title: Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression.
abstract: P11 (S100A10) has been associated with the pathophysiology of depression both in human and rodent models. Different types of antidepressants have been shown to increase P11 levels in distinct brain regions and P11 gene therapy was recently proven effective in reversing depressive-like behaviours in mice. However, the molecular mechanisms that govern P11 gene expression in response to antidepressants still remain elusive. In this study we report decreased levels of P11, associated with higher DNA methylation in the promoter region, in the prefrontal cortex of the Flinders Sensitive Line (FSL) genetic rodent model of depression. This hypermethylated pattern was reversed to normal, as indicated by the control line, after chronic administration of escitalopram (a selective serotonin reuptake inhibitor; SSRI). The escitalopram-induced hypomethylation was associated with both an increase in P11 gene expression and a reduction in mRNA levels of two DNA methyltransferases that have been shown to maintain DNA methylation in adult forebrain neurons (Dnmt1 and Dnmt3a). In conclusion, our data further support a role for P11 in depression-like states and suggest that this gene is controlled by epigenetic mechanisms that can be affected by antidepressant treatment.
authors.affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institute, Stockholm, Sweden. Philippe.Melas@ki.se
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Melas
authors.forename: Maria
authors.initials: M
authors.lastname: Rogdaki
authors.forename: Andreas
authors.initials: A
authors.lastname: Lennartsson
authors.forename: Karl
authors.initials: K
authors.lastname: Björk
authors.forename: Hongshi
authors.initials: H
authors.lastname: Qi
authors.forename: Anna
authors.initials: A
authors.lastname: Witasp
authors.forename: Martin
authors.initials: M
authors.lastname: Werme
authors.forename: Gregers
authors.initials: G
authors.lastname: Wegener
authors.forename: Aleksander A
authors.initials: AA
authors.lastname: Mathé
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.forename: Catharina
authors.initials: C
authors.lastname: Lavebratt
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000235:genetics* / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D003866:Depressive Disorder / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D057890:Epigenomics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D015283:Citalopram; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D012333:RNA, Messenger; D009418:S100 Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D000099248:S100 Calcium Binding Protein A10; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C000619382:Dnmt1 protein, rat