Transcriptional repressive H3K9 and H3K27 methylations contribute to DNMT1-mediated DNA methylation recovery.

Abstract

DNA methylation and histone modifications are two major epigenetic events regulating gene expression and chromatin structure, and their alterations are linked to human carcinogenesis. DNA methylation plays an important role in tumor suppressor gene inactivation, and can be revised by DNA methylation inhibitors. The reversible nature of DNA methylation forms the basis of epigenetic cancer therapy. However, it has been reported that DNA re-methylation and gene re-silencing could occur after removal of demethylation treatment and this may significantly hamper the therapeutic value of DNA methylation inhibitors. In this study we have provided detailed evidence demonstrating that mammalian cells possess a bona fide DNA methylation recovery system. We have also shown that DNA methylation recovery was mediated by the major human DNA methyltransferase, DNMT1. In addition, we found that H3K9-tri-methylation and H3K27-tri-methylation were closely associated with this DNA methylation recovery. These persistent transcriptional repressive histone modifications may have a crucial role in regulating DNMT1-mediated DNA methylation recovery. Our findings may have important implications towards a better understanding of epigenetic regulation and future development of epigenetic therapeutic intervention.

• Authors: Chun-Ming Wong, Carmen Chak-Lui Wong, Yeung-Lam Ng, Sandy Leung-Kuen Au, Frankie Chi-Fat Ko, Irene Oi-Lin Ng
• Journal: PloS one (PLoS One) Vol. 6 Issue 2 Pg. e16702 (Feb 08 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21347439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DLC1 protein, human
• GTPase-Activating Proteins
• Histones
• Tumor Suppressor Proteins
• Decitabine
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases
• DNMT1 protein, human
• Lysine
• Azacitidine

Topics

• Azacitidine (analogs & derivatives, pharmacology)
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases (metabolism)
• DNA Methylation (drug effects, genetics)
• Decitabine
• GTPase-Activating Proteins (genetics)
• Gene Silencing (drug effects)
• Genetic Loci (genetics)
• HCT116 Cells
• HeLa Cells
• Histones (chemistry, metabolism)
• Humans
• Lysine (metabolism)
• Stochastic Processes
• Transcription, Genetic (drug effects, genetics)
• Tumor Suppressor Proteins (genetics)