title: Basic helix-loop-helix transcription factor Twist1 inhibits transactivator function of master chondrogenic regulator Sox9.
abstract: Canonical Wnt signaling strongly inhibits chondrogenesis. Previously, we identified Twist1 as a critical downstream mediator of Wnt in repression of chondrocyte differentiation. However, the mechanistic basis for the antichondrogenic activity of Twist1 has not heretofore been established. Here, we show that Twist1 suppresses cartilage development by directly inhibiting the transcriptional activity of Sox9, the master regulator of chondrogenesis. Twist1, through its carboxyl-terminal Twist-box, binds to the Sox9 high mobility group DNA-binding domain, inhibiting Sox9 transactivation potential. In chondrocyte precursor cells, Twist1, in a Twist-box-dependent manner, inhibits Sox9-dependent activation of chondrocyte marker gene expression by blocking Sox9-enhancer DNA association. These findings identify Twist1 as an inhibitor of Sox9 and further suggest that the balance between Twist1 and Sox9 may determine the earliest steps of chondrogenesis.
authors.affiliation: Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA.
authors.forename: Shoujun
authors.initials: S
authors.lastname: Gu
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Boyer
authors.forename: Michael C
authors.initials: MC
authors.lastname: Naski
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D002356:Cartilage / Q000166:cytology / Q000378:metabolism; D020219:Chondrogenesis / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D009687:Nuclear Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D051153:Wnt Proteins; C067250:Twist1 protein, mouse