Sox9 Represses α-Sarcoglycan Gene Expression in Early Myogenic Differentiation

Alpha sarcoglycan (alpha-SG) is highly expressed in differentiated striated muscle, and its disruption causes limb-girdle muscular dystrophy. Accordingly, the myogenic master regulator MyoD finely modulates its expression. However, the mechanisms preventing alpha-SG gene expression at early stages of myogenic differentiation remain unknown. In this study, we uncovered Sox9, which was not previously known to directly bind muscle gene promoters, as a negative regulator of alpha-SG gene expression. Reporter gene and chromatin immunoprecipitation assays revealed three functional Sox-binding sites that mediate alpha-SG promoter activity repression during early myogenic differentiation. In addition, we show that Sox9-mediated inhibition of alpha-SG gene expression is independent of MyoD. Moreover, we provide evidence suggesting that Smad3 enhances the repressive activity of Sox9 over alpha-SG gene expression in a transforming growth factor-beta-dependent manner. On the basis of these results, we propose that Sox9 and Smad3 are responsible for preventing precocious activation of alpha-SG gene expression during myogenic differentiation. (C) 2009 Elsevier Ltd. All rights reserved.