Commonalities in gene expression and methylation changes across two rat models of acquired epilepsy

Changes in DNA methylation and gene expression play a major role in the epileptogenic process that turns a healthy brain into an epileptic brain. Previous investigations have focused either on changes in the transcriptome or epigenome, but rarely on both. The goal of this combined transcriptomic and epigenomic investigation was to identify shared and distinct changes in gene expression and DNA methylation in two widely used, but mechanistically distinct, rat models of temporal lobe epilepsy: intrahippocampal electrical kindling and systemic kainic acid induced epilepsy. RNA sequencing and reduced-representation bisulfite sequencing were used to assess differences in gene expression and DNA methylation. We found gene expression and methylation changes specific to each model, and genes with altered expression (n = 71) or methylation (n = 94) in the same direction in both models. Remarkably, there was no overlap between these genes that were either altered in their expression or methylation in the same direction in both models. Furthermore, there was no consistent relationship between the direction of methylation and expression changes in either model. These observations indicate that transcriptomic and epigenetic changes during epileptogenesis are distinct processes, which is of importance for the discovery of disease-modifying therapeutics that act on a transcriptomic or epigenomic level.