MyoD can induce cell cycle arrest but not muscle differentiation in the presence of dominant negative SWI/SNF chromatin remodeling enzymes

Cell cycle arrest is critical for muscle differentiation, and the two proce sses are closely coordinated but temporally separable. SWI/SNF complexes ar e ATP-dependent chromatin-remodeling enzymes that have been shown to be req uired for muscle differentiation in cell culture and have also been reporte d to be required for Rb-mediated cell cycle arrest. We therefore looked mor e closely at how SWI/SNF enzymes affect the events that occur during MyoD-i nduced myogenesis, namely, cell cycle regulation and muscle-specific gene e xpression, in cells that inducibly express dominant negative versions of Br ahma (BRM) and Brahma-related gene 1 (BRG1), the ATPase subunits of two dis tinct SWI/SNF complexes. Although dominant negative BRM and BRG1 inhibited expression of every muscle-specific regulator and structural gene assayed, there was no effect on MyoD-induced activation of cell cycle regulatory pro teins, and thus, cells arrested normally. In particular, in the presence or absence of dominant negative BRM or BRG1, MyoD was able to activate expres sion of p21, cyclin D3, and Rb, all of which are critical for cell cycle wi thdrawal in the G(1)/G(0) phase of the cell cycle. These findings suggest t hat at least one basis for the distinct mechanisms that regulate cessation of cell proliferation and muscle-specific gene expression during muscle dif ferentiation is that SWI/SNF-mediated chromatin-remodeling enzymes are requ ired only for the latter.