Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes

Abstract

Valproate (VPA)(1) has been used for decades in the treatment of epilepsy, and is also effective as a mood stabilizer and in migraine therapy. It has been shown that VPA is also a histone deacetylase (HDAC) inhibitor. We have previously shown that VPA could trigger active demethylation of ectopically methylated transiently transfected DNA in HEK 293 cells. We therefore tested whether VPA treatment could bring about stable changes in the epigenome by causing changes in the state of DNA methylation of genomic DNA. Using a microarray gene expression analysis we identified the genes whose expression is induced by VPA treatment in HEK 293 cells. We found that a subset of these genes could also be induced by the classical DNA methylation inhibitor 5-aza-2'-deoxy-cytidine (5-aza-CdR) suggesting that VPA can alter the state of expression of genes, which are stably suppressed by DNA methylation. We mapped the state of methylation of three of these genes, MELANOMA ANTIGEN B2 GENE (MAGEB2), METALLOPROTEINASE 2 (MMP2) and WIF1, which are involved in tumor growth and metastasis. A chromatin immunoprecipitation (ChIP) assay revealed that VPA treatment caused as expected a change in the state of acetylation of these genes. Our data supports the concept that chromatin acetylation and DNA methylation are found in a dynamic interrelation and that the consequences of HDAC inhibitors are not limited to changes in histone acetylation but that they also bring about a change in the state of modification of DNA. The implications of our results on the future therapeutic utilities of VPA in cancer will be discussed.

Relationships among MTHFR a1298c Gene Polymorphisms and Methylation Status of Dact1 Gene in Transitional Cell Carcinomas

“…DNA methylation is an epigenetic mechanism which plays an important part in regulating gene expression at the transcription level (Huang and Vieira , 2006). Through methylation on cytosine of the CpG island in the gene promoter and the other CpG-riched region, some redundant genes in certain tissues or cells can be silenced, while demethylation can function as an activating some tissue-or stage-specific genes, which contributed to the temporal and spatial regulation of gene expression (Milutinovic et al, 2007;Nicholson et al, 2008). Previous studies have described global genomic hypomehtylation in several malignant cancers including carcinomas of bladder (Chalitchagorn et al, 2004) and other organic carcinomas, by evaluating genomic repetitive sequence.…”

The social environment and the epigenome

“…DOI 10.1002/em Indeed, in contrast to DNMTs, which are recruited by chromatin silencing enzymes such as SUV39 [Fuks et al, 2003a] and EZH2 [Vire et al, 2006;, demethylation is facilitated by histone acetylation [Cervoni and Szyf, 2001;Cervoni et al, 2002]. Pharmacological acetylation using HDAC inhibitors such as TSA [Cervoni and Szyf, 2001] or valproic acid [Detich et al, 2003a] trigger replication-independent active demethylation of transiently transfected in vitro methylated plasmids and causes genomic demethylation [Milutinovic et al, 2007;Ou et al, 2007]. Interestingly TSA facilitates DNA demethylation in adult hippocampal neurons as well [Weaver et al, 2004], suggesting that the activity of TSA is not limited to cells in culture or to cycling cells.…”

Epigenetics and major depression disorder

“…. Poznato je i da valproat, inhibitor deacetilaza histona, lijek odobren za liječenje epilepsije i bipolarnog poremećaja, potiče globalno smanjenje razine metilacije molekule DNK u embrionalnim stanicama bubrega čovjeka i u stanicama jetra štakora 40 . Pokazano je i da antipsihotik klozapin potiče s demetilaciju molekule DNK u frontalnom korteksu mozga i striatumu štakora 41 .…”