L-Sox5 and Sox6 proteins enhance chondrogenic miR-140 microRNA expression by strengthening dimeric Sox9 activity

J Biol Chem. 2012 Jun 22;287(26):22206-15. doi: 10.1074/jbc.M112.343194. Epub 2012 Apr 30.


Sox9 plays a critical role in early chondrocyte initiation and promotion as well as repression of later maturation. Fellow Sox family members L-Sox5 and Sox6 also function as regulators of cartilage development by boosting Sox9 activation of chondrocyte-specific genes such as Col2a1 and Agc1; however, the regulatory mechanism and other target genes are largely unknown. MicroRNAs are a class of short, non-coding RNAs that act as negative regulators of gene expression by promoting target mRNA degradation and/or repressing translation. Analysis of genetically modified mice identified miR-140 as a cartilage-specific microRNA that could be a critical regulator of cartilage development and homeostasis. Recent findings suggest Sox9 promotes miR-140 expression, although the detailed mechanisms are not fully understood. In this study we demonstrate that the proximal upstream region of pri-miR-140 has chondrogenic promoter activity in vivo. We found an L-Sox5/Sox6/Sox9 (Sox trio) response element and detailed binding site in the promoter region. Furthermore, detailed analysis suggests the DNA binding and/or transactivation ability of Sox9 as a homodimer is boosted by L-Sox5 and Sox6. These findings provide new insight into cartilage-specific gene regulation by the Sox trio.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cartilage / metabolism*
  • Chondrocytes / cytology
  • Chromatin Immunoprecipitation
  • Dimerization
  • Gene Expression Regulation
  • HEK293 Cells
  • High Mobility Group Proteins / genetics
  • Humans
  • Mice
  • Mice, Knockout
  • MicroRNAs / metabolism*
  • Polymerase Chain Reaction / methods
  • Protein Isoforms
  • SOX9 Transcription Factor / metabolism*
  • SOXD Transcription Factors / metabolism*
  • Transcriptional Activation
  • Transgenes


  • High Mobility Group Proteins
  • MIRN140 microRNA, mouse
  • MicroRNAs
  • Mirn140 microRNA, human
  • Protein Isoforms
  • SOX5 protein, human
  • SOX6 protein, human
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • SOXD Transcription Factors
  • Sox5 protein, mouse
  • Sox6 protein, mouse
  • Sox9 protein, mouse