Sox9 represses alpha-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.
Hernández-Hernández
J Manuel
JM
Unidad de Investigación Médica en Genética Humana, Hospital de Pediatría, Centro Médico Nacional Siglo XXI-IMSS, México, D.F., México.
Delgado-Olguín
Paul
P
Aguillón-Huerta
Verónica
V
Furlan-Magaril
Mayra
M
Recillas-Targa
Félix
F
Coral-Vázquez
Ramón M
RM
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D024510:Muscle Development / Q000187:drug effects / Q000235:genetics*; D017570:MyoD Protein / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D049031:Sarcoglycans / Q000235:genetics* / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D017570:MyoD Protein; D012097:Repressor Proteins; D055758:SOX9 Transcription Factor; D049031:Sarcoglycans; D051900:Smad3 Protein; C527933:Sox9 protein, mouse; D016212:Transforming Growth Factor beta