title: Arginine Methylation by PRMT1 Regulates Muscle Stem Cell Fate.
abstract: Quiescent muscle stem cells (MSCs) become activated in response to skeletal muscle injury to initiate regeneration. Activated MSCs proliferate and differentiate to repair damaged fibers or self-renew to maintain the pool and ensure future regeneration. The balance between self-renewal, proliferation, and differentiation is a tightly regulated process controlled by a genetic cascade involving determinant transcription factors such as Pax7, Myf5, MyoD, and MyoG. Recently, there have been several reports about the role of arginine methylation as a requirement for epigenetically mediated control of muscle regeneration. Here we report that the protein arginine methyltransferase 1 (PRMT1) is expressed in MSCs and that conditional ablation of PRMT1 in MSCs using Pax7CreERT2causes impairment of muscle regeneration. Importantly, PRMT1-deficient MSCs have enhanced cell proliferation after injury but are unable to terminate the myogenic differentiation program, leading to regeneration failure. We identify the coactivator of Six1, Eya1, as a substrate of PRMT1. We show that PRMT1 methylates Eya1 in vitro and that loss of PRMT1 function in vivo prevents Eya1 methylation. Moreover, we observe that PRMT1-deficient MSCs have reduced expression of Eya1/Six1 target MyoD due to disruption of Eya1 recruitment at the MyoD promoter and subsequent Eya1-mediated coactivation. These findings suggest that arginine methylation by PRMT1 regulates muscle stem cell fate through the Eya1/Six1/MyoD axis.
authors.affiliation: Terry Fox Molecular Oncology Group and Segal Cancer Center, Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, and Departments of Oncology and Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Roméo Sébastien
authors.initials: RS
authors.lastname: Blanc
authors.affiliation: Terry Fox Molecular Oncology Group and Segal Cancer Center, Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, and Departments of Oncology and Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Gillian
authors.initials: G
authors.lastname: Vogel
authors.affiliation: Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.affiliation: Terry Fox Molecular Oncology Group and Segal Cancer Center, Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, and Departments of Oncology and Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Zhenbao
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: Li
authors.affiliation: Terry Fox Molecular Oncology Group and Segal Cancer Center, Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, and Departments of Oncology and Medicine, McGill University, Montréal, Québec, Canada stephane.richard@mcgill.ca.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D002478:Cells, Cultured; D018398:Homeodomain Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008745:Methylation; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000166:cytology; D024510:Muscle Development; D017570:MyoD Protein / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D040081:Protein Array Analysis; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology*; D013379:Substrate Specificity; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017570:MyoD Protein; D009687:Nuclear Proteins; D010455:Peptides; C490947:Six1 protein, mouse; D001120:Arginine; C546338:Prmt1 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; C501156:Eya1 protein, mouse; D017027:Protein Tyrosine Phosphatases
keywords: Eya1; Eya1/Six1; MyoD; PRMT1; cell fate; muscle regeneration; muscle stem cell