The Dystrophin Glycoprotein Complex Regulates the Epigenetic Activation of Muscle Stem Cell Commitment
Copyright © 2018 Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
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| Enthalten in: |
Cell stem cell - 22(2018), 5 vom: 03. Mai, Seite 755-768.e6 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chang, Natasha C [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.09.2019 Date Revised 06.09.2019 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.stem.2018.03.022 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM283294388 |
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| 100 | 1 | |a Chang, Natasha C |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The Dystrophin Glycoprotein Complex Regulates the Epigenetic Activation of Muscle Stem Cell Commitment |
| 264 | 1 | |c 2018 | |
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| 500 | |a Date Revised 06.09.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2018 Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Carm1 | |
| 650 | 4 | |a Duchenne muscular dystrophy | |
| 650 | 4 | |a Pax7 | |
| 650 | 4 | |a asymmetric division | |
| 650 | 4 | |a cell polarity | |
| 650 | 4 | |a muscle stem cell | |
| 650 | 4 | |a p38γ MAPK | |
| 650 | 4 | |a satellite cell | |
| 650 | 4 | |a stem cell expansion | |
| 650 | 4 | |a β1-syntrophin | |
| 650 | 7 | |a Myf5 protein, mouse |2 NLM | |
| 650 | 7 | |a Myogenic Regulatory Factor 5 |2 NLM | |
| 650 | 7 | |a PAX7 Transcription Factor |2 NLM | |
| 650 | 7 | |a Pax7 protein, mouse |2 NLM | |
| 650 | 7 | |a Protein-Arginine N-Methyltransferases |2 NLM | |
| 650 | 7 | |a EC 2.1.1.319 |2 NLM | |
| 650 | 7 | |a coactivator-associated arginine methyltransferase 1 |2 NLM | |
| 650 | 7 | |a EC 2.1.1.319 |2 NLM | |
| 650 | 7 | |a p38 Mitogen-Activated Protein Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 700 | 1 | |a Sincennes, Marie-Claude |e verfasserin |4 aut | |
| 700 | 1 | |a Chevalier, Fabien P |e verfasserin |4 aut | |
| 700 | 1 | |a Brun, Caroline E |e verfasserin |4 aut | |
| 700 | 1 | |a Lacaria, Melanie |e verfasserin |4 aut | |
| 700 | 1 | |a Segalés, Jessica |e verfasserin |4 aut | |
| 700 | 1 | |a Muñoz-Cánoves, Pura |e verfasserin |4 aut | |
| 700 | 1 | |a Ming, Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Rudnicki, Michael A |e verfasserin |4 aut | |
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