Role of histone methyltransferase G9a in CpG methylation of the Prader-Willi syndrome imprinting center

J Biol Chem. 2003 Apr 25;278(17):14996-5000. doi: 10.1074/jbc.M211753200. Epub 2003 Feb 13.


Imprinted genes in mammals are often located in clusters whose imprinting is subject to long range regulation by cis-acting sequences known as imprinting centers (ICs). The mechanisms by which these ICs exert their effects is unknown. The Prader-Willi syndrome IC (PWS-IC) on human chromosome 15 and mouse chromosome 7 regulates imprinted gene expression bidirectionally within an approximately 2-megabase region and shows CpG methylation and histone H3 Lys-9 methylation in somatic cells specific for the maternal chromosome. Here we show that histone H3 Lys-9 methylation of the PWS-IC is reduced in mouse embryonic stem (ES) cells lacking the G9a histone H3 Lys-9/Lys-27 methyltransferase and that maintenance of CpG methylation of the PWS-IC in mouse ES cells requires the function of G9a. We show by RNA fluorescence in situ hybridization (FISH) that expression of Snrpn, an imprinted gene regulated by the PWS-IC, is biallelic in G9a -/- ES cells, indicating loss of imprinting. By contrast, Dnmt1 -/- ES cells lack CpG methylation of the PWS-IC but have normal levels of H3 Lys-9 methylation of the PWS-IC and show normal monoallelic Snrpn expression. Our results demonstrate a role for histone methylation in the maintenance of parent-specific CpG methylation of imprinting regulatory regions and suggest a possible role of histone methylation in establishment of these CpG methylation patterns.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens
  • Cell Line
  • DNA Methylation*
  • Dinucleoside Phosphates / metabolism*
  • Embryo, Mammalian
  • Genomic Imprinting*
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase*
  • Histones / metabolism
  • In Situ Hybridization, Fluorescence
  • Methyltransferases / physiology*
  • Mice
  • Prader-Willi Syndrome / genetics*
  • Protein Methyltransferases
  • Repressor Proteins / physiology
  • Ribonucleoproteins, Small Nuclear / metabolism
  • Stem Cells / metabolism
  • Transgenes
  • snRNP Core Proteins


  • Autoantigens
  • Dinucleoside Phosphates
  • Histones
  • Repressor Proteins
  • Ribonucleoproteins, Small Nuclear
  • SNRPN protein, human
  • snRNP Core Proteins
  • cytidylyl-3'-5'-guanosine
  • Histone Methyltransferases
  • Methyltransferases
  • Protein Methyltransferases
  • Histone-Lysine N-Methyltransferase