Signal-dependent incorporation of MyoD-BAF60c into Brg1-based SWI/SNF chromatin-remodelling complex

Abstract

Tissue-specific transcriptional activators initiate differentiation towards specialized cell types by inducing chromatin modifications permissive for transcription at target loci, through the recruitment of SWItch/Sucrose NonFermentable (SWI/SNF) chromatin-remodelling complex. However, the molecular mechanism that regulates SWI/ SNF nuclear distribution in response to differentiation signals is unknown. We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/ SNF core to muscle genes. BAF60c phosphorylation on a conserved threonine by differentiation-activated p38a kinase is the signal that promotes incorporation of MyoD-BAF60c into a Brg1-based SWI/SNF complex, which remodels the chromatin and activates transcription of MyoD-target genes. Our data support an unprecedented two-step model by which pre-assembled BAF60c-MyoD complex directs recruitment of SWI/SNF to muscle loci in response to differentiation cues.

Brahma is required for cell cycle arrest and late muscle gene expression during skeletal myogenesis

“…More recently, Imbalzano's laboratory has exploited RNAi to knock down the levels of Brg1, showing that Brg1 controls muscle genes and muscle-specific microRNAs (myomiRs) expression in skeletal muscle cells [24]. Likewise, we have shown by RNAi-mediated knockdown the essential role of Brg1/BAF60C-based SWI/SNF complex in the activation of the myogenic program in C2C12 muscle cells [25]. Still, the specific function of Brm in skeletal myogenesis remains obscure to date.…”

“…Previous studies showed that Brg1 is required for the activation of myogenin expression during skeletal myogenesis [6,22,25]. Genetic and molecular studies have established that myogenin expression at early stages of skeletal myogenesis establishes a key restriction point for the activation of the differentiation program in skeletal myoblasts [37][38][39].…”

SWP73 Subunits of Arabidopsis SWI/SNF Chromatin Remodeling Complexes Play Distinct Roles in Leaf and Flower Development

“…In mammals, different alternative variants of SWP73/BAF60 SWI/SNF subunits have been uncovered to play major roles in tissue-specific regulation of gene expression (Takeuchi and Bruneau, 2009;Forcales et al, 2012). Detailed functional characterization of the two Arabidopsis SWP73 homologs has been so far handicapped due to lack of suitable null mutations.…”

“…The BAF60c-MyoD complex is identified in chromatin regions of MyoD target genes, and genetic studies indicate that BAF60c enables MyoD to access its target sites in repressive chromatin of undifferentiated myoblasts. Next, likely an extracellular differentiation stimulus triggers the recruitment of catalytic and core subunits of SWI/ SNF to the BAF60c-MyoD "pioneer complex," stimulating nucleosome remodeling (Albini et al, 2013), which is, in turn, dependent on phosphorylation of the BAF60c Thr-229 residue by the differentiation-activated p38a kinase (Forcales et al, 2012).…”

HDAC inhibitors for muscular dystrophies: progress and prospects

“…[13,14] In particular, studies from Saccone et al have identified an HDAC-regulated network that controls the functional phenotype of FAPs from dystrophic muscles. Treatment with HDACi promotes the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60c [15] and upregulates three myogenic microRNA involved into muscle differentiation (myomiRs; miR-1.2, miR-133 and miR-206) in FAPs. MyomiRs in turn target two alternative BAF60 variants -BAF60 A and B -that when incorporated into the Switch/Sucrose NonFermentable (SWI/SNF) chromatin-remodeling complex would otherwise promote the activation of the fibro-adipogenic program.…”