Valproate administration to mice increases hippocampal p21 expression by altering genomic DNA methylation

Neuroreport
Shu Aizawa, Yutaka Yamamuro

Abstract

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.

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Citations

Jun 23, 2016·Neuroscience and Biobehavioral Reviews·Gabriel R FriesJoao Quevedo
May 5, 2017·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Rebecca M HauserFarah D Lubin
Aug 1, 2020·The European Journal of Neuroscience·Roger B VarelaSamira S Valvassori
Jun 6, 2020·Cellular and Molecular Neurobiology·Huan ZhangYue-Sheng Long

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Methods Mentioned

BETA
PCR
Protein Assay
electrophoresis
reverse-transcription PCR
acetylation
histone acetylation

Software Mentioned

COBRA
MethPrimer
ImageJ
GraphPad Prism
GraphPad

Related Concepts

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