Shirato Haruki, Ogawa Satoko, Nakajima Kuniko, Inagawa Masayo, Kojima Mizuyo, Tachibana Makoto, Shinkai Yoichi, Takeuchi Takashi
Mitsubishi Kagaku Institute of Life Sciences, Kyoto, Japan.
J Biol Chem. 2009 Jan 9;284(2):733-9. doi: 10.1074/jbc.M804994200. Epub 2008 Nov 14.
Covalent modifications of histone tails have critical roles in regulating gene expression. Previously, we identified the jumonji (jmj, Jarid2) gene, the jmjC domain, and a Jmj family. Recently, many Jmj family proteins have been shown to be histone demethylases, and jmjC is the catalytic domain. However, Jmj does not have histone demethylase activity because the jmjC domain lacks conserved residues for binding to cofactors. Independently of these studies, we previously showed that Jmj binds to the cyclin D1 promoter and represses the transcription of cyclin D1. Here, we show the mechanisms by which Jmj represses the transcription of cyclin D1. We found that a protein complex of Jmj had histone methyltransferase activity toward histone H3 lysine 9 (H3-K9). We also found that Jmj bound to the H3-K9 methyltransferases G9a and GLP. Expression of Jmj recruited G9a and GLP to the cyclin D1 promoter and increased H3-K9 methylation. Inactivation of both G9a and GLP, but not of only G9a, inhibited the methylation of H3-K9 in the cyclin D1 promoter and repression of cyclin D1 expression by Jmj. These results suggest that Jmj methylates H3-K9 and represses cyclin D1 expression through G9a and GLP, and that Jmj family proteins can regulate gene expression by not only histone demethylation but also other histone modification.
组蛋白尾部的共价修饰在调控基因表达中起关键作用。此前，我们鉴定出了jumonji（jmj，Jarid2）基因、jmjC结构域以及一个Jmj家族。最近，许多Jmj家族蛋白已被证明是组蛋白去甲基化酶，且jmjC是催化结构域。然而，Jmj不具有组蛋白去甲基化酶活性，因为jmjC结构域缺乏与辅因子结合的保守残基。独立于这些研究之外，我们之前表明Jmj与细胞周期蛋白D1启动子结合并抑制细胞周期蛋白D1的转录。在此，我们展示了Jmj抑制细胞周期蛋白D1转录的机制。我们发现Jmj的一个蛋白复合物对组蛋白H3赖氨酸9（H3-K9）具有组蛋白甲基转移酶活性。我们还发现Jmj与H3-K9甲基转移酶G9a和GLP结合。Jmj的表达将G9a和GLP募集到细胞周期蛋白D1启动子并增加H3-K9甲基化。G9a和GLP两者失活，但仅G9a失活则不会，抑制了细胞周期蛋白D1启动子中H3-K9的甲基化以及Jmj对细胞周期蛋白D1表达的抑制。这些结果表明，Jmj使H3-K9甲基化并通过G9a和GLP抑制细胞周期蛋白D1的表达，并且Jmj家族蛋白不仅可以通过组蛋白去甲基化，还可以通过其他组蛋白修饰来调控基因表达。
