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Epilepsy progression is associated with cumulative DNA methylation changes in inflammatory genes

2022-02Journal article Restricted access
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dc.contributor.authorMartins-Ferreira, Ricardo
dc.contributor.authorLeal, Bárbara
dc.contributor.authorChaves, João
dc.contributor.authorLi, Tianlu
dc.contributor.authorCiudad, Laura
dc.contributor.authorRangel, Rui
dc.contributor.authorSantos, Agostinho
dc.contributor.authorMartins da Silva, António
dc.contributor.authorPinho Costa, Paulo
dc.contributor.authorBallestar, Esteban
dc.date.accessioned2023-03-20T15:31:39Z
dc.date.available2023-03-20T15:31:39Z
dc.date.issued2022-02
dc.description.abstractMesial 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.pt_PT
dc.description.abstractHighlights: 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.pt_PT
dc.description.sponsorshipE.B. is funded by the Spanish Ministry of Science and Innovation (MICINN) [SAF2017-88086-R, PID2020117212RB-I00; AEI/10.13039/501100011033]. This work was supported by a BICE Tecnifar Grant. R.M.-F was funded by an FCT (Fundação para a Ciência e Tecnologia) fellowship (grant number SFRH/BD/137900/2018). Unit for Multidisciplinary Research in Biomedicine (UMIB) is funded by FCT Portugal (grant numbers UIDB/00215/2020, and UIDP/00215/2020), and Laboratory for Integrative and Translational Research in Population Health (ITR) (LA/P/0064/2020).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationProg Neurobiol. 2022 Feb;209:102207. doi: 10.1016/j.pneurobio.2021.102207. Epub 2021 Dec 16.pt_PT
dc.identifier.doi10.1016/j.pneurobio.2021.102207pt_PT
dc.identifier.issn0301-0082
dc.identifier.urihttp://hdl.handle.net/10400.18/8578
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationUnit for Multidisciplinary Research in Biomedicine
dc.relationUnit for Multidisciplinary Research in Biomedicine
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S0301008221002215?via%3Dihubpt_PT
dc.subjectDNA Methylation;pt_PT
dc.subjectEpilepsypt_PT
dc.subjectHippocampuspt_PT
dc.subjectInflammationpt_PT
dc.subjectNeocortexpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleEpilepsy progression is associated with cumulative DNA methylation changes in inflammatory genespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleUnit for Multidisciplinary Research in Biomedicine
oaire.awardTitleUnit for Multidisciplinary Research in Biomedicine
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00215%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F00215%2F2020/PT
oaire.citation.startPage102207pt_PT
oaire.citation.titleProgress in Neurobiologypt_PT
oaire.citation.volume209pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication5e782b2f-511f-446a-9c30-de1ea4f326df
relation.isProjectOfPublication3b59bbc6-7ac7-4600-b3e8-58aab73d3816
relation.isProjectOfPublication.latestForDiscovery5e782b2f-511f-446a-9c30-de1ea4f326df

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