The role of m6A/m-RNA methylation in stress response regulation

N6-Methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m6A/m, in the stress response in the adult brain in vivo are currently unknown. Here, we provide a detailed analysis of the stress-epitranscriptome using m6A/m-Seq, global and gene-specific m6A/m measurements. We show that stress exposure and glucocorticoids region- and time-specifically alter m6A/m and its regulatory network. We demonstrate that deletion of the methyltransferase Mettl3 or the demethylase Fto in adult neurons alter the m6A/m epitranscriptome, increase fear memory, alter the transcriptome response to fear and synaptic plasticity. Moreover, we report that regulation of m6A/m is impaired in major depressive disorder (MDD) patients following glucocorticoid stimulation. Our findings indicate that brain m6A/m represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A/m-response may contribute to the pathophysiology of stress-related psychiatric disorders. Refer to individual Series