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

EMBO J. 2008 Oct 22;27(20):2681-90. doi: 10.1038/emboj.2008.192. Epub 2008 Sep 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalysis
  • CpG Islands
  • DNA Methylation*
  • Embryonic Stem Cells / metabolism
  • Gene Expression Regulation*
  • Gene Silencing*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histone-Lysine N-Methyltransferase / physiology*
  • Histones / chemistry*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Mutation
  • Transcription, Genetic*


  • Histones
  • G9a protein, mouse
  • Histone-Lysine N-Methyltransferase