Epilepsy progression is associated with cumulative DNA methylation changes in inflammatory genes. (February 2022)

• Record Type: Journal Article
• Authors: Martins-Ferreira, Ricardo; Leal, Bárbara; Chaves, João; Li, Tianlu; Ciudad, Laura; Rangel, Rui; Santos, Agostinho; Martins da Silva, António; Pinho Costa, Paulo; Ballestar, Esteban
• Is Part Of: Progress in neurobiology. Volume 209(2022)
• Publication Date: 2022-02
• Subjects: ASD anti-seizure drug -- beta diff difference in mean beta values -- CGI CpG island -- DAM disease-associated microglia -- DAVID Database for Annotation Visualization and Integrated Discovery -- DEGs differentially expressed genes -- DMP differentially methylated CpG position -- DMR differentially methylated region -- DoRothEA Discriminant Regulon Expression Analysis -- DVP differentially variable CpG position -- EGA European Genome-Phenome Archive -- FDR false-discovery rate -- GEO Gene Expression Omnibus -- GO gene ontology -- GREAT Genomic Regions Enrichment of Annotations Tool -- GSEA gene set enrichment analysis -- HS hippocampal sclerosis -- LTM long-term video-EEG monitoring -- MAF minimum allele frequency -- mCSEA methylated CpGs set enrichment analysis -- meDIP methylated DNA immunoprecipitation -- MHC major histocompatibility complex -- MTLE mesial temporal lobe epilepsy -- NES normalized enrichment score -- NFkB nuclear factor kappa-light-chain-enhancer of activated B cells -- PCA principal component analysis -- SPECT single photon emission computed tomography -- SRS spontaneous recurrent seizure -- TF transcription factor -- t-SNE t-distributed stochastic neighbour embedding -- TSS transcription start site; Epilepsy -- Hippocampus -- Neocortex -- DNA methylation -- Inflammation; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2021.102207
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: DNA methylation of epileptogenic pathways is altered in MTLE-HS brain. Neocortical DNA methylation changes are more striking. DNA methylation correlates with epileptic transcriptomic traits. DNA methylation may modulate a self-propagating inflammatory cycle in epilepsy. Abstract: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is the most common focal epilepsy in adults. It is characterized by alarming rates of pharmacoresistance. Epileptogenesis is associated with the occurrence of epigenetic alterations, and the few epigenetic studies carried out in MTLE-HS have mainly focused on the hippocampus. In this study, we obtained the DNA methylation profiles from both the hippocampus and anterior temporal neocortex of MTLE-HS patients subjected to resective epilepsy surgery and autopsied non-epileptic controls. We assessed the progressive nature of DNA methylation changes in relation to epilepsy duration. We identified significantly altered hippocampal DNA methylation patterns encompassing multiple pathways known to be involved in epileptogenesis. DNA methylation changes were even more striking in the neocortex, wherein pathogenic pathways and genes were common to both tissues. Most importantly, DNA methylation changes at many genomic sites varied significantly with epilepsy duration. Such progressive changes were associated with inflammation-related genes in the hippocampus. Our results suggest that the neocortex, relatively spared of extensive histopathological damage, may also be involved in epilepsy development. These results also open the possibility that the observed neocortical impairment could represent a preliminary stage of epileptogenesis before the establishment of chronic lesions or a consequence of prolonged seizure exposure. Our two-tissue multi-level characterization of the MTLE-HS DNA methylome suggests the occurrence of a self-propagating inflammatory wave of epigenetic dysregulation.