Differential DNA methylation patterns define status epilepticus and epileptic tolerance.

Suzanne F C Miller-Delaney, Royal College of Surgeons in Ireland
Sudipto Das, Royal College of Surgeons in Ireland
Takanori Sano, Royal College of Surgeons in Ireland
Eva M. Jimenez-Mateos, Royal College of Surgeons in Ireland
Kenneth Bryan, Royal College of Surgeons in Ireland
Patrick G. Buckley, Royal College of Surgeons in Ireland
Raymond L. Stallings, Royal College of Surgeons in Ireland
David C. Henshall, Royal College of Surgeons in Ireland

Document Type Article

This article is also available at http://www.jneurosci.org/content/32/5/1577.long

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 >90% 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.