Differential DNA Methylation Patterns Define Status Epilepticus and Epileptic Tolerance

Abstract

Prolonged seizures (status epilepticus) produce pathophysiological changes in the hippocampus that are associated with large-scale, wide-ranging changes in gene expression. Epileptic tolerance is an endogenous program of cell protection that can be activated in the brain by previous exposure to a non-harmful seizure episode before status epilepticus. A major transcriptional feature of tolerance is gene downregulation. Here, through methylation analysis of 34,143 discrete loci representing all annotated CpG islands and promoter regions in the mouse genome, we report the genome-wide DNA methylation changes in the hippocampus after status epilepticus and epileptic tolerance in adult mice. A total of 321 genes showed altered DNA methylation after status epilepticus alone or status epilepticus that followed seizure preconditioning, with Ͼ90% of the promoters of these genes undergoing hypomethylation. These profiles included genes not previously associated with epilepsy, such as the polycomb gene Phc2. Differential methylation events generally occurred throughout the genome without bias for a particular chromosomal region, with the exception of a small region of chromosome 4, which was significantly overrepresented with genes hypomethylated after status epilepticus. Surprisingly, only few genes displayed differential hypermethylation in epileptic tolerance. Nevertheless, gene ontology analysis emphasized the majority of differential methylation events between the groups occurred in genes associated with nuclear functions, such as DNA binding and transcriptional regulation. The present study reports select, genome-wide DNA methylation changes after status epilepticus and in epileptic tolerance, which may contribute to regulating the gene expression environment of the seizure-damaged hippocampus.

Epigenetic Downregulation of Scn3a Expression by Valproate: a Possible Role in Its Anticonvulsant Activity

“…The expression alterations of a number of genes resulted from the changes in CpG methylations occur in seizure mice [34], including our previous findings that Scn3a upregulation under a seizure condition is resulted from the MBD2-mediated CpG demethylation of the -39C site in its promoter [11]. Furthermore, in this study, we show that VPA induces the -39C methylation, which then decreases Scn3a expression (Fig.…”

“…It is interesting to note that FTO, a m 6 A demethylase [37,38], is strongly associated with body weight mass [32][33][34][35][36]. Furthermore, chronic administration of VPA is shown to contribute to obesity in patients [29][30][31].…”

“…In view of the fact that fat mass and obesity-associated (FTO) protein is strongly associated with body weight mass [32][33][34][35][36], and FTO has been shown to catalyze m 6 A demethylation on RNAs [37,38]; thus, it is possible that VPA could posttranscriptionally regulate gene expression through a FTO-mediated epigenetic pathway, since a link between FTO, RNA epigenetics, and epilepsy has been previously put forward [39].…”

“…Abnormal alterations in DNA methylation profiles are also found in animal seizure models. For example, the differential CpG methylation patterns identified by a genome-wide CpG methylation analysis in the brains of prolonged seizures (status epilepticus) and epileptic tolerance mice may contribute to the altered gene expressions in the seizure-damaged hippocampus [34]. These evidences suggest a critical role of epigenetic-mediated gene expression in epilepsy development.…”

Seizure Disorders and Epilepsy

“…19 By contrast, patients with MTLE show enhanced expression of the DNA methyltransferase gene, which would be expected to lead to enhanced transcriptional silencing of DNA.…”