Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell. 2009 Dec 24;139(7):1290-302. doi: 10.1016/j.cell.2009.12.002.
Polycomb Repressive Complex 2 (PRC2) regulates key developmental genes in embryonic stem (ES) cells and during development. Here we show that Jarid2/Jumonji, a protein enriched in pluripotent cells and a founding member of the Jumonji C (JmjC) domain protein family, is a PRC2 subunit in ES cells. Genome-wide ChIP-seq analyses of Jarid2, Ezh2, and Suz12 binding reveal that Jarid2 and PRC2 occupy the same genomic regions. We further show that Jarid2 promotes PRC2 recruitment to the target genes while inhibiting PRC2 histone methyltransferase activity, suggesting that it acts as a "molecular rheostat" that finely calibrates PRC2 functions at developmental genes. Using Xenopus laevis as a model we demonstrate that Jarid2 knockdown impairs the induction of gastrulation genes in blastula embryos and results in failure of differentiation. Our findings illuminate a mechanism of histone methylation regulation in pluripotent cells and during early cell-fate transitions.
多梳抑制复合物 2 (PRC2) 在胚胎干细胞 (ES 细胞) 和发育过程中调节关键的发育基因。在这里，我们表明，Jarid2/Jumonji 是多能细胞中丰富的一种蛋白质，也是 Jumonji C (JmjC) 结构域蛋白家族的创始成员之一，是 ES 细胞中 PRC2 的一个亚基。Jarid2、Ezh2 和 Suz12 结合的全基因组 ChIP-seq 分析表明，Jarid2 和 PRC2 占据相同的基因组区域。我们进一步表明，Jarid2 促进 PRC2 募集到靶基因，同时抑制 PRC2 组蛋白甲基转移酶活性，这表明它作为一个“分子变阻器”，可以精细地调节发育基因中 PRC2 的功能。我们使用非洲爪蟾作为模型，证明了 Jarid2 敲低会损害囊胚胚胎中原肠胚基因的诱导，并导致分化失败。我们的发现阐明了多能细胞和早期细胞命运转变过程中组蛋白甲基化调控的一种机制。
