BDNFIV promoter methylation and antidepressant action: a complex interplay

Background: BDNFIV promoter methylation is a potential biomarker for treatment response to antidepressants in MDD. We have previously shown CpG-87 methylation as a successful biomarker for prediction of non-response to monoaminergic antidepressants like the SSRI Fluoxetine or the SNRI Venlafaxine. This study aimed to dissect the biological evidence and mechanisms for functionality of CpG-87 methylation in a cell culture model. Results: We observed a significant interaction between methylation and antidepressant mediated transcriptional activity in BDNFIV promoter. In addition, antidepressant treatment increased the BDNFIV methylation in a concentration dependent manner. Further single CpG methylation of -87 did not change the promoter activity, but methylation of CREB domain CpG-39 increased the transcriptional activity in an antidepressant dependent manner. Interestingly, DNMT3a over-expression also increases the BDNFIV transcription and more so in Venlafaxine treated cells. Conclusions: : The study strengthens the previously reported association between antidepressant treatment and BDNFIV methylation as well as hints towards the mechanism of action. We argue that potential CpG methylation biomarkers display a complex synergy with the molecular changes at the neighboring CpG positions, thus highlighting the importance of epiallele analyses.