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Valproate induces replication-independent active DNA demethylation
Nancy Detich1, Veronica Bovenzi, Moshe Szyf
1Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6 Canada.
The Journal of Biological Chemistry
|May 16, 2003
Summary
Valproic acid (VPA) reverses DNA methylation patterns in non-dividing cells by triggering active DNA demethylation. This drug enhances demethylase activity via histone acetylation, offering a new therapeutic avenue.
Area of Science:
- Epigenetics
- Molecular Biology
- Pharmacology
Background:
- Valproic acid (VPA) is a widely used epilepsy and mood disorder drug.
- Its role in regulating methylated genes is known, but the mechanism, particularly active DNA demethylation, remained unclear.
- Dissociating active demethylation from DNA replication has been a challenge.
Purpose of the Study:
- To investigate the mechanism by which VPA influences DNA methylation.
- To determine if VPA can induce active DNA demethylation independently of DNA replication.
- To explore the role of histone acetylation and MBD2/dMTase in VPA-mediated demethylation.
Main Methods:
- Utilized an assay for measuring active DNA demethylation independent of DNA replication in human embryonal kidney 293 cells.
- Administered VPA and its analogue valpromide to assess dose-dependent effects.
- Employed antisense knockdown of MBD2/dMTase to evaluate its role.
Main Results:
- VPA induced histone acetylation, DNA demethylation, and expression of a methylated plasmid in a dose-dependent manner.
- Valpromide, lacking histone acetylation-inducing properties, did not cause demethylation.
- Knockdown of MBD2/dMTase reduced VPA-induced demethylation, indicating its involvement.
Conclusions:
- VPA triggers replication-independent active DNA demethylation.
- VPA enhances intracellular demethylase activity through histone acetylation.
- DNA methylation may be reversible in non-dividing cells via commonly prescribed drugs like VPA.