JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells
JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells
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DOI：
10.1038/nature08788
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发表时间：
2010-03-11
期刊：
影响因子：
64.8
通讯作者：
Helin, Kristian
中科院分区：
文献类型：
--
作者：
Pasini, Diego;Cloos, Paul A. C.;Helin, Kristian
多梳蛋白家族（PcG）在控制对细胞命运的发育、分化和维持至关重要的基因表达方面具有重要作用（1,2）。多梳抑制复合物2（PRC2）被认为通过催化组蛋白H3上赖氨酸27的二甲基化和三甲基化（H3K27me2/3）来调节转录抑制（2）。目前，尚不清楚PcG蛋白是如何被招募到哺乳动物细胞中的靶启动子上的（3）。在此我们表明，PRC2与含Jumonji和ARID结构域的蛋白JARID2形成稳定的复合物（参考文献4）。通过全基因组定位分析，我们表明JARID2与超过90%先前定位的PcG靶基因结合。值得注意的是，我们表明JARID2足以将PcG蛋白招募到异源启动子上，并且抑制JARID2的表达会导致PcG结合的大量丧失以及靶基因上H3K27me3水平的降低。与PcG蛋白在早期发育中的重要作用一致（5 - 8），我们证明JARID2是小鼠胚胎干细胞分化所必需的。因此，这些结果表明JARID2对于PcG蛋白与靶基因的结合是必不可少的，并且与此一致的是，对于胚胎干细胞的正常分化和正常发育也是必不可少的。
The Polycomb group (PcG) proteins have an important role in controlling the expression of genes essential for development, differentiation and maintenance of cell fates(1,2). The Polycomb repressive complex 2 (PRC2) is believed to regulate transcriptional repression by catalysing the di- and tri-methylation of lysine 27 on histone H3 (H3K27me2/3)(2). At present, it is unknown how the PcG proteins are recruited to their target promoters in mammalian cells(3). Here we show that PRC2 forms a stable complex with the Jumonji- and ARID-domain-containing protein, JARID2 (ref. 4). Using genome-wide location analysis, we show that JARID2 binds to more than 90% of previously mapped PcG target genes. Notably, we show that JARID2 is sufficient to recruit PcG proteins to a heterologous promoter, and that inhibition of JARID2 expression leads to a major loss of PcG binding and to a reduction of H3K27me3 levels on target genes. Consistent with an essential role for PcG proteins in early development(5-8), we demonstrate that JARID2 is required for the differentiation of mouse embryonic stem cells. Thus, these results demonstrate that JARID2 is essential for the binding of PcG proteins to target genes and, consistent with this, for the proper differentiation of embryonic stem cells and normal development.