Valproate administration to mice increases hippocampal p21 expression by altering genomic DNA methylation.
Although valproate (VPA) is used widely in the treatment of bipolar mood disorder and epilepsy, the precise mechanism of action in the brain remains elusive. In this study, we investigated the effects of subchronic VPA administrations on the expression of the cyclin-dependent kinase inhibitor (Cdkn) family in the hippocampus of adult mice. The administration of VPA specifically increased hippocampal p21 expression involving both mRNA and protein levels, but other members of the Cdkn family were not affected. We identified two CpG islands in the p21 gene regulatory region, located distal and proximal to the transcription start site. VPA altered genomic DNA methylation patterns in the distal region, but not in the proximal promoter region. However, no change was found in DNA methyltransferase (Dnmt) 1 or Dnmt3a protein levels, suggesting an involvement in active demethylation mechanisms. These findings suggest that VPA alters the gene expression of cell cycle regulators by modulating promoter DNA methylation, and this resulted in altered hippocampal cell proliferation. These findings promote understanding of the actions of VPA in the brain.
Laboratory of Animal Genetics and Physiology, Department of Animal Science, College of Bioresource Sciences, Nihon University, Kanagawa, Japan.
Shu
S
Aizawa
Yutaka
Y
Yamamuro
D000818:Animals; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D023281:Genomics; D006201:Hair Diseases; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D005499:Folliculitis
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C000715535:Dnmt3a protein, mouse; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014635:Valproic Acid; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A