Role of hPHF1 in H3K27 methylation and Hox gene silencing
Role of hPHF1 in H3K27 methylation and Hox gene silencing
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DOI：
10.1128/mcb.01589-07
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发表时间：
2008-03-01
影响因子：
5.3
通讯作者：
Zhang, Yi
中科院分区：
文献类型：
--
作者：
Cao, Ru;Wang, Hengbin;Zhang, Yi
Polycomb group（PcG）蛋白是维持同源异型基因和其他重要发育调节因子的沉默状态所必需的。PcG蛋白的沉默功能与其内在的组蛋白修饰酶活性有关。EED-EZH 2复合物包含核心亚基EZH 2、EED、SUZ 12和RbAp 48，其功能为组蛋白H3 K27特异性甲基转移酶。在这里，我们描述了一个相关的EED-EZH 2蛋白复合物的鉴定和表征，该复合物与之前的复合物的区别在于存在另一种PcG蛋白，hPHF 1。与hPHF 1在体外刺激核心EED-EZH 2复合物的酶活性的能力一致，在NIH 3 T3细胞和小鼠雄性生殖细胞系GC 1 spg细胞中操作mPcl 1（hPHF 1的小鼠对应物）导致H3 K27 me 2和H3 K27 me 3水平以及Hox基因表达的总体改变。小干扰RNA介导的mPcl 1敲低影响Eed-Ezh 2复合物与某些Hox基因（如HoxA 10）的关联，以及Hox基因表达伴随相应启动子H3 K27 me 2水平的改变。因此，我们的研究结果揭示了hPHF 1作为一种新的EED-EZH 2复合物的组成部分，并证明了其在H3 K27甲基化和Hox基因沉默中的重要作用。
Polycomb group (PcG) proteins are required for maintaining the silent state of the homeotic genes and other important developmental regulators. The silencing function of the PcG proteins has been linked to their intrinsic histone modifying enzymatic activities. The EED-EZH2 complex, containing the core subunits EZH2, EED, SUZ12, and RbAp48, functions as a histone H3K27-specific methyltransferase. Here we describe the identification and characterization of a related EED-EZH2 protein complex which is distinguished from the previous complex by the presence of another PcG protein, hPHF1. Consistent with the ability of hPHF1 to stimulate the enzymatic activity of the core EED-EZH2 complex in vitro, manipulation of mPcl1, the mouse counterpart of hPHF1, in NIH 3T3 cells and cells of the mouse male germ cell line GC1spg results in global alteration of H3K27me2 and H3K27me3 levels and Hox gene expression. Small interfering RNA-mediated knockdown of mPcl1 affects association of the Eed-Ezh2 complex with certain Hox genes, such as HoxA10, as well as Hox gene expression concomitant with an alteration on the H3K27me2 levels of the corresponding promoters. Therefore, our results reveal hPHF1 as a component of a novel EED-EZH2 complex and demonstrate its important role in H3K27 methylation and Hox gene silencing.