Abstract
Acute muscle injury and physiological stress from chronic muscle diseases and aging lead to impairment of skeletal muscle function. This raises the question of whether p53, a cellular stress sensor, regulates muscle tissue repair under stress conditions. By investigating muscle differentiation in the presence of genotoxic stress, we discovered that p53 binds directly to the myogenin promoter and represses transcription of myogenin, a member of the MyoD family of transcription factors that plays a critical role in driving terminal muscle differentiation. This reduction of myogenin protein is observed in G1-arrested cells and leads to decreased expression of late but not early differentiation markers. In response to acute genotoxic stress, p53-mediated repression of myogenin reduces post-mitotic nuclear abnormalities in terminally differentiated cells. This study reveals a mechanistic link previously unknown between p53 and muscle differentiation, and suggests new avenues for managing p53-mediated stress responses in chronic muscle diseases or during muscle aging.
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Abbreviations
- MRF:
-
myogenic regulatory factor
- ER:
-
estrogen receptor
- BFP:
-
blue fluorescent protein
- 4OHT:
-
4-hydroxytamoxifen
- MEF:
-
mouse embryonic fibroblast
- IR:
-
ionizing radiation
- PI:
-
propidium iodide
- BrdU:
-
bromodeoxyuridine
- ChIP-seq:
-
chromatin immunoprecipitation followed by high-throughput DNA sequencing
- RE:
-
response element
- TAD:
-
transcriptional activation domain
- DHB:
-
human DNA helicase B
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Acknowledgements
We thank members of the Wang laboratory for technical support and stimulating discussions. We are grateful to Drs Ingrid Lawhorn, Phillip Patten, Stefano Biressi, and Maddalena Adorno for valuable discussions and comments on the manuscript; Teddy Yewdell from the Dr Aaron Straight laboratory for helpful discussions; Emma Chory from the Dr Gerald Crabtree laboratory, and Rose Tran and Brook Hunt from the Dr Paul Khavari laboratory for generously providing histone antibodies for preliminary ChIP validations. We thank Dr Foteini Mourkioti for providing antibodies for initial testing of muscle differentiation markers. We also thank the Stanford FACS facility for technical support. This study was supported by NIH-5R21AG040360-02 to CLW and Swiss National Science Foundation Fellowships to DKB.
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Yang, Z., Kenzelmann Broz, D., Noderer, W. et al. p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress. Cell Death Differ 22, 560–573 (2015). https://doi.org/10.1038/cdd.2014.189
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DOI: https://doi.org/10.1038/cdd.2014.189
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