title: Search for common targets of lithium and valproic acid identifies novel epigenetic effects of lithium on the rat leptin receptor gene.
abstract: Epigenetics may have an important role in mood stabilizer action. Valproic acid (VPA) is a histone deacetylase inhibitor, and lithium (Li) may have downstream epigenetic actions. To identify genes commonly affected by both mood stabilizers and to assess potential epigenetic mechanisms that may be involved in their mechanism of action, we administered Li (N = 12), VPA (N = 12), and normal chow (N = 12) to Brown Norway rats for 30 days. Genomic DNA and mRNA were extracted from the hippocampus. We used the mRNA to perform gene expression analysis on Affymetrix microarray chips, and for genes commonly regulated by both Li and VPA, we validated expression levels using quantitative real-time PCR. To identify potential mechanisms underlying expression changes, genomic DNA was bisulfite treated for pyrosequencing of key CpG island 'shores' and promoter regions, and chromatin was prepared from both hippocampal tissue and a hippocampal-derived cell line to assess modifications of histones. For most genes, we found little evidence of DNA methylation changes in response to the medications. However, we detected histone H3 methylation and acetylation in the leptin receptor gene, Lepr, following treatment with both drugs. VPA-mediated effects on histones are well established, whereas the Li effects constitute a novel mechanism of transcriptional derepression for this drug. These data support several shared transcriptional targets of Li and VPA, and provide evidence suggesting leptin signaling as an epigenetic target of two mood stabilizers. Additional work could help clarify whether leptin signaling in the brain has a role in the therapeutic action of Li and VPA in bipolar disorder.
authors.affiliation: Johns Hopkins Mood Disorders Center of the Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Lee
authors.affiliation: Johns Hopkins Mood Disorders Center of the Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: M
authors.identifier: 0000000242106458
authors.initials: M
authors.lastname: Pirooznia
authors.affiliation: 1] Johns Hopkins Mood Disorders Center of the Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA [2] Graduate Program in Human Genetics, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Guintivano
authors.affiliation: Johns Hopkins Mood Disorders Center of the Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ly
authors.affiliation: Johns Hopkins Mood Disorders Center of the Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Ewald
authors.affiliation: Johns Hopkins Mood Disorders Center of the Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Tamashiro
authors.affiliation: Departments of Psychiatry, Pharmacology, and Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: Gould
authors.affiliation: Johns Hopkins Mood Disorders Center of the Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Moran
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Potash
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D005796:Genes / Q000187:drug effects; D018020:Lithium Compounds / Q000494:pharmacology*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011914:Rats, Inbred BN; D060888:Real-Time Polymerase Chain Reaction; D054411:Receptors, Leptin / Q000187:drug effects* / Q000235:genetics; D059467:Transcriptome; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018020:Lithium Compounds; D054411:Receptors, Leptin; D014635:Valproic Acid