Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 394, Issue 1, Pages 1-14Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2009.08.057
Keywords
alpha sarcoglycan promoter; dystrophy; skeletal muscle; Sox9; Smad3
Categories
Funding
- Association Francaise contre les Myopathies
- Instituto Mexicano del Seguro Social [2005/1/1/197]
- Direccion General de Asuntos del Personal Academico-UNAM [IN214407]
- Consejo Nacional de Ciencia y Tecnologia (CONACyT) [42653-Q, 58767, 189007, 170087]
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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.
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