RGD Reference Report - Antidepressants inhibit DNA methyltransferase 1 through reducing G9a levels. - Rat Genome Database

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Antidepressants inhibit DNA methyltransferase 1 through reducing G9a levels.

Authors: Zimmermann, N  Zschocke, J  Perisic, T  Yu, S  Holsboer, F  Rein, T 
Citation: Zimmermann N, etal., Biochem J. 2012 Nov 15;448(1):93-102. doi: 10.1042/BJ20120674.
RGD ID: 9588218
Pubmed: (View Article at PubMed) PMID:22880885
DOI: Full-text: DOI:10.1042/BJ20120674

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.

Annotation

Gene Ontology Annotations    

Biological Process

Cellular Component
nucleus  (IDA)

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Dnmt1  (DNA methyltransferase 1)
Dnmt3a  (DNA methyltransferase 3 alpha)
Ehmt2  (euchromatic histone lysine methyltransferase 2)


Additional Information