Histone deacetylase inhibition alters histone methylation associated with heat shock protein 70 promoter modifications in astrocytes and neurons.
The mood-stabilizing and anticonvulsant drug valproic acid (VPA) inhibits histone deacetylases (HDACs). The aim of the present study was to determine the effect of HDAC inhibition on overall and target gene promoter-associated histone methylation in rat cortical neurons and astrocytes. We found that VPA and other HDAC inhibitors, including sodium butyrate (SB), trichostatin A (TSA), and the Class I HDAC inhibitors MS-275 and apicidin all increased levels of histone 3 lysine 4 dimethylation and trimethylation (H3K4Me2 and H3K4Me3); these processes are linked to transcriptional activation in rat cortical neurons and astrocytes. VPA, SB, TSA, MS-275, and apicidin also upregulated levels of the neuroprotective heat shock protein 70 (HSP70) in rat astrocytes. Moreover, Class I HDAC inhibition by VPA and MS-275 increased H3K4Me2 levels at the HSP70 promoter in astrocytes and neurons. We also found that VPA treatment facilitated the recruitment of acetyltransferase p300 to the HSP70 promoter and that p300 interacted with the transcription factor NF-Y in astrocytes. Taken together, the results suggest that Class I HDAC inhibition is key to upregulating overall and gene-specific H3K4 methylation in primary neuronal and astrocyte cultures. In addition, VPA-induced activation of the HSP70 promoter in astrocytes appears to involve an increase in H3K4Me2 levels and recruitment of p300. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
Marinova
Zoya
Z
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1363, USA.
Leng
Yan
Y
Leeds
Peter
P
Chuang
De-Maw
DM
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology; D023081:CCAAT-Binding Factor / Q000187:drug effects / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism / Q000502:physiology; D008745:Methylation / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050880:p300-CBP Transcription Factors / Q000187:drug effects / Q000502:physiology; D000099224:p300-CBP-Associated Factor
D001549:Benzamides; D023081:CCAAT-Binding Factor; D018840:HSP70 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D011725:Pyridines; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C118739:entinostat