title: Valproic acid exposure leads to upregulation and increased promoter histone acetylation of sepiapterin reductase in a serotonergic cell line.
abstract: Valproic acid (VPA) is a widely used antiepileptic drug and first-line treatment in bipolar disorder, although the mechanisms underlying its therapeutic effects are largely unknown. Recently, the recognition of VPA as an epigenetic drug offers new opportunities for understanding its therapeutic actions. In a rat serotonergic cell line (RN46A) we observed that VPA exposure has a strong upregulatory effect on the gene for sepiapterin reductase (SPR), a key enzyme involved in the tetrahydrobiopterin (BH4) synthetic pathway. BH4 is an essential cofactor in the biosynthesis of neurotransmitters like serotonin, dopamine and noradrenalin, and the BH4 pathway may thus be important in mood biology. Using real-time quantitative PCR we show that VPA, at therapeutically relevant doses, increases the expression of the Spr gene by about 8-fold in RN46A cells. In addition, Spr protein levels in VPA-exposed cells were elevated, as were the intracellular BH4 levels. HDAC inhibitors (HDACI) trichostatin A and sodium butyrate also upregulated Spr, but this was not observed using the VPA-analogue valpromide, which lacks HDAC inhibitory activity. Further examination of this effect revealed that exposure to VPA increased the acetylated histone mark H3K9/K14ac at the Spr promoter. The DNMT inhibitor 5'aza-dC also upregulated Spr by over 8-fold. However, DNA methylation status across the Spr promoter did not change in response to VPA. The BH4 pathway is fundamental to the regulation of neurotransmitters relevant to mood disorders, and this epigenetic effect of VPA at the Spr promoter may represent a novel mechanism through which VPA achieves its therapeutic action.
authors.affiliation: Gene Structure and Function Laboratory and Carney Centre for Pharmacogenomics, Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Diana
authors.initials: D
authors.lastname: Balasubramanian
authors.affiliation: Gene Structure and Function Laboratory and Carney Centre for Pharmacogenomics, Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Alicia X
authors.initials: AX
authors.lastname: Deng
authors.affiliation: Gene Structure and Function Laboratory and Carney Centre for Pharmacogenomics, Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Kit
authors.initials: K
authors.lastname: Doudney
authors.affiliation: Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Hampton
authors.affiliation: Gene Structure and Function Laboratory and Carney Centre for Pharmacogenomics, Department of Pathology, University of Otago, Christchurch, New Zealand. Electronic address: martin.kennedy@otago.ac.nz.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kennedy
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D018692:Antimanic Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D018692:Antimanic Agents; D006657:Histones; D014635:Valproic Acid; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase
keywords: Epigenetics; HDAC inhibition; Mood stabilizer; Sepiapterin reductase; Tetrahydrobiopterin; Valproic acid