Decreased Methylation Level of H3K27me3 Increases Seizure Susceptibility

Epigenetic modifications including histone modifications are associated with seizure development and epileptogenesis; however, its underlying mechanism remains to be elucidated. Dipeptidyl peptidase 4 (DPP4) and IL6 are identified as febrile seizure (FS)-related genes using gene microarray analysis in hyperthermia prone (HP) rats. This purpose of the study focused on exploring whether epigenetic modifications marker histone H3 lysine 27 trimethylation (H3K27me3)-regulated DPP4 and IL6 expression further affected seizures development. Herein, we reported broad between-group differences in the global levels of H3K27me3 with increased seizure severity in vivo. Using chromatin immunoprecipitation (ChIP), we identified markedly decreased H3K27me3 enrichment at their promoters of DPP4 and IL6 in vivo. We further showed that hyperthermia significantly decreased protein levels of H3K27me3, increased mRNA levels of DPP4 and IL6 by decreasing H3K27me3 enrichment at their promoters of DPP4 and IL6 in vitro. Importantly, H3K27me3 loss via enhancer of zeste homolog 2 (EZH2) knockdown promoted expression of DPP4 and IL6 via the same mechanism in vitro. EZH2 knockdown also increased neuronal firing frequency in vitro and FS susceptibility in vivo companied with upregulation expression of DPP4 and IL6. Taken together, our study provided the first evidence that hyperthermia-induced decreased of H3K27me3 promoted seizure susceptibility via regulating the expression pattern of DPP4 and IL6. These findings suggested that the methylation level of H3K27me3 might be a key regulator of seizure susceptibility.