Howard Hughes Medical Institute, New York University Medical School, New York, New York 10016, USA.
Genes Dev. 2010 Feb 15;24(4):368-80. doi: 10.1101/gad.1886410. Epub 2010 Feb 1.
The Polycomb group proteins foster gene repression profiles required for proper development and unimpaired adulthood, and comprise the components of the Polycomb-Repressive Complex 2 (PRC2) including the histone H3 Lys 27 (H3K27) methyltransferase Ezh2. How mammalian PRC2 accesses chromatin is unclear. We found that Jarid2 associates with PRC2 and stimulates its enzymatic activity in vitro. Jarid2 contains a Jumonji C domain, but is devoid of detectable histone demethylase activity. Instead, its artificial recruitment to a promoter in vivo resulted in corecruitment of PRC2 with resultant increased levels of di- and trimethylation of H3K27 (H3K27me2/3). Jarid2 colocalizes with Ezh2 and MTF2, a homolog of Drosophila Pcl, at endogenous genes in embryonic stem (ES) cells. Jarid2 can bind DNA and its recruitment in ES cells is interdependent with that of PRC2, as Jarid2 knockdown reduced PRC2 at its target promoters, and ES cells devoid of the PRC2 component EED are deficient in Jarid2 promoter access. In addition to the well-documented defects in embryonic viability upon down-regulation of Jarid2, ES cell differentiation is impaired, as is Oct4 silencing.
多梳抑制复合物蛋白促进了适当发育和未受损成年所需的基因抑制谱，并且包含多梳抑制复合物 2（PRC2）的组成部分，包括组蛋白 H3 赖氨酸 27（H3K27）甲基转移酶 Ezh2。然而，哺乳动物 PRC2 如何接近染色质尚不清楚。我们发现，Jarid2 与 PRC2 相关，并在体外刺激其酶活性。Jarid2 含有一个 Jumonji C 结构域，但缺乏可检测的组蛋白去甲基化酶活性。相反，其在体内被人为募集到启动子上，导致 PRC2 的核心募集，从而导致 H3K27（H3K27me2/3）的二甲基化和三甲基化水平增加。Jarid2 与 Ezh2 和 MTF2（果蝇 Pcl 的同源物）在胚胎干细胞（ES 细胞）中的内源性基因共定位。Jarid2 可以结合 DNA，并且其在 ES 细胞中的募集与 PRC2 的募集是相互依赖的，因为 Jarid2 的敲低降低了其靶启动子上的 PRC2，并且缺乏 PRC2 成分 EED 的 ES 细胞缺乏对 Jarid2 启动子的访问。除了下调 Jarid2 后胚胎活力的明显缺陷外，ES 细胞分化受损，Oct4 沉默也受损。
