title: Antidepressants inhibit DNA methyltransferase 1 through reducing G9a levels.
abstract: The discovery of epigenetic processes as possible pivotal regulatory mechanisms in psychiatric diseases raised the question of how psychoactive drugs may impact the epigenetic machinery. In the present study we set out to explore the specificity and the mode of action of the reported inhibitory effect of the TCA (tricyclic antidepressant) amitriptyline on DNMT (DNA methyltransferase) activity in primary astrocytes from the rat cortex. We found that the impact on DNMT was shared by another TCA, imipramine, and by paroxetine, but not by venlafaxine or the mood stabilizers carbamazepine and valproic acid. DNMT activity in subventricular neural stem cells was refractory to the action of ADs (antidepressants). Among the established DNMTs, ADs primarily targeted DNMT1. The reduction of enzymatic DNMT1 activity was neither due to reduced DNMT1 expression nor due to direct drug interference. We tested putative DNMT1-inhibitory mechanisms and discovered that a known stimulator of DNMT1, the histone methyltransferase G9a, exhibited decreased protein levels and interactions with DNMT1 upon AD exposure. Adding recombinant G9a completely reversed the AD repressive effect on DNMT1 function. In conclusion, the present study presents a model where distinct ADs affect DNMT1 activity via G9a with important repercussions for possible novel treatment regimes.
authors.affiliation: Chaperone Research Group, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Zimmermann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Zschocke
authors.forename: Tatjana
authors.initials: T
authors.lastname: Perisic
authors.forename: Shuang
authors.initials: S
authors.lastname: Yu
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D002220:Carbamazepine / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D015283:Citalopram / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006017:Glycolipids / Q000494:pharmacology; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D017374:Paroxetine / Q000494:pharmacology; D025941:Protein Interaction Mapping; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D000069470:Venlafaxine Hydrochloride
chemical_list: C577331:1-(6-hydroxymethylinositol)-2-O-methyl-3-O-octadecyl-sn-glycerocarbonate; C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D000928:Antidepressive Agents; D003511:Cyclohexanols; D004791:Enzyme Inhibitors; D006017:Glycolipids; D007211:Indoles; D008301:Maleimides; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D015283:Citalopram; D002220:Carbamazepine; D017374:Paroxetine; D000069470:Venlafaxine Hydrochloride; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; C000619382:Dnmt1 protein, rat; C577330:Ehmt2 protein, rat; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D007099:Imipramine