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Neuron. 2018 Jul 25;99(2):389-403.e9. doi: 10.1016/j.neuron.2018.07.009.

The Role of m6A/m-RNA Methylation in Stress Response Regulation.

Author information

1
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.
2
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
3
Clinical Laboratory, Max Planck Institute of Psychiatry, Munich 80804, Germany.
4
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
5
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
6
Bioinformatics Unit, Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 76100, Israel.
7
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
8
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany; Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: alon_chen@psych.mpg.de.

Abstract

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.

KEYWORDS:

Fto; Mettl3; RNA modification; m(6)A; m(6)Am; major depressive disorder; post-transcriptional regulation; stress

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