Abstract 984: Myocardin is a Potent Repressor of Skeletal Muscle Differentiation
Myogenic regulatory factors (MRFs), in conjunction with MEF2 factors, coordinately orchestrate a skeletal muscle program of differentiation. Myocardin (MYOCD) is an SRF-associated coactivator that powerfully activates a number of smooth muscle contractile genes across different non-muscle cell types. Here, we report that ectopic expression of MYOCD blocks the skeletal muscle program of differentiation through transcriptional repression of the MRF, myogenin (MYOG). Skeletal muscle cells stably expressing MYOCD are completely refractory to myotube formation. The inhibition in MYOG expression and skeletal muscle differentiation appears to be SRF-independent. In cultured SMC with a propensity for transdifferentiating into skeletal muscle, siRNA to MYOCD enhances MYOG expression. Deletion mapping studies reveal multiple functional domains in MYOCD that confer transcriptional suppression of MYOG promoter activity. GST pull down, mammalian two- and three-hybrid, as well as co-immunoprecipitation assays suggest that MYOCD disrupts MEF2-MyoD interactions as well as MyoD DNA binding. Moreover, we provide evidence for MYOCD-mediated recruitment of HDAC5 to the MYOG promoter. Our results indicate that the MyoD program of skeletal muscle differentiation is subservient to MYOCD-mediated SMC differentiation and that MYOCD acts as a fate switch during embryonic and postnatal muscle transdifferentiation.