SWI/SNF complexes, chromatin remodeling and skeletal myogenesis: it's time to exchange!

Abstract

Skeletal muscle differentiation relies on the coordinated activation and repression of specific subsets of genes. This reflects extensive changes in chromatin architecture, composition of chromatin-associated complexes and histone modifications at the promoter/enhancer elements of skeletal muscle genes. An early, key event in the activation of muscle-specific gene transcription is the disruption of the repressive conformation imposed by nucleosomes, which impede the access of pioneer transcription factors, such as the muscle-specific basic helix-loop-helix (bHLH) factors MyoD and Myf5, to their DNA-binding sites. This review focuses on our current understanding of the role of the SWI/SNF ATP-dependent chromatin-remodeling complex in the activation of the myogenic program, by inducing conformational changes permissive for muscle-gene expression. Recent findings suggest that specific combinations of individual SWI/SNF components can generate sub-complexes with specialized functions that are engaged at sequential stages of muscle-gene activation--e.g., initial displacement of the nucleosome followed by the loading of the complete myogenic transcriptosome that promotes gene transcription. SWI/SNF composition and function is regulated by the exchange of specific variants of structural sub-units. In turn, an exchange of histone variants and related epigenetic modifications might reflect the impact of distinct SWI/SNF complexes on the architecture and activity of target promoter/enhancer elements. Thus, the SWI/SNF complexes should be regarded not just as simple executors of the program imposed by transcription factors, but as multifaceted "readers" and "shapers" of the chromatin/DNA landscape within target muscle genes along the transition from myoblasts to myotubes.

Fig. 1

The myogenin locus (which is representative of other muscle loci) is typically silent in myoblasts, due to the repressive conformation of the chromatin. A critical step in the activation of previously silent loci is the disruption of the nucleosome, which imposes a physical barrier to the promoter access of the pioneer muscle determination factors — MyoD or Myf5 — which possess the unique property of penetrating the repressive chromatin in muscle genes. This task is probably achieved by a sequence of events initiated by the indirect interaction of MyoD (or Myf5) with non-canonical Eboxes adjacent to the nucleosome. Pbx/Meis is one proposed mediator of this interaction, which results in the partial displacement of the nucleosome via engagement of histone acetyltransferases (HAT) and SWI/SNF sub-complexes not necessarily endowed with ATPase activity. The consequence of this initial event is the exposure of the canonical binding sites for muscle bHLH and MEF2 factors that allow the loading of the myogenic transcriptosome containing a full repertoire of chromatin remodelers. Different combinations of tissue-specific BAFs and ATPase variants might generate a number of different SWI/SNF sub-complexes with specialized functions and possibly gene-specific activity—see possible combinations of BAF60-based SWI/SNF complexes.