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Cell Rep. 2015 Jul 14;12(2):229-43. doi: 10.1016/j.celrep.2015.06.013. Epub 2015 Jul 2.

Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte.

Author information

1
Department of Bioengineering, the University of Tokyo Graduate School of Engineering, Tokyo 113-0033, Japan. Electronic address: ohba@bioeng.t.u-tokyo.ac.jp.
2
Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, W.M. Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
3
Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, W.M. Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: amcmahon@med.usc.edu.

Abstract

Sox9 encodes an essential transcriptional regulator of chondrocyte specification and differentiation. When Sox9 nuclear activity was compared with markers of chromatin organization and transcriptional activity in primary chondrocytes, we identified two distinct categories of target association. Class I sites cluster around the transcriptional start sites of highly expressed genes with no chondrocyte-specific signature. Here, Sox9 association reflects protein-protein association with basal transcriptional components. Class II sites highlight evolutionarily conserved active enhancers that direct chondrocyte-related gene activity through the direct binding of Sox9 dimer complexes to DNA. Sox9 binds through sites with sub-optimal binding affinity; the number and grouping of enhancers into super-enhancer clusters likely determines the levels of target gene expression. Interestingly, comparison of Sox9 action in distinct chondrocyte lineages points to similar regulatory strategies. In addition to providing insights into Sox family action, our comprehensive identification of the chondrocyte regulatory genome will facilitate the study of skeletal development and human disease.

PMID:
26146088
PMCID:
PMC4504750
DOI:
10.1016/j.celrep.2015.06.013
[Indexed for MEDLINE]
Free PMC Article

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