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.
Highlights
The SWI/SNF complex (SWI, mating type switch; SNF, sucrose non-fermenting) is an evolutionarily well-conserved ATPase-powered chromatin-remodeling complex
SWI/SNF chromatin remodeling complex subunits are differently involved in muscle differentiation Throughout the study, we focused on BAF47 tumor suppressor subunit and performed comparative studies with BAF53a and the catalytic subunit BRG1, since the latter has been well studied in muscle terminal differentiation (33)
Skeletal muscle terminal differentiation is a two-step process starting with an irreversible cell cycle withdrawal followed by the activation of the muscle genetic program resulting in cell fusion and formation of multinucleated myotubes [36,45,49]
Summary
The SWI/SNF complex (SWI, mating type switch; SNF, sucrose non-fermenting) is an evolutionarily well-conserved ATPase-powered chromatin-remodeling complex. This complex, composed of a dozen of proteins, is implicated in the sliding or removing of nucleosomes, influencing gene expression regulation, DNA repair and replication (for review [1,2]). SWI/ SNF contains one of two related ATPases: Brahma (BRM, encoded by SMARCA2) or Brahma-Related Gene 1 (BRG1, encoded by SMARCA4). The complex contains BAFs (BRM or BRG1-Associated Factors). Combinatorial assembly of six to eight additional BAFs confers specificity of function to individual SWI/SNF complexes (for review [1,3]).
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