Department of Biochemistry and Molecular Pharmacology; Imbalzano Lab
Amino Acids, Peptides, and Proteins | Cell and Developmental Biology | Enzymes and Coenzymes
Skeletal muscle regeneration is mediated by myoblasts that undergo epigenomic changes to establish the gene expression program of differentiated myofibers. mSWI/SNF chromatin remodeling enzymes coordinate with lineage-determining transcription factors to establish the epigenome of differentiated myofibers. Bromodomains bind to acetylated lysines on histone N-terminal tails and other proteins. The mutually exclusive ATPases of mSWI/SNF complexes, BRG1 and BRM, contain bromodomains with undefined functional importance in skeletal muscle differentiation. Pharmacological inhibition of mSWI/SNF bromodomain function using the small molecule PFI-3 reduced differentiation in cell culture and in vivo through decreased myogenic gene expression, while increasing cell cycle-related gene expression and the number of cells remaining in the cell cycle. Comparative gene expression analysis with data from myoblasts depleted of BRG1 or BRM showed that bromodomain function was required for a subset of BRG1- and BRM-dependent gene expression. Reduced binding of BRG1 and BRM after PFI-3 treatment showed that the bromodomain is required for stable chromatin binding at target gene promoters to alter gene expression. Our findings demonstrate that mSWI/SNF ATPase bromodomains permit stable binding of the mSWI/SNF ATPases to promoters required for cell cycle exit and establishment of muscle-specific gene expression.
skeletal muscle, differentiation, bromodomains
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Copyright © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org.
DOI of Published Version
Sharma T, Robinson DCL, Witwicka H, Dilworth FJ, Imbalzano AN. The Bromodomains of the mammalian SWI/SNF (mSWI/SNF) ATPases Brahma (BRM) and Brahma Related Gene 1 (BRG1) promote chromatin interaction and are critical for skeletal muscle differentiation. Nucleic Acids Res. 2021 Aug 20;49(14):8060-8077. doi: 10.1093/nar/gkab617. PMID: 34289068; PMCID: PMC8373147. Link to article on publisher's site
Nucleic acids research
Sharma T, Robinson DC, Witwicka H, Dilworth FJ, Imbalzano AN. (2021). The Bromodomains of the mammalian SWI/SNF (mSWI/SNF) ATPases Brahma (BRM) and Brahma Related Gene 1 (BRG1) promote chromatin interaction and are critical for skeletal muscle differentiation. Open Access Publications by UMass Chan Authors. https://doi.org/10.1093/nar/gkab617. Retrieved from https://escholarship.umassmed.edu/oapubs/4904
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License