The Role of m ⁶A/m-RNA Methylation in Stress Response Regulation

Summary

N ⁶-methyladenosine (m ⁶A) and N ⁶,2′-O-dimethyladenosine (m ⁶Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m ⁶A/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 m ⁶A/m-seq, global and gene-specific m ⁶A/m measurements. We show that stress exposure and glucocorticoids region and time specifically alter m ⁶A/m and its regulatory network. We demonstrate that deletion of the methyltransferase Mettl3 or the demethylase Fto in adult neurons alters the m ⁶A/m epitranscriptome, increases fear memory, and changes the transcriptome response to fear and synaptic plasticity. Moreover, we report that regulation of m ⁶A/m is impaired in major depressive disorder patients following glucocorticoid stimulation. Our findings indicate that brain m ⁶A/m represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m ⁶A/m response may contribute to the pathophysiology of stress-related psychiatric disorders.

Graphical Abstract

Highlights

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  m ⁶A/m mRNA methylation in the adult mouse brain is regulated by stress

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  m ⁶A/m mRNA regulation is brain region, time, and gene specific

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  Mettl3 and Fto cKO alter m ⁶A/m, fear memory, expression, and synaptic plasticity

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  The m ⁶A/m glucocorticoid response is impaired in major depressive disorder patients

Abstract

Engel et al. demonstrate a region- and time-dependent role of brain m ⁶A/m methylation in stress-response regulation. Manipulating m ⁶A/m alters fear memory, transcriptome response, and synaptic plasticity. Altered m ⁶A/m dynamics in depressed patients suggest importance of m ⁶A/m modifications for stress-related psychiatric disorders.