Downregulation of FTO in hippocampus of rats participates in the Mental Disorders during pregnancy induced by fear-stress

Mental disorders (MD) during pregnancy is a disease with mood abnormalities and cognitive impairments leading to adverse pregnancy outcomes, but the underlying mechanisms remain unclear. N6-methyladenosine (m6A) is widely studied as the most common post-transcriptional modification of RNA, however, the role of m6A modification in MD during pregnancy caused by fear-stress is unclear. Study of our group have observed that FTO is downregulated in the hippocampus of pregnant rats with MD caused by fear-stress. To investigate the role of FTO in MD during pregnancy caused by fear-stress, we reduced FTO expression in the hippocampus by the FTO inhibitor R-2-hydroxyglutarate (R-2HG). Results of Western blot and real-time quantitative polymerase chain reaction (RT-qPCR) showed that the expression level of FTO in the R-2HG group was reduced, while its overall methylation level was increased. Cross-analysis of MeRIP-seq and RNA-seq showed that there were 83 aberrantly modified and expressed genes (double aberrant genes) in the model group and 39 double aberrant genes in the R-2HG group compared to the control group. Using MeRIP-qPCR and RT-qPCR, we identified and validated four key genes (Angpt2, Fgf10, Rpl21, Adcy7) under FTO-mediated m6A modification, in which Angpt2, Fgf10, Rpl21 may induce MD by regulating PI3K/Akt and Rap1 signaling pathways. This study suggests that FTO-mediated m6A modifications play an important regulatory role in MD during pregnancy caused by fear-stress. Our work explores the RNA epigenetic regulation pattern of MD during pregnancy for the first time.