G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription

G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription
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DOI：
10.1038/emboj.2008.192
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发表时间：
2008-10-22
期刊：
EMBO JOURNAL
影响因子：
11.4
通讯作者：
Shinkai, Yoichi
Shinkai, Yoichi
中科院分区：
生物学1区
文献类型：
--
作者：
Tachibana, Makoto;Matsumura, Yasuko;Shinkai, Yoichi

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DNA 甲基化和组蛋白 H3 (H3K9) 的赖氨酸 9 是转录沉默的高度保守的表观遗传标记。尽管 H3K9 甲基化在丝状真菌和植物中指导 DNA 甲基化，但该途径尚未在哺乳动物中得到证实。 G9a 和 GLP/Eu-HMTase1 是两种相关的哺乳动物赖氨酸甲基转移酶，G9a/GLP 异聚复合物调节常染色质的 H3K9 甲基化。为了阐明 G9a/GLP 介导的 H3K9 甲基化在 DNA 甲基化和转录沉默调节中的功能，我们表征了表达 G9a 和/或 GLP 催化失活突变体的 ES 细胞。有趣的是，在表达 G9a 突变体/GLP 复合物的 ES 细胞中，G9a 突变体/GLP 复合物不能挽救全局 H3K9 甲基化，G9a/GLP 靶基因保持沉默。这些基因启动子区的 CpG 位点在此类突变 ES 细胞中高甲基化，但在 G9a-或 GLP-KO ES 细胞中低甲基化。用 DNA 甲基转移酶抑制剂处理可重新激活表达催化失活 G9a/GLP 蛋白（但不表达野生型蛋白）的 ES 细胞中的这些 G9a/GLP 靶基因。这是 G9a/GLP 通过独立诱导 H3K9 和 DNA 甲基化来抑制转录的第一个明确证据。
Methylation of DNA and lysine 9 of histone H3 (H3K9) are well-conserved epigenetic marks for transcriptional silencing. Although H3K9 methylation directs DNA methylation in filamentous fungi and plants, this pathway has not been corroborated in mammals. G9a and GLP/Eu-HMTase1 are two-related mammalian lysine methyltransferases and a G9a/GLP heteromeric complex regulates H3K9 methylation of euchromatin. To elucidate the function of G9a/GLP-mediated H3K9 methylation in the regulation of DNA methylation and transcriptional silencing, we characterized ES cells expressing catalytically inactive mutants of G9a and/or GLP. Interestingly, in ES cells expressing a G9a-mutant/GLP complex that does not rescue global H3K9 methylation, G9a/GLP-target genes remain silent. The CpG sites of the promoter regions of these genes were hypermethylated in such mutant ES cells, but hypomethylated in G9a-or GLP-KO ES cells. Treatment with a DNA methyltransferase inhibitor reactivates these G9a/GLP-target genes in ES cells expressing catalytically inactive G9a/GLP proteins, but not the wild-type proteins. This is the first clear evidence that G9a/GLP suppresses transcription by independently inducing both H3K9 and DNA methylation.