Journal
NEURON
Volume 99, Issue 2, Pages 389-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2018.07.009
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Funding
- Boehringer Ingelheim Fonds
- European Research Council (FP7 grant) [260463]
- Israel Science Foundation [1565/15, 1916/12, 355/17, 107/14]
- ERANET Program
- Chief Scientist Office of the Israeli Ministry of Health [3-11389]
- Federal Ministry of Education and Research [01KU1501A]
- I-CORE Program of the Planning and Budgeting Committee
- Nella and Leon Benoziyo Center for Neurological Diseases
- Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics
- Perlman Family Foundation
- Adelis Foundation
- Irving I. Moskowitz Foundation
- FAMRI grant
- NYSCF grant
- European Research Council (ERC) [260463] Funding Source: European Research Council (ERC)
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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.
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