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SOX9 directly regulates the type-II collagen gene
D M Bell1, K K Leung, S C Wheatley
1Department of Biochemistry, University of Hong Kong, Hong Kong.
Nature Genetics
|June 1, 1997
Summary
SOX9 protein directly regulates type-II collagen (COL2A1) gene expression in chondrocytes. This finding links SOX9 regulation of COL2A1 to skeletal abnormalities in campomelic dysplasia.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Mutations in SOX9 cause campomelic dysplasia (CD), a disorder featuring skeletal malformations and XY sex reversal.
- SOX9 is co-expressed with type-II collagen (COL2A1) during chondrogenesis, suggesting COL2A1 is a regulatory target.
Purpose of the Study:
- To investigate the direct regulatory relationship between SOX9 and the COL2A1 gene.
- To determine if SOX9 binding to COL2A1 regulatory elements is crucial for chondrocyte-specific expression.
Main Methods:
- ChIP assays to detect SOX9 binding to human COL2A1 first intron sequences.
- Analysis of COL2A1-lacZ reporter gene expression in transgenic mice with mutations in SOX9 binding sites.
- Assessing the effect of ectopic SOX9 expression on reporter gene and endogenous Col2a1 expression in transgenic mice.
Main Results:
- SOX9 protein specifically binds to conserved sequences within the first intron of the human COL2A1 gene.
- Mutating these SOX9 binding sites abolished both SOX9 binding and chondrocyte-specific reporter gene expression.
- Ectopic SOX9 expression activated both a COL2A1 reporter gene and the endogenous Col2a1 gene.
Conclusions:
- COL2A1 expression is directly regulated by SOX9 protein in vivo.
- Abnormal COL2A1 regulation due to SOX9 dysfunction likely contributes to the skeletal defects observed in campomelic dysplasia.