Myogenin and the SWI/SNF ATPase Brg1 Maintain Myogenic Gene Expression at Different Stages of Skeletal Myogenesis

Abstract

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 chromatinremodeling 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.

Cdx2 Regulates Gene Expression through Recruitment of Brg1-associated Switch-Sucrose Non-fermentable (SWI-SNF) Chromatin Remodeling Activity

“…Enzyme accessibility assays have been used as a surrogate measure of such activity and have revealed, for example, Brg1-dependent changes in chromatin structure (42,52). Using such an assay, we assessed the consequence of Brg1 or Cdx2 loss of function on the chromatin structure at the Dll1 locus and found that chromatin accessibility was comparably affected by loss of either factor.…”

“…4, C and E). As the ATPase activity of Brg1 is essential for the chromatin remodeling activity of the SWI-SNF complex (20,22,41,42), these observations suggests that the expression of a subset of Cdx target genes depends on Brg1-mediated SWI-SNF remodeling. …”

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

“…MRF competence to promote transcription of muscle genes relies on the interaction with the SWI/SNF chromatinremodeling complex [4,5]. SWI/SNF complex appears to mediate the unique ability of MyoD and Myf5 to remodel the chromatin and activate transcription at previously silent muscle loci [6,7], but is also required for the maintenance of muscle gene expression at later stages of skeletal myogenesis [8]. SWI/SNF complexes are composed of two mutually exclusive enzymatic subunits (the ATPases Brahma (Brm) and Brm-related gene 1 (Brg1)) and a number of structural subunits, collectively referred to as Brg1/Brm-associated factors (BAFs) [9,10].…”

Epigenetics in development

“…Relative histone acetylation state affects factor recruitment and/or structural changes in chromatin. The ATPase Brahma-related gene 1 (Brg1), a member of the epigenetic activators trithorax group, is also a component of the SWI/SNF nucleosome remodeling complex, and regulates neurogenesis, myogenesis, and left-right asymmetry (Seo et al, 2005;Ohkawa et al, 2006;Takeuchi et al, 2007). SWI/SNF causes nucleosomes to slide along DNA, either exposing or occluding regulatory elements that affect the transcriptional status of nearby genes.…”