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

Title

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

Creator

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

Publisher

Neuropharmacology

Date

2017
2017-10

Description

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.

Subject

Acetylation/drug effects; Animals; Butyrates/pharmacology; Cell Line; Cell Survival/drug effects; Dopamine Plasma Membrane Transport Proteins/*metabolism; Dopamine transporter; Dopaminergic Neurons/cytology/drug effects/metabolism; Dose-Response Relationship; Drug; Epigenesis; Epigenetics; Genetic; Genetic/drug effects; Group A; HDAC; Histone deacetylase; Histone Deacetylase Inhibitors/*pharmacology; Histone Deacetylases/metabolism; Histones/*drug effects/metabolism; Homeodomain Proteins/metabolism; Hydroxamic Acids/pharmacology; Member 2/*metabolism; Messenger/metabolism; Nuclear Receptor Subfamily 4; Nurr1; Pitx3; Promoter Regions; Rats; RNA; Transcription Factors/metabolism; Valproate; Valproic Acid/*pharmacology

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

189–196

Volume

125

Citation

Green Ashley L; Zhan Le; Eid Aseel; Zarbl Helmut; Guo Grace L; Richardson Jason R, “Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1.,” NEOMED Bibliography Database, accessed April 16, 2021, https://neomed.omeka.net/items/show/3725.

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