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

Abstract

SummaryN6-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.

Topologies of N6‐adenosine methylation (m6A) in land plant mitochondria and their putative effects on organellar gene expression

“…4–5 m 6 A modifications per 1000 adenosine nucleotides) in Arabidopsis and cauliflower mitochondria, respectively (Table S2). Analyses of the relative m 6 A levels using calorimetric measurements have been previously shown to be well correlated with those of liquid MS/MS analyses (Slobodin et al , ; Engel et al , ). The data were also in agreement with previous reports by Luo et al () and Wang et al (), which suggested that the extent of m 6 A modifications in Arabidopsis organelles (i.e.…”

Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

“…Inaccuracy, failure, or misuse of each of these pathways can trigger very different consequences on the genome. DSB repair pathway choice can be influenced by cell cycle phase (Hustedt and Durocher, 2016), DNA end complexity (Schipler and Iliakis, 2013), and the type of damaged locus (Clouaire and Legube, 2015, Engel et al., 2018). …”

The m6A reader Ythdf restricts axonal growth inDrosophilathrough target selection modulation of the Fragile X mental retardation protein

“…Increasing evidence suggests a central role of m 6 A during nervous system development and functions (Angelova et al, 2018;Du et al, 2019;Jung and Goldman, 2018;Li et al, 2019;Livneh et al, 2020;Widagdo and Anggono, 2018). m 6 A is present at particularly high levels in the nervous system of different model animals (Lence et al, 2016;Meyer et al, 2012), and these levels can vary following behavioral stimuli or sensory experience (Engel et al, 2018;Koranda et al, 2018;Widagdo et al, 2016;Yoon et al, 2018). In mouse, m 6 A controls brain development Li et al, 2017;Li et al, 2018;Ma et al, 2018;Wang et al, 2018;Zhuang et al, 2019) and is also required for axon regeneration and synaptic functions (Engel et al, 2018;Koranda et al, 2018;Merkurjev et al, 2018;Shi et al, 2018;Yu et al, 2018).…”

“…m 6 A is present at particularly high levels in the nervous system of different model animals (Lence et al, 2016;Meyer et al, 2012), and these levels can vary following behavioral stimuli or sensory experience (Engel et al, 2018;Koranda et al, 2018;Widagdo et al, 2016;Yoon et al, 2018). In mouse, m 6 A controls brain development Li et al, 2017;Li et al, 2018;Ma et al, 2018;Wang et al, 2018;Zhuang et al, 2019) and is also required for axon regeneration and synaptic functions (Engel et al, 2018;Koranda et al, 2018;Merkurjev et al, 2018;Shi et al, 2018;Yu et al, 2018). Similarly, in Drosophila, m 6 A promotes flight and locomotion via a neuronal function (Haussmann et al, 2016;Kan et al, 2017;Lence et al, 2016;Lence et al, 2017).…”