Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte
2015; Cell Press; Volume: 12; Issue: 2 Linguagem: Inglês
10.1016/j.celrep.2015.06.013
ISSN2639-1856
AutoresShinsuke Ohba, Xinjun He, Hironori Hojo, Andrew McMahon,
Tópico(s)NF-κB Signaling Pathways
ResumoHighlights•Sox9 has two distinct modes of action on the chondrocyte genome•Sox9 associates indirectly with the TSS domain to engage basal cell activities•Sub-optimal Sox9-dimer binding to multiple enhancers regulates chondrocyte genes•The Sox9 program is similar in mesoderm- and neural-crest-derived chondrocytesSummarySox9 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.Graphical abstract
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