| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Papers In Press, published online ahead of print May 14, 2003
Pharmacology, McGill University, Montreal, Quebec H3G 1Y6
Corresponding Author: mszyf{at}pharma.mcgill.ca
In this paper, 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 HEK 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 (VPM), 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 knock down 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.
J. Biol. Chem, 10.1074/jbc.M303740200
Submitted on April 9, 2003
Revised on May 13, 2003
Accepted on May 14, 2003
Valproate induces replication independent active DNA demethylation
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  L.-P. Wu, X. Wang, L. Li, Y. Zhao, S. Lu, Y. Yu, W. Zhou, X. Liu, J. Yang, Z. Zheng, et al. Histone Deacetylase Inhibitor Depsipeptide Activates Silenced Genes through Decreasing both CpG and H3K9 Methylation on the Promoter Mol. Cell. Biol., May 15, 2008; 28(10): 3219 - 3235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Szyf The Dynamic Epigenome and its Implications in Toxicology Toxicol. Sci., November 1, 2007; 100(1): 7 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Jiang, A. Espeseth, D. J. Hazuda, and D. M. Margolis c-Myc and Sp1 Contribute to Proviral Latency by Recruiting Histone Deacetylase 1 to the Human Immunodeficiency Virus Type 1 Promoter J. Virol., October 15, 2007; 81(20): 10914 - 10923. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S Oliveri, M. Kalisz, C. K. Schjerling, C. Y. Andersen, R. Borup, and A. G. Byskov Evaluation in mammalian oocytes of gene transcripts linked to epigenetic reprogramming Reproduction, October 1, 2007; 134(4): 549 - 558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. K. Hwang, K. Y. Song, C. S. Kim, H. S. Choi, X.-H. Guo, P.-Y. Law, L.-N. Wei, and H. H. Loh Evidence of Endogenous Mu Opioid Receptor Regulation by Epigenetic Control of the Promoters Mol. Cell. Biol., July 1, 2007; 27(13): 4720 - 4736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Brown and M. Szyf Epigenetic Programming of the rRNA Promoter by MBD3 Mol. Cell. Biol., July 1, 2007; 27(13): 4938 - 4952. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Dong, A. Guidotti, D. R. Grayson, and E. Costa Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters PNAS, March 13, 2007; 104(11): 4676 - 4681. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Milutinovic, A. C. D'Alessio, N. Detich, and M. Szyf Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes Carcinogenesis, March 1, 2007; 28(3): 560 - 571. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-h. Feng and S. C. Kenney Valproic Acid Enhances the Efficacy of Chemotherapy in EBV-Positive Tumors by Increasing Lytic Viral Gene Expression. Cancer Res., September 1, 2006; 66(17): 8762 - 8769. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Chen, J. Huang, C. Zhang, S. Huang, G. Nunnari, F.-x. Wang, X. Tong, L. Gao, K. Nikisher, and H. Zhang Alpha Interferon Potently Enhances the Anti-Human Immunodeficiency Virus Type 1 Activity of APOBEC3G in Resting Primary CD4 T Cells. J. Virol., August 1, 2006; 80(15): 7645 - 7657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kawai and I. J. Arinze Valproic Acid-Induced Gene Expression through Production of Reactive Oxygen Species. Cancer Res., July 1, 2006; 66(13): 6563 - 6569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Simonini, L. M. Camargo, E. Dong, E. Maloku, M. Veldic, E. Costa, and A. Guidotti From The Cover: The benzamide MS-275 is a potent, long-lasting brain region-selective inhibitor of histone deacetylases PNAS, January 31, 2006; 103(5): 1587 - 1592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Dong, R. C. Agis-Balboa, M. V. Simonini, D. R. Grayson, E. Costa, and A. Guidotti Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia PNAS, August 30, 2005; 102(35): 12578 - 12583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Achachi, A. Florins, N. Gillet, C. Debacq, P. Urbain, G. M. Foutsop, F. Vandermeers, A. Jasik, M. Reichert, P. Kerkhofs, et al. Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo PNAS, July 19, 2005; 102(29): 10309 - 10314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Iseki, R. Shimizukawa, F. Sugiyama, S. Kunita, A. Iwama, M. Onodera, H. Nakauchi, and K.-i. Yagami Parvovirus Nonstructural Proteins Induce an Epigenetic Modification through Histone Acetylation in Host Genes and Revert Tumor Malignancy to Benignancy J. Virol., July 15, 2005; 79(14): 8886 - 8893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Bug, H. Gul, K. Schwarz, H. Pfeifer, M. Kampfmann, X. Zheng, T. Beissert, S. Boehrer, D. Hoelzer, O. G. Ottmann, et al. Valproic Acid Stimulates Proliferation and Self-renewal of Hematopoietic Stem Cells Cancer Res., April 1, 2005; 65(7): 2537 - 2541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Veldic, A. Guidotti, E. Maloku, J. M. Davis, and E. Costa In psychosis, cortical interneurons overexpress DNA-methyltransferase 1 PNAS, February 8, 2005; 102(6): 2152 - 2157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Noh, R. P. Sharma, M. Veldic, A. A. Salvacion, X. Jia, Y. Chen, E. Costa, A. Guidotti, and D. R. Grayson DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures PNAS, February 1, 2005; 102(5): 1749 - 1754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Campbell, V. Bovenzi, and M. Szyf Methylated DNA-binding protein 2 antisense inhibitors suppress tumourigenesis of human cancer cell lines in vitro and in vivo Carcinogenesis, April 1, 2004; 25(4): 499 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ghoshal, S. Majumder, J. Datta, T. Motiwala, S. Bai, S. M. Sharma, W. Frankel, and S. T. Jacob Role of Human Ribosomal RNA (rRNA) Promoter Methylation and of Methyl-CpG-binding Protein MBD2 in the Suppression of rRNA Gene Expression J. Biol. Chem., February 20, 2004; 279(8): 6783 - 6793. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
