Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1

Ashley L. Green, Le Zhan, Aseel Eid, Helmut Zarbl, Grace L. Guo, Jason R. Richardson

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The dopamine transporter (DAT) is the key regulator of dopaminergic transmission and is a target of several xenobiotics, including pesticides and pharmacological agents. Previously, we identified a prominent role for histone deacetylases in the regulation of DAT expression. Here, we utilized a rat dopaminergic cell line (N27) to probe the responsiveness of DAT mRNA expression to inhibitors of histone acetylation. Inhibition of histone deacetylases (HDACs) by valproate, butyrate and Trichostatin A led to a 3–10-fold increase in DAT mRNA expression, a 50% increase in protein levels, which were accompanied by increased H3 acetylation levels. To confirm the mechanism of valproate-mediated increase in DAT mRNA, chromatin immunoprecipitation (ChIP) assays were used and demonstrated a significant increase in enrichment of acetylation of histone 3 on lysines 9 and 14 (H3K9/K14ac) in the DAT promoter. Expression of Nurr1 and Pitx3, key regulators of DAT expression, were increased following valproate treatment and Nurr1 binding was enriched in the DAT promoter. Together, these results indicate that histone acetylation and subsequent enhancement of transcription factor binding are plausible mechanisms for DAT regulation by valproate and, perhaps, by other xenobiotics.

Original languageEnglish (US)
Pages (from-to)189-196
Number of pages8
JournalNeuropharmacology
Volume125
DOIs
StatePublished - Oct 2017

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

Keywords

  • Dopamine transporter
  • Epigenetics
  • HDAC
  • Histone deacetylase
  • Nurr1
  • Pitx3
  • Valproate

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