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
| Autor: | F. Jeffrey Dilworth, Tapan Sharma, Daniel C.L. Robinson, Anthony N. Imbalzano, Hanna Witwicka |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
AcademicSubjects/SCI00010 Pyridines Biology Muscle Development Chromatin remodeling Histones 03 medical and health sciences 0302 clinical medicine Gene expression Genetics Animals Humans Muscle Skeletal Epigenomics Adenosine Triphosphatases Chromatin binding Gene regulation Chromatin and Epigenetics DNA Helicases Nuclear Proteins Cell Differentiation Chromatin Assembly and Disassembly SWI/SNF Chromatin Cell biology Bromodomain DNA-Binding Proteins 030104 developmental biology Histone 030220 oncology & carcinogenesis biology.protein Azabicyclo Compounds Transcription Factors |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | 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. Graphical Abstract Graphical AbstractEffects of PFI-3 induced bromodomain inhibition on skeletal myogenesis. In normal conditions, BRG1/BRM with active bromodomains can bind to promoters of target genes when muscle differentiation is induced. This in turn affects two important aspects of skeletal myogenesis: cell cycle exit and the formation of differentiated multinucleated myotubes. In the presence of PFI-3, BRG1 and BRM show reduced binding to target gene promoters leading to continued cell-cycle and incomplete differentiation resulting in shorter myotubes. |
| Databáze: | OpenAIRE |
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