The role of m6A-RNA methylation in stress response regulation

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Abstract

Summary N6-Methyladenosine (m6A) is an abundant internal RNA modification that regulates transcript processing and translation. The regulation of brain m6A by stressful stimuli in vivo and its role in the stress response are currently unknown. Here, we provide a detailed analysis of the stress-epitranscriptome using m6A-Seq, global and gene-specific m6A measurements. We show that stress exposure and glucocorticoids alter m6A and its regulatory network in a region- and time-specific manner. We demonstrate that depletion of the methyltransferase Mettl3 and the demethylase Fto in adult neurons increases fear memory, and alters the transcriptome response to fear as well as synaptic plasticity. Finally, we report that regulation of m6A is impaired in major depressive disorder patients following glucocorticoid receptor activation. Our findings indicate that brain m6A represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A-response may contribute to the pathophysiology of stress-related psychiatric disorders. Highlights m 6 A RNA methylation in adult mouse brain is regulated by stress Brain m 6 A levels are temporally and spatially regulated by stress Mettl3 and Fto-KO alter fear memory, transcriptome response and synaptic plasticity The m 6 A-glucocorticoid-response is impaired in major depressive disorder patients eTOC blurb Engel et al. demonstrate a brain-area-specific and time-dependent role for the mRNA modification, m 6 A, in stress-response regulation. Manipulating m 6 A-enzymes alters fear-memory, transcriptome-response and synaptic-plasticity. Altered m 6 A dynamics in depressed patients suggest an involvement of m6A-modifications in stress-related psychiatric disorders.

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