title: Deep sequencing reveals increased DNA methylation in chronic rat epilepsy.
abstract: Epilepsy is a frequent neurological disorder, although onset and progression of seizures remain difficult to predict in affected patients, irrespective of their epileptogenic condition. Previous studies in animal models as well as human epileptic brain tissue revealed a remarkably diverse pattern of gene expression implicating epigenetic changes to contribute to disease progression. Here we mapped for the first time global DNA methylation patterns in chronic epileptic rats and controls. Using methyl-CpG capture associated with massive parallel sequencing (Methyl-Seq) we report the genomic methylation signature of the chronic epileptic state. We observed a predominant increase, rather than loss of DNA methylation in chronic rat epilepsy. Aberrant methylation patterns were inversely correlated with gene expression changes using mRNA sequencing from same animals and tissue specimens. Administration of a ketogenic, high-fat, low-carbohydrate diet attenuated seizure progression and ameliorated DNA methylation mediated changes in gene expression. This is the first report of unsupervised clustering of an epigenetic mark being used in epilepsy research to separate epileptic from non-epileptic animals as well as from animals receiving anti-convulsive dietary treatment. We further discuss the potential impact of epigenetic changes as a pathogenic mechanism of epileptogenesis.
authors.affiliation: Department of Neuropathology, University Hospital Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany, katja.kobow@uk-erlangen.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Kobow
authors.forename: Antony
authors.initials: A
authors.lastname: Kaspi
authors.forename: K N
authors.initials: KN
authors.lastname: Harikrishnan
authors.forename: Katharina
authors.initials: K
authors.lastname: Kiese
authors.forename: Mark
authors.initials: M
authors.lastname: Ziemann
authors.forename: Ishant
authors.initials: I
authors.lastname: Khurana
authors.forename: Ina
authors.initials: I
authors.lastname: Fritzsche
authors.forename: Jan
authors.initials: J
authors.lastname: Hauke
authors.forename: Eric
authors.initials: E
authors.lastname: Hahnen
authors.forename: Roland
authors.initials: R
authors.lastname: Coras
authors.forename: Angelika
authors.initials: A
authors.lastname: Mühlebner
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.forename: Ingmar
authors.initials: I
authors.lastname: Blümcke
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000235:genetics*; D055423:Diet, Ketogenic; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000235:genetics*; D004827:Epilepsy / Q000178:diet therapy / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D059467:Transcriptome