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

被引:295
作者
Tachibana, Makoto [1 ]
Matsumura, Yasuko [1 ]
Fukuda, Mikiko [1 ]
Kimura, Hiroshi
Shinkai, Yoichi [1 ]
机构
[1] Kyoto Univ, Inst Virus Res, Expt Res Ctr Infect Dis, Sakyo Ku, Kyoto 6068507, Japan
关键词
DNA methylation; G9a; GLP; histone lysine methylation;
D O I
10.1038/emboj.2008.192
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2681 / 2690
页数:10
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