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.
The Role of m6A/m-RNA Methylation in Stress Response Regulation
Engel et al. demonstrate a region- and time-dependent role of brain m6 A/m methylation in stress-response regulation. Manipulating m6 A/m alters fear memory, transcriptome response, and synaptic plasticity. Altered m6 A/m dynamics in depressed patients suggest importance of m6 A/m modifications for stress-related psychiatric disorders.
Max Planck Institute of Psychiatry
