Elsevier

Experimental Cell Research

Volume 316, Issue 18, 1 November 2010, Pages 3073-3080
Experimental Cell Research

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

https://doi.org/10.1016/j.yexcr.2010.05.023Get rights and content

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.

Introduction

During cellular differentiation, the activation of tissue- and lineage-specific genes coincides with the disruption of the repressive conformation imposed by nucleosomes at previously silent loci. This task is achieved by the combinatorial activities of tissue-specific transcription factors and multi-sub-unit machineries that decompose the chromatin by disassembling and reassembling the nucleosomes [1]. For instance, during skeletal muscle differentiation the myogenic bHLH proteins MyoD and Myf5, which are expressed in myoblasts prior to the differentiation, face the challenge of gaining access to their binding sites (the so-called Eboxes-CANNTG) on muscle genes, by overcoming the unfavorable conformation of repressive chromatin [2]. Physical and functional interactions between muscle bHLH proteins and ATP-dependent SWI/SNF chromatin-remodeling complexes [3], [4] promote the displacement of nucleosomes and generate the landscape conducive for the activation of transcription, by favoring the access of muscle bHLH proteins and MEF2 factors, and the assembly of the myogenic transcriptosome. The alternative presence of two catalytic sub-units, either Brg1 or Brm, confers on the SWI/SNF complex the ATPase activity necessary to remodel the chromatin [5]; moreover, different combinations of non-enzymatic, structural sub-units, such as the Brg1/Brm-associated factors (BAFs), can generate different sub-complexes, thereby providing the molecular variability by which SWI/SNF complexes select the interactions with different tissue-specific transcription factors and with other chromatin-modifying enzymes [6], [7]. Thus, the specific composition of SWI/SNF sub-complexes determines their activity and specificity for particular subsets of genes. An exchange of SW/SNF variant sub-units at key transitions of the myogenic program might generate sub-complexes dedicated to specific tasks, such as facilitating the access of pioneer transcriptional activators and “reading” the combinations of histone marks generated by the activity of muscle-specific transcription factors and components of the epigenetic machinery.

Section snippets

Transcriptional control by chromatin remodelers during skeletal muscle differentiation

The muscle regulatory factors (MRFs) belonging to the bHLH family — MyoD, Myf5, MRF4 and myogenin — activates and perpetuates the skeletal myogenic program by promoting the gradual expression of muscle-specific genes in myoblasts [8]. This task is achieved with the contribution of other transcription factors, such as the MEF2 family members, which are expressed ubiquitously and cooperate with muscle bHLH proteins to activate muscle-gene transcription in myoblasts [9]. Recent evidence supports

SWI/SNF sub-complexes and cellular differentiation: a tissue-specific regulation of sub-unit exchange

The multitude of interaction between SWI/SNF and other chromatin-associated proteins, as well as the temporal and gene-specific SWI/SNF distribution during skeletal myogenesis, suggest that distinct SWI/SNF sub-complexes can perform specific tasks and are subjected to different types of regulation. Indeed, increasing evidence is supporting the concept that SWI/SNF composition can vary depending on the cell type and in response to specific cues.

Conclusions and perspectives

The fundamental contribution of chromatin remodelers to the re-configuration of the chromatin architecture during skeletal myogenesis suggests the involvement of SWI/SNF complexes in many transcriptional events, including repression and activation of gene expression, but also regulation of control long-distance genome interactions and the non-coding (nc) epigenome. Indeed, the essential role of Brg1 in the activation of muscle-specific micro-RNAs activated by MyoD has recently been reported by

Acknowledgments

PLP is an Associate Scientist of Telethon Dulbecco Institute (DTI) and of the Sanford Children' Health Center at Sanford/Burnham Medical Institute, and was partially supported by AIRC and NIAMS (RO1AR052779).

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