707. Promises and pitfalls of DNA methylation and miRNA for stratification and treatment optimization: two sides of one coin

Abstract

Abstract Background DNA methylation and micro-RNA (miRNA) both act as gene-regulatory mechanisms. Their merit and challenge are two sides of the same coin: they respond to the environment and show the impact of longitudinal processes such as response to treatment and recovery from illness at the molecular level. However, it remains challenging to disentangle the ‘desired’ exposure of the whole environment, particularly in the context of psychiatric disorders. For DNA methylation and miRNA to become aids for stratification and markers of treatment response for depression, multiple analysis strategies are required to address this problem from multiple angles. Aims & Objectives We give an overview of current analysis strategies and present published and unpublished results to show how these molecular markers can contribute to useful stratification of patients with depression. Method For this purpose, a combination of methods is typically required and most informative. We discuss differential analyses for DNA methylation and miRNA in response to treatment and environmental exposure, such as specific kinds of trauma. We also show the merit of methods integrating DNA methylation information in the form of DNA-methylation-based immunological cell type estimates, ‘immunomethylomics, the application of overall DNA methylation variability, and DNA-methylation clocks. Results We present published and unpublished results that show how DNA methylation and miRNA, as gene-regulatory mechanisms, can contribute to useful stratification and early optimization of treatment and treatment response in patients with depression. We highlight the application of immunomethylomics and DNA methylation in the prediction of treatment response and symptom improvement in samples treated with ketamine and augmentation with celecoxib. Furthermore, we show how different kinds of trauma and exposure can impact both DNA methylation at the CpG level and beyond, as well as miRNA. The methods and their results that we present can also be extrapolated to other psychiatric disorders. Discussion & Conclusions In this presentation, we discuss the latest insights on the response of DNA methylation to treatment, e.g., personalized response-guided dosing with ketamine. We then extend towards analysis strategies that combine DNA methylation markers, such as immunomethylomics, overall DNA methylation variability, etc., as well as distinct signatures of miRNA depending on the environmental exposure. We discuss published and unpublished results that show the potential of DNA methylation and miRNA as gene-regulatory mechanisms. Overall, we can show that miRNA and DNA methylation as molecular markers involved in gene regulation are promising to stratify patients in response to treatment and other environmental exposures.