Neuronal and glial DNA methylation and gene expression changes in early epileptogenesis

Mesial Temporal Lobe Epilepsy is characterized by progressive changes of both neurons and glia, also referred to as epileptogenesis. No curative treatment options, apart from surgery, are available. DNA methylation (DNAm) is a potential upstream mechanism in epileptogenesis and may serve as a novel...

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Bibliographic Details
Published in:PloS one 2019, Vol.14 (12), p.e0226575-e0226575
Main Authors: Berger, Toni C, Vigeland, Magnus D, Hjorthaug, Hanne S, Etholm, Lars, Nome, Cecilie G, Taubøll, Erik, Heuser, Kjell, Selmer, Kaja K
Format: Article
Language:eng ; nor
Subjects:
Animals
Biology and Life Sciences
Bisulfite
Convulsions & seizures
Deoxyribonucleic acid
Disease Models, Animal
DNA
DNA Methylation
Dopamine D1 receptors
Epigenesis, Genetic
Epilepsy
Epilepsy, Temporal Lobe - chemically induced
Epilepsy, Temporal Lobe - genetics
Flow cytometry
Galanin - genetics
Gene expression
Gene Expression Profiling - methods
Gene Expression Regulation
Gene Regulatory Networks
Gene sequencing
Genes
Genetic Predisposition to Disease
Hippocampus
Histone Deacetylases - genetics
Hospitals
Injection
Kainic acid
Kainic Acid - adverse effects
Male
Medicine and Health Sciences
Mice
Neuroglia - chemistry
Neurology
Neuronal-glial interactions
Neurons
Neurons - chemistry
Osteopontin - genetics
Receptors, Dopamine D1 - genetics
Sequence Analysis, DNA
Sequence Analysis, RNA
Statistical analysis
Surgery
Temporal lobe
Therapeutic applications
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Summary:Mesial Temporal Lobe Epilepsy is characterized by progressive changes of both neurons and glia, also referred to as epileptogenesis. No curative treatment options, apart from surgery, are available. DNA methylation (DNAm) is a potential upstream mechanism in epileptogenesis and may serve as a novel therapeutic target. To our knowledge, this is the first study to investigate epilepsy-related DNAm, gene expression (GE) and their relationship, in neurons and glia. We used the intracortical kainic acid injection model to elicit status epilepticus. At 24 hours post injection, hippocampi from eight kainic acid- (KA) and eight saline-injected (SH) mice were extracted and shock frozen. Separation into neurons and glial nuclei was performed by flow cytometry. Changes in DNAm and gene expression were measured with reduced representation bisulfite sequencing (RRBS) and mRNA-sequencing (mRNAseq). Statistical analyses were performed in R with the edgeR package. We observed fulminant DNAm- and GE changes in both neurons and glia at 24 hours after initiation of status epilepticus. The vast majority of these changes were specific for either neurons or glia. At several epilepsy-related genes, like HDAC11, SPP1, GAL, DRD1 and SV2C, significant differential methylation and differential gene expression coincided. We found neuron- and glia-specific changes in DNAm and gene expression in early epileptogenesis. We detected single genetic loci in several epilepsy-related genes, where DNAm and GE changes coincide, worth further investigation. Further, our results may serve as an information source for neuronal and glial alterations in both DNAm and GE in early epileptogenesis.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0226575