Antidepressants inhibit DNA methyltransferase 1 through reducing G9a levels

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 DNMT I 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 DNMT I, the histone methyltransferase G9a, exhibited decreased protein levels and interactions with DNMT I upon AD exposure. Adding recombinant G9a completely reversed the AD repressive effect on DNMT I function. In conclusion, the present study presents a model where distinct ADs affect DNMT I activity via G9a with important repercussions for possible novel treatment regimes.