title: Valproate and amitriptyline exert common and divergent influences on global and gene promoter-specific chromatin modifications in rat primary astrocytes.
abstract: Aberrant biochemical processes in the brain frequently go along with subtle shifts of the cellular epigenetic profile that might support the pathogenic progression of psychiatric disorders. Although recent reports have implied the ability of certain antidepressants and mood stabilizers to modulate epigenetic parameters, studies comparing the actions of these compounds under the same conditions are lacking. In this study, we screened amitriptyline (AMI), venlafaxine, citalopram, as well as valproic acid (VPA), carbamazepine, and lamotrigine for their potential actions on global and local epigenetic modifications in rat primary astrocytes. Among all drugs, VPA exposure evoked the strongest global chromatin modifications, including histone H3/H4 hyperacetylation, 2MeH3K9 hypomethylation, and DNA demethylation, as determined by western blot and luminometric methylation analysis, respectively. CpG demethylation occurred independently of DNA methyltransferase (DNMT) suppression. Strikingly, AMI also induced slight cytosine demethylation, paralleled by the reduction in DNMT enzymatic activity, without affecting the global histone acetylation status. Locally, VPA-induced chromatin modifications were reflected at the glutamate transporter (GLT-1) promoter as shown by bisulfite sequencing and acetylated histone H4 chromatin immunoprecipitation analysis. Distinct CpG sites in the distal part of the GLT-1 promoter were demethylated and enriched in acetylated histone H4 in response to VPA. For the first time, we could show that these changes were associated with an enhanced transcription of this astrocyte-specific gene. In contrast, AMI failed to stimulate GLT-1 transcription and to alter promoter methylation levels. In conclusion, VPA and AMI globally exerted chromatin-modulating activities using different mechanisms that divergently precipitated at an astroglial gene locus.
authors.affiliation: Chaperone Research Group, Max-Planck-Institute of Psychiatry, Munich, Bavaria, Germany.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Perisic
authors.forename: Nicole
authors.initials: N
authors.lastname: Zimmermann
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirmeier
authors.forename: Maria
authors.initials: M
authors.lastname: Asmus
authors.forename: Francesca
authors.initials: F
authors.lastname: Tuorto
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
authors.forename: Jürgen
authors.initials: J
authors.lastname: Zschocke
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D002843:Chromatin; D000639:Amitriptyline; D014635:Valproic Acid