Valproate Induces Replication-independent Active DNA Demethylation
| Autor: | Veronica Bovenzi, Moshe Szyf, Nancy Detich |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
DNA Replication
Blotting Western Green Fluorescent Proteins Biology Transfection Biochemistry Cell Line Histones Histone methylation Humans Sulfites Enzyme Inhibitors Molecular Biology Epigenomics Demethylation Dose-Response Relationship Drug DNA synthesis Valproic Acid DNA replication DNA Cell Biology DNA Methylation Physical Chromosome Mapping Precipitin Tests Molecular biology Blotting Southern Luminescent Proteins DNA demethylation Histone DNA methylation biology.protein CpG Islands lipids (amino acids peptides and proteins) Plasmids Protein Binding |
| Zdroj: | Journal of Biological Chemistry. 278:27586-27592 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m303740200 |
| Popis: | In this report, we demonstrate that valproic acid (VPA), a drug that has been used for decades in the treatment of epilepsy and as a mood stabilizer, triggers replication-independent active demethylation of DNA. Thus, this drug can potentially reverse DNA methylation patterns and erase stable methylation imprints on DNA in non-dividing cells. Recent discoveries support a role for VPA in the regulation of methylated genes; however, the mechanism has been unclear because it is difficult to dissociate active demethylation from the absence of DNA methylation during DNA synthesis. We therefore took advantage of an assay that measures active DNA demethylation independently from other DNA methylation and DNA replication activities in human embryonal kidney 293 cells. We show that VPA induces histone acetylation, DNA demethylation, and expression of an ectopically methylated CMV-GFP plasmid in a dose-dependent manner. In contrast, valpromide, an analogue of VPA that does not induce histone acetylation, does not induce demethylation or expression of CMV-GFP. Furthermore, we illustrate that methylated DNA-binding protein 2/DNA demethylase (MBD2/dMTase) participates in this reaction since antisense knockdown of MBD2/dMTase attenuates VPA-induced demethylation. Taken together, our data support a new mechanism of action for VPA as enhancing intracellular demethylase activity through its effects on histone acetylation and raises the possibility that DNA methylation is reversible independent of DNA replication by commonly prescribed drugs. |
| Databáze: | OpenAIRE |
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