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

Engel, Mareen; Eggert, Carola; Kaplick, Paul M.; Eder, Matthias; Röh, Simone; Tietze, Lisa; Namendorf, Christian; Arloth, Janine; Weber, Peter; Rex-Haffner, Monika; Geula, Shay; Jakovcevski, Mira; Hanna, Jacob H.; Leshkowitz, Dena; Uhr, Manfred; Wotjak, Carsten T.; Schmidt, Mathias V.; Deussing, Jan M.; Binder, Elisabeth B.; Chen, Alon

doi:10.1016/j.neuron.2018.07.009

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

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Engel, Mareen
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons226690

Eggert, Carola
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons222130

Kaplick, Paul M.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80315

Eder, Matthias
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons128467

Röh, Simone
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80553

Tietze, Lisa
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80456

Namendorf, Christian
Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons98244

Arloth, Janine
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80580

Weber, Peter
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80495

Rex-Haffner, Monika
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons123271

Jakovcevski, Mira
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80563

Uhr, Manfred
Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80598

Wotjak, Carsten T.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80514

Schmidt, Mathias V.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80301

Deussing, Jan M.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;
RG Molecular Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80272

Binder, Elisabeth B.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons129892

Chen, Alon
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Engel, M., Eggert, C., Kaplick, P. M., Eder, M., Röh, S., Tietze, L., et al. (2018). The Role of m⁶A/m-RNA Methylation in Stress Response Regulation. NEURON, 99(2), 389-403. doi:10.1016/j.neuron.2018.07.009.

Cite as: https://hdl.handle.net/21.11116/0000-0002-5EA9-7

Abstract

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