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