Brg1 Controls the Expression of Pax7 to Promote Viability and Proliferation of Mouse Primary Myoblasts

Abstract

Brg1 (Brahma-related gene 1) is a catalytic component of the evolutionarily conserved mammalian SWI/SNF ATP-dependent chromatin remodeling enzymes that disrupt histone-DNA contacts on the nucleosome. While the requirement for the SWI/SNF enzymes in cell differentiation has been extensively studied, its role in precursor cell proliferation and survival is not as well defined. Muscle satellite cells constitute the stem cell pool that sustains and regenerates myofibers in adult skeletal muscle. Here we show that deletion of Brg1 in primary mouse myoblasts derived from muscle satellite cells cultured ex vivo leads to a cell proliferation defect and apoptosis. We determined that Brg1 regulates cell proliferation and survival by controlling chromatin remodeling and activating transcription at the Pax7 promoter, which is expressed during somite development and is required for controlling viability of the satellite cell population. Reintroduction of catalytically active Brg1 or of Pax7 into Brg1-deficient satellite cells rescued the apoptotic phenotype and restored proliferation. These data demonstrate that Brg1 functions as a positive regulator for cellular proliferation and survival of primary myoblasts. Therefore the regulation of gene expression through Brg1-mediated chromatin remodeling is critical not just for skeletal muscle differentiation but for maintaining the myoblast population as well.

Induction of CCAAT/Enhancer-Binding Protein β Expression With the Phosphodiesterase Inhibitor Isobutylmethylxanthine Improves Myoblast Engraftment Into Dystrophic Muscle

“…Indeed, IBMX-treated donor cells were less apoptotic than vehicletreated cells after transplantation into injured muscle, and this effect was dependent on C/EBPb expression. Recently, Brg1, a component of the Swi/Snf chromatin remodeling complex, was shown to be required for maintaining viability in myoblasts through regulation of Pax7 expression [51]. Pax7 is required for maintenance of the satellite cell pool as deletion of Pax7 triggers cell cycle abnormalities characterized by an extended G2/M phase, and a progressive loss of muscle precursors to cell death [39].…”

SWI/SNF-directed stem cell lineage specification: dynamic composition regulates specific stages of skeletal myogenesis

“…Since STAT3 activates MyoD expression in MuSCs [51], it is possible that the mechanism by which Brg1/SWI/SNF-mediated chromatin remodeling at STAT3 binding sites can be extended to the early commitment of MuSCs to the myogenic lineage. On the other hand, Brg1 is required for maintaining Pax7 expression that supports proliferation and survival of the expanding population of MuSCs that has broken quiescence [52]. Interestingly, it appears that the SWI/SNF complex implicated in establishing the landscape conducive for MuSC quiescence relies on the activity of the other ATPase and Brm, which has the unique ability to interact with critical components of the notch signaling [53]—an essential pathway for keeping MuSC quiescence [54–56].…”

PAX7mutation in a syndrome of failure to thrive, hypotonia, and global neurodevelopmental delay

“…PAX7 has also been shown to act in regulating function and proliferation of muscle progenitor cells, and plays a role in muscle regeneration. It is expressed in fast proliferating embryonal myoblasts, yet also in quiescent satellite cells, the resident stem cell pool of skeletal muscle that are quiescent in adults until activated to generate proliferating myoblasts, regenerating myofibers in adults (Padilla‐Benavides, Nasipak, & Imbalzano, ). In line with this expression pattern, PAX7 is involved in determination of the myogenic cell lineage during the development of vertebrates, yet is also required in the postnatal period for the specification of muscle satellite cells (Padilla‐Benavides et al., ; Vorobyov & Horst, ).…”