Overexpression of FTO alleviates traumatic brain injury induced posttraumatic epilepsy by upregulating NR4A2 expression via m6A demethylation

Abstract

Post-traumatic epilepsy (PTE) is a debilitating chronic outcome of traumatic brain injury (TBI). Although FTO has been reported as a possible intervention target of TBI, its precise roles in the PTE remain incompletely understood. Here we used mild or serious mice TBI model to probe the role and molecular mechanism of FTO in PTE. The results of electroencephalography showed that frequency of epilepsy in serious TBI model mice was more obvious. Using quantitative PCR (qPCR) and western blot analysis, we demonstrated that FTO and NR4A2 were downregulated, while m6A level of NR4A2 mRNA was upregulated in the hippocampus of serious TBI mice. Functionally, FTO overexpression was found to reduce epilepsy susceptibility, blood–brain barrier (BBB) disruption and neuronal damage in TBI mice, suggested a role for FTO in PTE. In addition, RNA-binding protein immunoprecipitation and dual-luciferase assay experiment showed that NR4A2 was a target of FTO, and FTO upregulated NR4A2 expression through m6A-YTHDF2 manner. Furthermore, the molecular and histological changes caused by FTO overexpression are markedly reversed by NR4A2 knockdown in TBI mice. Collectively, our results demonstrate that FTO alleviates epilepsy susceptibility and brain injury after TBI by mediating epigenetic up-regulation of NR4A2, which implicates it as a potential therapeutic target for PTE.