title: Regulation of alternative gene transcription in the striatum in response to antidepressant drugs.
abstract: The mechanisms that control the selection of transcription initiation and termination sites in response to pharmacological stimulation of neuronal cells are poorly understood. We used next-generation sequencing and bioinformatics to construct a genome-wide inventory of protein-coding and non-coding transcripts altered by antidepressant treatment. We analyzed available ChIP-seq data to identify mechanisms that control drug-inducible expression of alternative gene variants in the brain. We identified 153 transcripts of various biotypes regulated in the mouse striatum in response to tranylcypromine or mianserin (at a 0.1% FDR threshold). Five drug-responsive gene patterns are enriched in protein-coding variants (77%), regulated by different sets of transcriptional factors (including SRF/CREB1 and GR/CTCF) and expressed in separate cellular compartments of the brain. We found that alterations mediated by proximal promoters in neurons are more specific in the selection of regulated transcriptional isoforms compared with enhancer-dependent alterations in glia. The change in transcriptional programs, from housekeeping to inducible, provides cells with the resource of functionally distinct proteins. We conclude that the regulation of drug-induced brain plasticity may occur at the level of transcripts rather than genes. The expression of specific isoforms in response to antidepressants may constitute a trigger that initiates the long-lasting effects of these drugs.
authors.affiliation: Department of Molecular Neuropharmacology, Institute of Pharmacology PAS, Krakow, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Piechota
authors.affiliation: Department of Molecular Neuropharmacology, Institute of Pharmacology PAS, Krakow, Poland.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Golda
authors.affiliation: Department of Molecular Neuropharmacology, Institute of Pharmacology PAS, Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Ficek
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology PAS, Krakow, Poland.
authors.forename: Danuta
authors.initials: D
authors.lastname: Jantas
authors.affiliation: Department of Molecular Neuropharmacology, Institute of Pharmacology PAS, Krakow, Poland; Department of Neurobiology and Neuropsychology, IPS, UJ, Krakow, Poland.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Przewlocki
authors.affiliation: Department of Molecular Neuropharmacology, Institute of Pharmacology PAS, Krakow, Poland. Electronic address: michkor@if-pan.krakow.pl.
authors.forename: Michal
authors.initials: M
authors.lastname: Korostynski
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008803:Mianserin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D014191:Tranylcypromine / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D008803:Mianserin; D014191:Tranylcypromine
keywords: Alternative splicing; Antidepressants; Gene expression; Pharmacogenomics; Striatum; Transcriptional regulation