title: The mood stabilizer valproate activates human FGF1 gene promoter through inhibiting HDAC and GSK-3 activities.
abstract: Valproic acid (VPA) is the primary mood-stabilizing drug to exert neuroprotective effects and to treat bipolar disorder in clinic. Fibroblast growth factor 1 (FGF1) has been shown to regulate cell proliferation, cell division, and neurogenesis. Human FGF1 gene 1B promoter (-540 to +31)-driven green fluorescence (F1BGFP) has been shown to recapitulate endogenous FGF1 gene expression and facilitates the isolation of neural stem/progenitor cells (NSPCs) from developing and adult mouse brains. In this study, we provide several lines of evidence to demonstrate the underlying mechanisms of VPA in activating FGF-1B promoter activity: (i) VPA significantly increased the FGF-1B mRNA expression and the percentage of F1BGFP(+) cells; (ii) the increase of F1BGFP expression by VPA involves changes of regulatory factor X (RFX) 1-3 transcriptional complexes and the increase of histone H3 acetylation on the 18-bp cis-element of FGF-1B promoter; (iii) treatments of other histone deacetylases (HDAC) inhibitors, sodium butyrate and trichostatin A, significantly increased the expression levels of FGF-1B, RFX2, and RFX3 transcripts; (iv) treatments of glycogen synthase kinase 3 (GSK-3) inhibitor, lithium, or GSK-3 siRNAs also significantly activated FGF-1B promoter; (v) VPA specifically enhanced neuronal differentiation in F1BGFP(+) embryonic stem cells and NSPCs rather than GFP(-) cells. This study suggested, for the first time, that VPA activates human FGF1 gene promoter through inhibiting HDAC and GSK-3 activities.
authors: Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors: Chien-Yu
authors: CY
authors: Kao
authors: Yi-Chao
authors: YC
authors: Hsu
authors: Jen-Wei
authors: JW
authors: Liu
authors: Don-Ching
authors: DC
authors: Lee
authors: Yu-Fen
authors: YF
authors: Chung
authors: Ing-Ming
authors: IM
authors: Chiu
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D053595:Embryonic Stem Cells / Q000187:drug effects; D016220:Fibroblast Growth Factor 1 / Q000187:drug effects* / Q000235:genetics*; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D058953:Neural Stem Cells / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018692:Antimanic Agents; D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; D016220:Fibroblast Growth Factor 1; D014635:Valproic Acid; D038362:Glycogen Synthase Kinase 3; D006655:Histone Deacetylases; D018021:Lithium Chloride