SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression.
SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression.
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DOI：
10.1371/journal.pgen.1002356
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发表时间：
2011-11
期刊：
影响因子：
4.5
通讯作者：
Cheah KS
中科院分区：
文献类型：
--
作者：
Leung VY;Gao B;Leung KK;Melhado IG;Wynn SL;Au TY;Dung NW;Lau JY;Mak AC;Chan D;Cheah KS
软骨和软骨内骨发育需要SOX 9活性来调节软骨形成、软骨细胞增殖和向非有丝分裂肥大状态的转变。胶原X基因，Col 10a 1，在肥大的软骨细胞和Sox 9在未成熟的软骨细胞中的限制性和相互表达的缩影的精确时空控制的基因表达的软骨细胞的进展，通过阶段的分化，但这是如何实现的还不清楚。在这里，我们已经确定了一个调控元件上游的Col 10a 1，增强其在体内肥大软骨细胞的表达。在未成熟的软骨细胞中，其中Col 10a 1不表达，SOX 9与该元件内的保守序列相互作用，该元件类似于胶原蛋白II基因Col 2a 1的内含子增强子内的保守序列，Col 2a 1是SOX 9的已知反式激活靶点。通过分析一系列的Col 10a 1报告基因在转基因小鼠中，我们表明，SOX 9结合共识，在这个元素是必需的，以抑制表达的转基因在非肥大软骨细胞。在体外和小鼠肥大软骨细胞中强制异位Sox 9表达导致Col 10a 1下调。GLI转录因子是印度刺猬信号的效应子，靠近Col 10a 1调节元件中的SOX 9位点，GLI转录因子的结合共有基序突变也可抑制非肥大软骨细胞中的转基因表达。GLI 2和GLI 3与Col 10a 1调控元件结合，但不与Col 2a 1的增强子结合。除了Col 10a 1，成对的SOX 9-GLI结合基序存在于几个基因的保守非编码区，这些基因优先在肥大软骨细胞中表达，配对的发生不太可能是偶然的。我们提出了一个监管模式，即直接伴随的正和负的转录控制SOX 9确保软骨细胞分化阶段特异性基因表达。这些相反的转录控制模式之间的歧视SOX 9可以介导的合作与不同的合作伙伴，如GLI因子。软骨分化是软骨内骨形成的关键过程。尽管关于基因表达模式和信号传导途径的信息对这一过程很重要，但目前尚不清楚转录的分化状态特异性是如何控制的。转录因子SOX 9调节软骨细胞分化、增殖和进入肥大，并且在未成熟/增殖的软骨细胞中高度表达。它直接反式激活Col 2a 1，增强该基因在未成熟/增殖软骨细胞中的表达。Col 10a 1基因在Sox 9下调的肥大软骨细胞中特异性表达。在软骨细胞中，特别是在肥大过程中，基因的分化阶段特异性转录是如何控制的？我们发现SOX 9直接抑制生长板的未成熟/增殖软骨细胞中的Col 10a 1表达，因此其表达仅限于肥大软骨细胞。这种伴随的相反的转录控制的歧视可能涉及SOX 9和不同的合作伙伴，如GLI因子（刺猬信号的效应）之间的合作。因此，软骨细胞成熟的SOX 9控制可能与hedgehog信号转导整合。人类S 0X 9中的突变导致骨骼畸形综合征肢端发育不良，这归因于由于未能表达S 0X 9靶基因而导致的软骨形成分化程序的破坏。这一解释应加以修订，以包括通常被SOX 9抑制的基因的不适当表达。
Cartilage and endochondral bone development require SOX9 activity to regulate chondrogenesis, chondrocyte proliferation, and transition to a non-mitotic hypertrophic state. The restricted and reciprocal expression of the collagen X gene, Col10a1, in hypertrophic chondrocytes and Sox9 in immature chondrocytes epitomise the precise spatiotemporal control of gene expression as chondrocytes progress through phases of differentiation, but how this is achieved is not clear. Here, we have identified a regulatory element upstream of Col10a1 that enhances its expression in hypertrophic chondrocytes in vivo. In immature chondrocytes, where Col10a1 is not expressed, SOX9 interacts with a conserved sequence within this element that is analogous to that within the intronic enhancer of the collagen II gene Col2a1, the known transactivation target of SOX9. By analysing a series of Col10a1 reporter genes in transgenic mice, we show that the SOX9 binding consensus in this element is required to repress expression of the transgene in non-hypertrophic chondrocytes. Forced ectopic Sox9 expression in hypertrophic chondrocytes in vitro and in mice resulted in down-regulation of Col10a1. Mutation of a binding consensus motif for GLI transcription factors, which are the effectors of Indian hedgehog signaling, close to the SOX9 site in the Col10a1 regulatory element, also derepressed transgene expression in non-hypertrophic chondrocytes. GLI2 and GLI3 bound to the Col10a1 regulatory element but not to the enhancer of Col2a1. In addition to Col10a1, paired SOX9–GLI binding motifs are present in the conserved non-coding regions of several genes that are preferentially expressed in hypertrophic chondrocytes and the occurrence of pairing is unlikely to be by chance. We propose a regulatory paradigm whereby direct concomitant positive and negative transcriptional control by SOX9 ensures differentiation phase-specific gene expression in chondrocytes. Discrimination between these opposing modes of transcriptional control by SOX9 may be mediated by cooperation with different partners such as GLI factors. Chondrogenic differentiation is a key process in the formation of endochondral bone. Despite the wealth of information about gene expression patterns and signaling pathways important for this process, it is not clear how differentiation state-specificity of transcription is controlled. The transcription factor SOX9 regulates chondrocyte differentiation, proliferation, and entry into hypertrophy and is highly expressed in immature/proliferating chondrocytes. It directly transactivates Col2a1, enhancing this gene's expression in immature/proliferating chondrocytes. The Col10a1 gene is specifically expressed in hypertrophic chondrocytes in which Sox9 is downregulated. How is differentiation phase-specific transcription of genes controlled in chondrocytes, particularly during hypertrophy? We found that SOX9 directly represses Col10a1 expression in immature/proliferating chondrocytes of the growth plate, so that its expression is restricted to hypertrophic chondrocytes. Discrimination of this concomitant opposing transcriptional control may involve cooperation between SOX9 and different partners such as GLI factors (effectors of hedgehog signaling). SOX9 control of chondrocyte maturation therefore may be integrated with hedgehog signaling. Mutations in human SOX9 cause the skeletal malformation syndrome campomelic dysplasia, which is attributed to the disruption of the chondrogenic differentiation program because of failure to express SOX9 target genes. This interpretation should be revised to include inappropriate expression of genes normally repressed by SOX9.
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影响因子：
2.7
作者：
Guo, J;Chung, UI;Kronenberg, HM
通讯作者：
Kronenberg, HM
影响因子：
10.5
作者：
Akiyama, H;Chaboissier, MC;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
11.8
作者：
Arnold, Michael A.;Kim, Yuri;Olson, Eric N.
通讯作者：
Olson, Eric N.
DOI：
10.1111/j.1432-1033.1993.tb17739.x
发表时间：
1993-04-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
KONG, RYC;KWAN, KM;CHEAH, KSE
通讯作者：
CHEAH, KSE
影响因子：
5.3
作者：
Han, Yu;Lefebvre, Veronique
通讯作者：
Lefebvre, Veronique