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

Abstract

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.

• Authors: Zhenghan Xin, Makoto Tachibana, Michele Guggiari, Edith Heard, Yoichi Shinkai, Joseph Wagstaff
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 17 Pg. 14996-5000 (Apr 25 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12586828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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