title: Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte.
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.
authors.affiliation: Department of Bioengineering, the University of Tokyo Graduate School of Engineering, Tokyo 113-0033, Japan. Electronic address: ohba@bioeng.t.u-tokyo.ac.jp.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ohba
authors.affiliation: 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.
authors.forename: Xinjun
authors.initials: X
authors.lastname: He
authors.affiliation: 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.
authors.forename: Hironori
authors.initials: H
authors.lastname: Hojo
authors.affiliation: 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.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015533:Transcriptional Activation
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D055758:SOX9 Transcription Factor