Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte.
Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte.
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DOI：
10.1016/j.celrep.2015.06.013
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发表时间：
2015-07-14
期刊：
影响因子：
8.8
通讯作者：
McMahon AP
中科院分区：
文献类型：
--
作者：
Ohba S;He X;Hojo H;McMahon AP
Sox 9编码软骨细胞特化和分化的重要转录调节因子。当Sox 9核活性与原代软骨细胞中染色质组织和转录活性的标志物进行比较时，我们确定了两种不同的靶点关联。I类位点聚集在没有软骨细胞特异性标记的高表达基因的转录起始位点周围。在这里，Sox 9协会反映了蛋白质-蛋白质协会与基础转录组件。II类位点突出了进化上保守的活性增强子，其通过Sox 9二聚体复合物与DNA的直接结合来指导软骨细胞相关的基因活性。Sox 9通过具有次优结合亲和力的位点结合;增强子的数量和分组成超级增强子簇可能决定靶基因表达的水平。有趣的是，Sox 9在不同软骨细胞谱系中的作用的比较指向类似的调控策略。除了提供对Sox家族作用的深入了解外，我们对软骨细胞调控基因组的全面鉴定将有助于骨骼发育和人类疾病的研究。
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 directing chondrocyte-related gene activity through 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 study of skeletal development and human disease.