title: Acetylation of histone H3 and adrenergic-regulated gene transcription in rat pinealocytes.
abstract: In this study we investigated the effect of histone acetylation on the transcription of adrenergic-induced genes in rat pinealocytes. We found that treatment of pinealocytes with trichostatin A (TSA), a histone deacetylase inhibitor, caused hyperacetylation of histone H3 (H3) Lys14 at nanomolar concentrations. Hyperacetylation of H3 was also observed after treatment with scriptaid, a structurally unrelated histone deacetylase inhibitor. The effects of TSA and scriptaid were inhibitory on the adrenergic induction of arylalkylamine-n-acetyltransferase (aa-nat) mRNA, protein, and enzyme activity, and on melatonin production. TSA at higher concentrations also inhibited the adrenergic induction of mapk phosphatase-1 (mkp-1) and inducible cAMP early repressor mRNAs. In contrast, the effect of TSA on the norepinephrine induction of the c-fos mRNA was stimulatory. Moreover, the effect of TSA on adrenergic-induced gene transcription was dependent on the time of its addition; its effect was only observed during the active phase of transcription. Chromatin immunoprecipitation with antibodies against acetylated Lys14 of H3 showed an increase in DNA recovery of the promoter regions of aa-nat, mkp-1, and c-fos after treatment with TSA. Together, our results demonstrate that histone acetylation differentially influences the transcription of adrenergic-induced genes, an enhancing effect for c-fos but inhibitory for aa-nat, mkp-1, and inducible cAMP early repressor. Moreover, both inhibitory and enhancing effects appear to be mediated through specific modification of promoter-bound histones during gene transcription.
authors.affiliation: Department of Physiology, 7-26 Medical Sciences Building, Edmonton, Alberta, Canada. anho@ualberta.ca
authors.forename: A K
authors.initials: AK
authors.lastname: Ho
authors.forename: D M
authors.initials: DM
authors.lastname: Price
authors.forename: W G
authors.initials: WG
authors.lastname: Dukewich
authors.forename: N
authors.initials: N
authors.lastname: Steinberg
authors.forename: T G
authors.initials: TG
authors.lastname: Arnason
authors.forename: C L
authors.initials: CL
authors.lastname: Chik
mesh_terms: D000107:Acetylation; D018663:Adrenergic Agents / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D047068:Arylalkylamine N-Acetyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D002478:Cells, Cultured; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics; D004334:Drug Administration Schedule; D054638:Dual Specificity Phosphatase 1; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D006898:Hydroxylamines / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000235:genetics; D008550:Melatonin / Q000096:biosynthesis; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000235:genetics; D010870:Pineal Gland / Q000166:cytology / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D018663:Adrenergic Agents; D000316:Adrenergic alpha-Agonists; D018797:Cell Cycle Proteins; C497412:Crem protein, rat; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D006898:Hydroxylamines; D017874:Immediate-Early Proteins; D016760:Proto-Oncogene Proteins c-fos; D011804:Quinolines; D012333:RNA, Messenger; C410733:scriptaid; D051786:Cyclic AMP Response Element Modulator; C012589:trichostatin A; C520223:Aanat protein, rat; D047068:Arylalkylamine N-Acetyltransferase; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases; D008550:Melatonin; D009638:Norepinephrine