Myogenin and the SWI/SNF ATPase Brg1 Maintain Myogenic Gene Expression at Different Stages of Skeletal Myogenesis
Many studies have examined transcriptional regulation during the initiation of skeletal muscle differentiation; however, there is less information regarding transcriptional control during adult myogenesis and during the maintenance of the differentiated state. MyoD and the mammalian SWI/SNF chromatin-remodeling enzymes containing the Brg1 ATPase are necessary to induce myogenesis in cell culture models and in developing embryonic tissue, whereas myogenin and Brg1 are critical for the expression of the late genes that induce terminal muscle differentiation. Here, we demonstrate that myogenin also binds to its own promoter during the late stages of embryonic muscle development. As is the case during embryonic myogenesis, MyoD and Brg1 co-localize to the myogenin promoter in primary adult muscle satellite cells. However, in mature myofibers, myogenin and Brg1 are preferentially co-localized to the myogenin promoter. Thus, the myogenin promoter is occupied by different myogenic factors at different times of myogenesis. The relevance of myogenin in the continued expression from its own promoter is demonstrated in culture, where we show that myogenin, in the absence of MyoD, is capable of maintaining its own expression by recruiting the Brg1 ATPase to modify promoter chromatin structure and facilitate myogenin expression. Finally, we utilized in vivo electroporation to demonstrate that Brg1 is required for the continued production of the myogenin protein in newborn skeletal muscle tissue. These findings strongly suggest that the skeletal muscle phenotype is maintained by myogenin and the continuous activity of Brg1-based SWI/SNF chromatin-remodeling enzymes.
Available from: Julien Pontis
- "The BAF47 effect on Cyclin D1 repression and cell cycle exit is specific and somehow not directly correlated to BAF47 requirement in myoblast differentiation since BRG1 and BAF53 do not modify permanent cell cycle exit but are, anyhow, essential in myoblast terminal differentiation. The different and complex roles played by SWI/SNF BAFs are far from being totally elucidated.The essential roles of BRG1 and BAF60c in myogenic differentiation have been already clearly demonstrated , , . Our present study demonstrates that BAF47 and BAF53a are also required for proper myogenic differentiation. "
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ABSTRACT: Myogenic terminal differentiation is a well-orchestrated process starting with permanent cell cycle exit followed by muscle-specific genetic program activation. Individual SWI/SNF components have been involved in muscle differentiation. Here, we show that the master myogenic differentiation factor MyoD interacts with more than one SWI/SNF subunit, including the catalytic subunit BRG1, BAF53a and the tumor suppressor BAF47/INI1. Downregulation of each of these SWI/SNF subunits inhibits skeletal muscle terminal differentiation but, interestingly, at different differentiation steps and extents. BAF53a downregulation inhibits myotube formation but not the expression of early muscle-specific genes. BRG1 or BAF47 downregulation disrupt both proliferation and differentiation genetic programs expression. Interestingly, BRG1 and BAF47 are part of the SWI/SNF remodeling complex as well as the N-CoR-1 repressor complex in proliferating myoblasts. However, our data show that, upon myogenic differentiation, BAF47 shifts in favor of N-CoR-1 complex. Finally, BRG1 and BAF47 are well-known tumor suppressors but, strikingly, only BAF47 seems essential in the myoblasts irreversible cell cycle exit. Together, our data unravel differential roles for SWI/SNF subunits in muscle differentiation, with BAF47 playing a dual role both in the permanent cell cycle exit and in the regulation of muscle-specific genes.
PLoS ONE 10/2014; 9(10):e108858. DOI:10.1371/journal.pone.0108858 · 3.23 Impact Factor
Available from: Anthony N Imbalzano
- "As expected, binding of MyoD was found in muscle promoters both in proliferating myoblasts and in myotubes, with a significant enhancement of MyoD binding at the MCK gene (32). In contrast, myogenin protein was inducibly recruited to muscle regulatory regions upon cell differentiation, in agreement with prior studies (33–35). The IgH enhancer was used as a negative sequence control because it contains a consensus E box but does not bind to myogenic transcription factors in myoblasts or in differentiated cells (4,26,34,36–40). "
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ABSTRACT: The regulation of skeletal muscle gene expression during myogenesis is mediated by lineage-specific transcription factors in combination with numerous cofactors, many of which modify chromatin structure. However, the involvement of scaffolding proteins that organize chromatin and chromatin-associated regulatory proteins has not extensively been explored in myogenic differentiation. Here, we report that Scaffold attachment factor b1 (Safb1), primarily associated with transcriptional repression, functions as a positive regulator of myogenic differentiation. Knockdown of Safb1 inhibited skeletal muscle marker gene expression and differentiation in cultured C2C12 myoblasts. In contrast, over-expression resulted in the premature expression of critical muscle structural proteins and formation of enlarged thickened myotubes. Safb1 co-immunoprecipitated with MyoD and was co-localized on myogenic promoters. Upon Safb1 knockdown, the repressive H3K27me3 histone mark and binding of the Polycomb histone methyltransferase Ezh2 persisted at differentiation-dependent gene promoters. In contrast, the appearance of histone marks and regulators associated with myogenic gene activation, such as myogenin and the SWI/SNF chromatin remodelling enzyme ATPase, Brg1, was blocked. These results indicate that the scaffold protein Safb1 contributes to the activation of skeletal muscle gene expression during myogenic differentiation by facilitating the transition of promoter sequences from a repressive chromatin structure to one that is transcriptionally permissive.
Nucleic Acids Research 04/2013; 41(11). DOI:10.1093/nar/gkt285 · 9.11 Impact Factor
Available from: Alain Fautrel
- "Additionally, we report the overexpression of histone modifying enzymes including protein arginine methyltransferase 4 (PRTM4/CARM1) and 5 (PRTM5), which, in zebrafish, have a major role in controlling MRF expression and proper myogenesis . Among the SWI/SNF chromatin remodelling enzymes overexpressed in our analysis it is worth noting that Brg1/Smarca4 has been shown to alter chromatin structure at myogenic loci facilitating transcription . "
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ABSTRACT: A unique feature of fish is that new muscle fibres continue to be produced throughout much of the life cycle; a process termed muscle hyperplasia. In trout, this process begins in the late embryo stage and occurs in both a discrete, continuous layer at the surface of the primary myotome (stratified hyperplasia) and between existing muscle fibres throughout the myotome (mosaic hyperplasia). In post-larval stages, muscle hyperplasia is only of the mosaic type and persists until 40% of the maximum body length is reached. To characterise the genetic basis of myotube neoformation in trout, we combined laser capture microdissection and microarray analysis to compare the transcriptome of hyperplastic regions of the late embryo myotome with that of adult myotomal muscle, which displays only limited hyperplasia.
BMC Genomics 03/2013; 14(1):173. DOI:10.1186/1471-2164-14-173 · 3.99 Impact Factor
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