MyoD Can Induce Cell Cycle Arrest but Not Muscle Differentiation in the Presence of Dominant Negative SWI/SNF Chromatin Remodeling Enzymes

Abstract

Cell cycle arrest is critical for muscle differentiation, and the two processes are closely coordinated but temporally separable. SWI/SNF complexes are ATP-dependent chromatin-remodeling enzymes that have been shown to be required for muscle differentiation in cell culture and have also been reported to be required for Rb-mediated cell cycle arrest. We therefore looked more closely at how SWI/SNF enzymes affect the events that occur during MyoD-induced myogenesis, namely, cell cycle regulation and muscle-specific gene expression, in cells that inducibly express dominant negative versions of Brahma (BRM) and Brahma-related gene 1 (BRG1), the ATPase subunits of two distinct 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 proteins, and thus, cells arrested normally. In particular, in the presence or absence of dominant negative BRM or BRG1, MyoD was able to activate expression of p21, cyclin D3, and Rb, all of which are critical for cell cycle withdrawal in the G 1 /G 0 phase of the cell cycle. These findings suggest that at least one basis for the distinct mechanisms that regulate cessation of cell proliferation and musclespecific gene expression during muscle differentiation is that SWI/SNF-mediated chromatin-remodeling enzymes are required only for the latter.

MyoD induces apoptosis in the absence of RB function through a p21WAF1-dependent re-localization of cyclin/cdk complexes to the nucleus

“…MyoD is capable of starting the entire differentiation program, even when ectopically expressed in several non-muscle cell types (Davis et al, 1987;Weintraub et al, 1989). Several reports have shown that the tissue-specific and the growth arrest functions of MyoD can be independently regulated (Crescenzi et al, 1990;Sorrentino et al, 1990;de La Serna et al, 2001). The muscle-specific activity of MyoD involves the transcriptional activation of downstream muscle specific regulators, such as myogenin as well as members of the MEF2 family, which act in concert to induce the expression of 'late' muscle structural genes (Naya and Olson, 1999).…”

Interplay between chromatin remodelers and protein arginine methyltransferases

“…Chromatin remodeling assays showed that both forms of BRG1 complex and the BRM complex remodel nucleosomes differently in vitro (Sif et al, 2001). Although, BRG1 and BRM complexes interact with common transcription factors like c-MYC and MYOD, reflecting redundancy in their function, both complexes also exhibit specific interactions that differentially target them to distinct cellular genes (de La Serna et al, 2001;Kadam and Emerson, 2003;Pal et al, 2003;Harikrishnan et al, 2005;Wang et al, 2005). Through its Nterminal region BRG1 interacts specifically with zinc finger containing transcription factors like KLF, Sp1, GATA, and hormone receptors like RAR and RXR; while BRM can interact with CBF-1 and ICD22 ankyrin repeat proteins, which are involved in Notch signaling (Kadam and Emerson, 2003).…”

v-Src inhibits myogenic differentiation by interfering with the regulatory network of muscle-specific transcriptional activators at multiple levels

“…Recent work has indicated that muscle-specific gene expression induced in fibroblasts by all MRFs requires SWI/SNF chromatin remodeling enzymes (de la Serna et al, 2001b;Roy et al, 2002) and that failure to induce muscle gene expression correlates with inhibition of chromatin remodeling in the promoter region of endogenous differentiation-specific loci (de la Serna et al, 2001a). As discussed above, the similarity in the phenotypes imposed on myoblasts by v-Src and by dominant-negative SWI/SNF makes it attractive to speculate that the activity of the SWI/SNF complex is affected by v-Src in transformed myoblasts.…”