Regulation of the osteoblast-specific transcription factor Osterix by NO66, a Jumonji family histone demethylase.
Regulation of the osteoblast-specific transcription factor Osterix by NO66, a Jumonji family histone demethylase.
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DOI：
10.1038/emboj.2009.332
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发表时间：
2010-01-06
期刊：
影响因子：
11.4
通讯作者：
de Crombrugghe, Benoit
中科院分区：
文献类型：
--
作者：
Sinha, Krishna M.;Yasuda, Hideyo;Coombes, Madelene M.;Dent, Sharon Y. R.;de Crombrugghe, Benoit
Osterix（Osx）是成骨细胞分化和骨形成所需的成骨细胞特异性转录因子。Osx基因缺失小鼠发育出正常的软骨骨骼，但不能形成骨，也不能表达成骨细胞特异性标记基因。为了更好地了解Osx对转录调控的控制，我们使用蛋白质组学方法鉴定了Osx相互作用蛋白。在这里，我们报告了一种包含Jumonji C（JmjC）结构域的蛋白质，称为NO 66，直接与Osx相互作用并抑制Osx介导的启动子激活。NO 66基因的敲低可促进成骨细胞的分化和矿化，并显著刺激Osx靶基因的表达。NO 66具有JmjC依赖的组蛋白去甲基化酶活性，其在体外和体内对H3 K4 me和H3 K36 me都具有特异性，并且这种活性对于成骨细胞特异性启动子的调节是必需的。在BMP-2诱导的前成骨细胞分化过程中，NO 66占用率降低与Osx靶启动子Osx占用率增加相关。我们的研究结果表明，NO 66和Osx之间的相互作用调节Osx靶基因在成骨细胞通过调节组蛋白甲基化状态。
Osterix (Osx) is an osteoblast-specific transcription factor required for osteoblast differentiation and bone formation. Osx null mice develop a normal cartilage skeleton but fail to form bone and to express osteoblast-specific marker genes. To better understand the control of transcriptional regulation by Osx, we identified Osx-interacting proteins using proteomics approaches. Here, we report that a Jumonji C (JmjC)-domain containing protein, called NO66, directly interacts with Osx and inhibits Osx-mediated promoter activation. The knockdown of NO66 in preosteoblast cells triggered accelerated osteoblast differentiation and mineralization, and markedly stimulated the expression of Osx target genes. A JmjC-dependent histone demethylase activity was exhibited by NO66, which was specific for both H3K4me and H3K36me in vitro and in vivo, and this activity was needed for the regulation of osteoblast-specific promoters. During BMP-2-induced differentiation of preosteoblasts, decreased NO66 occupancy correlates with increased Osx occupancy at Osx-target promoters. Our results indicate that interactions between NO66 and Osx regulate Osx-target genes in osteoblasts by modulating histone methylation states.
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