/10.1016/j.stem.2018.03.022
• dc.identifier.issn 1934-5909
• dc.identifier.uri http://hdl.handle.net/10230/56533
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Cell Stem Cell. 2018 May 3;22(5):755-768.e6
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/741966
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-67369-R
• dc.rights © Elsevier http://dx.doi.org/10.1016/j.stem.2018.03.022
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Carm1
• dc.subject.keyword Duchenne muscular dystrophy
• dc.subject.keyword Pax7
• dc.subject.keyword Asymmetric division
• dc.subject.keyword Cell polarity
• dc.subject.keyword Muscle stem cell
• dc.subject.keyword p38γ MAPK
• dc.subject.keyword Satellite cell
• dc.subject.keyword Stem cell expansion
• dc.subject.keyword β1-syntrophin
• dc.title The dystrophin glycoprotein complex regulates the epigenetic activation of muscle stem cell commitment
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion