Abstract
Myogenic differentiation requires the coordination between permanent cell cycle withdrawal, mediated by members of the cyclin-dependent kinase inhibitor (CKI) family, and activation of a cascade of myogenic transcription factors, particularly MYOGENIN (MYOG). Recently, it has been reported that the Protein aRginine Methyl Transferase PRMT5 modulates the early phase of induction of MYOG expression. Here, we show that the histone- and PRMT5-associated protein COPR5 (cooperator of PRMT5) is required for myogenic differentiation. C2C12 cells, in which COPR5 had been silenced, could not irreversibly exit the cell cycle and differentiate into muscle cells. This phenotype might be explained by the finding that, in cells in which COPR5 was downregulated, p21 and MYOG induction was strongly reduced and PRMT5 recruitment to the promoters of these genes was also altered. Moreover, we suggest that COPR5 interaction with the Runt-related transcription factor 1 (RUNX1)–core binding factor-β (CBFβ) complex contributes to targeting the COPR5–PRMT5 complex to these promoters. Finally, we present evidence that COPR5 depletion delayed the in vivo regeneration of cardiotoxin-injured mouse skeletal muscles. Altogether, these data extend the role of COPR5 from an adaptor protein required for nuclear functions of PRMT5 to an essential coordinator of myogenic differentiation.
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Abbreviations
- CKI:
-
cyclin-dependent kinase inhibitor
- MYOG :
-
MYOGENIN
- PRMT5 :
-
protein arginine methyl transferase 5
- COPR5 :
-
cooperator of PRMT5
- RUNX1 :
-
Runt-related transcription factor 1
- CBFβ:
-
core binding factor-β
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Acknowledgements
We thank G Carnac for primary human skeletal muscle myoblasts; S Ait-Sit-Ali for RUNX1 constructs; our animal facility staff, the RHEM facility (Réseau d’Histologie Expérimentale de Montpellier) and all members of the CS laboratory for helpful discussions. This work was realized with institutional supports of the French CNRS and grants from the FRM, ANR (CS,équipe labélisée 2007) and ARC (EF).
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Paul, C., Sardet, C. & Fabbrizio, E. The histone- and PRMT5-associated protein COPR5 is required for myogenic differentiation. Cell Death Differ 19, 900–908 (2012). https://doi.org/10.1038/cdd.2011.193
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DOI: https://doi.org/10.1038/cdd.2011.193
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