MethylMiR · The microRNA-m6A epitranscriptome: Integrative analysis of its role in normal brain behaviour and the development of epilepsy

Evidence is emerging that persistent changes in gene expression regulation and post-transcriptional regulation underlies the epileptogenic process. The current proposal builds on preliminary data which suggests that microRNAs (miRNA), which have recently emerged as critical regulators of epileptogenesis, may be subjected to adenosine methylation (m6A), and that this process may also be disrupted in epilepsy, representing an unexplored layer of gene expression regulation likely to influence neuronal activity and seizures. The current proposal will evaluate the effect of m6A on miRNA function, to understand how this influences normal brain behaviour and epileptogenesis. To achieve this, a combined strategy will be used, including interdisciplinary approaches, international and national secondments (University of Aarhus and RSCI), and intersectoral collaborations, which encompasses clinicians (Beaumont Hospital) and industry (STORM Therapeutics). First, hippocampal m6A-tagged miRNAs both during epileptogenesis and in chronic epilepsy will be profiled using an adapted m6A-seq approach using an epilepsy mouse model and resected human epilepsy brain tissue. Then, the effect of m6A on miRNA function and neuronal integrity will be evaluated by targeting miRNA methylation in both mouse and human cell lines. Next, clinical outcomes of pharmacological targeting of miRNA methylation on epilepsy development will be evaluated using an epilepsy mouse model. Together this proposal represents the first miRNA methylation study in the brain, which is hoped will illuminate novel therapeutic strategies for the treatment of epilepsy. This project is ideal to further my interest in translational neuroscience while also developing a network of collaborators across Europe and develop my scientific skills. This fellowship represents the best option to achieve my career goal of establishing myself as an independent researcher and consolidating my career in the European research environment.