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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / genetics
  • Adenosine / metabolism
  • Adult
  • Animals
  • Cell Line, Transformed
  • Humans
  • Male
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism*
  • Stress, Psychological / genetics*
  • Stress, Psychological / metabolism*
  • Stress, Psychological / psychology

Substances

  • RNA, Messenger
  • N(6)-methyladenosine
  • Adenosine