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 is 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 alters the m⁶A/m epitranscriptome, increases fear memory, and changes the transcriptome response to fear and synaptic plasticity. Moreover, we report that regulation of m⁶A/m is impaired in major depressive disorder 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.