{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T01:53:52Z","timestamp":1793843632726,"version":"4.6.1"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Epilepsy is characterized by highly abnormal synchronous discharge of brain neurons, and ion channels are fundamental in the generation and modulation of neural excitability. Considering that abnormal methylation can either activate or repress genes, this study was designed to explore the DNA methylation signature of pathogenic genes encoding ion channels in temporal lobe epilepsy (TLE). In total, 38 TLE patients and 38 healthy controls were enrolled in the study, and genomic DNA and total protein of the lymphocytes were extracted from peripheral blood samples to assess methylation and protein levels. The DNA methylation levels of all 12 genes examined were significantly lower in the TLE group than in the control group. After false-positive correction, 83.3% (10\/12) of these genes, namely, gamma-aminobutyric acid type A receptor subunit beta1 <jats:italic>(GABRB1)<\/jats:italic>, gamma-aminobutyric acid type A receptor subunit beta2 <jats:italic>(GABRB2)<\/jats:italic>, gamma-aminobutyric acid type A receptor subunit beta1 <jats:italic>(GABRB3)<\/jats:italic>, glutamate ionotropic receptor NMDA type subunit 1 <jats:italic>(GRIN1)<\/jats:italic>, glutamate ionotropic receptor NMDA type subunit 2A <jats:italic>(GRIN2A)<\/jats:italic>, glutamate ionotropic receptor NMDA type subunit 2B <jats:italic>(GRIN2B)<\/jats:italic>, hyperpolarization activated cyclic nucleotide gated potassium channel 1 <jats:italic>(HCN1)<\/jats:italic>, potassium voltage-gated channel subfamily A member 2 <jats:italic>(KCNA2)<\/jats:italic>, potassium voltage-gated channel subfamily B member 1 <jats:italic>(KCNB1)<\/jats:italic>, and potassium sodium-activated channel subfamily T member 1 (<jats:italic>KCNT1)<\/jats:italic>, were still differentially expressed. Among these ion channels, <jats:italic>HCN1<\/jats:italic> and <jats:italic>KCNA2<\/jats:italic> were selected to evaluate the effects of DNA methylation, and the levels of these proteins were inversely upregulated in the TLE group compared to the control group. As the genes identified as having differential methylation levels are involved in both excitatory and inhibitory ion channels, this study observed by binary logistic regression that hypermethylated <jats:italic>GARAB1<\/jats:italic> was an independent risk factor for TLE, indicating that the overwhelming effect of ion channels on TLE is probably inhibitory from the perspective of DNA methylation. All these findings support the involvement of DNA methylation in TLE pathologies, but the mechanisms need to be further investigated.<\/jats:p>","DOI":"10.3389\/fneur.2021.692412","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T14:26:39Z","timestamp":1627568799000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["DNA Methylation Signature of Epileptic Encephalopathy-Related Pathogenic Genes Encoding Ion Channels in Temporal Lobe Epilepsy"],"prefix":"10.3389","volume":"12","author":[{"given":"Hua","family":"Tao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengqiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawu","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaowen","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haihong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangtao","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keshen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1007\/s13311-014-0263-4","article-title":"Origins of temporal lobe epilepsy: febrile seizures and febrile status epilepticus","volume":"11","author":"Patterson","year":"2014","journal-title":"Neurotherapeutics."},{"key":"B2","doi-asserted-by":"publisher","first-page":"863702","DOI":"10.1155\/2012\/863702","article-title":"Genetics of temporal lobe epilepsy: a review","volume":"2012","author":"Salzmann","year":"2012","journal-title":"Epilep Res Treat."},{"key":"B3","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/nrg3230","article-title":"Functions of DNA methylation: islands, start sites, gene bodies and beyond","volume":"13","author":"Jones","year":"2012","journal-title":"Nat Rev Genet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/nature14192","article-title":"Function and information content of DNA methylation","volume":"517","author":"Sch\u00fcbeler","year":"2015","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.2147\/NDT.S142032","article-title":"Genetic and epigenetic mechanisms of epilepsy: a review","volume":"13","author":"Chen","year":"2017","journal-title":"Neuropsych Dis Treat."},{"key":"B6","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1093\/brain\/awu373","article-title":"Differential DNA methylation profiles of coding and non-coding genes define hippocampal sclerosis in human temporal lobe epilepsy","volume":"138","author":"Miller-Delaney","year":"2015","journal-title":"Brain."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1111\/cns.13394","article-title":"CpG methylation signature defines human temporal lobe epilepsy and predicts drug-resistant","volume":"26","author":"Xiao","year":"2020","journal-title":"CNS Neurosci Therap"},{"key":"B8","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1007\/s12264-017-0134-1","article-title":"Ion channel genes and epilepsy: functional alteration, pathogenic potential, and mechanism of epilepsy","volume":"33","author":"Wei","year":"2017","journal-title":"Neurosci Bull."},{"key":"B9","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1093\/hmg\/ddt403","article-title":"A genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy","volume":"23","author":"Speed","year":"2014","journal-title":"Hum Mol Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.jns.2016.01.052","article-title":"Role of glyoxalase I gene polymorphisms in late-onset epilepsy and drug-resistant epilepsy","volume":"363","author":"Tao","year":"2016","journal-title":"J Neurol Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1111\/jcmm.13473","article-title":"SRR intronic variation inhibits expression of its neighbouring SMG6 gene and protects against temporal lobe epilepsy","volume":"22","author":"Tao","year":"2018","journal-title":"J Cell Mol Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"37","DOI":"10.3390\/jpm8040037","article-title":"The impact of potassium channel gene polymorphisms on antiepileptic drug responsiveness in Arab patients with epilepsy","volume":"8","author":"Al-Eitan","year":"2018","journal-title":"J Personal Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1038\/gim.2015.186","article-title":"Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy","volume":"18","author":"Helbig","year":"2016","journal-title":"Genet Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41436-018-0011-y","article-title":"Evaluating the pathogenic potential of genes with de novo variants in epileptic encephalopathies","volume":"21","author":"He","year":"2019","journal-title":"Genet Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1684\/epd.2012.0518","article-title":"Cryptogenic West syndrome and subsequent mesial temporal lobe epilepsy","volume":"14","author":"Agari","year":"2012","journal-title":"Epil Disord."},{"key":"B16","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1177\/1550059418794347","article-title":"Mesial temporal sclerosis in SCN1A-related epilepsy: two long-term EEG case studies","volume":"50","author":"Tiefes","year":"2019","journal-title":"Clin EEG Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1017\/S204017441300041X","article-title":"Interplay between polymorphisms and methylation in the H19\/IGF2 gene region may contribute to obesity in Mexican-American children","volume":"4","author":"Hern\u00e1ndez-Valero","year":"2013","journal-title":"J Dev Orig Health Dis."},{"key":"B18","first-page":"1","article-title":"DNA methylation and genetic polymorphisms of the Leptin gene interact to influence lung function outcomes and asthma at 18 years of age","volume":"7","author":"Mukherjee","year":"2016","journal-title":"Int J Mol Epidem Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.scr.2017.01.005","article-title":"The role of methylation, DNA polymorphisms and microRNAs on HLA-G expression in human embryonic stem cells","volume":"19","author":"Verloes","year":"2017","journal-title":"Stem Cell Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1111\/j.1528-1167.2009.02397.x","article-title":"Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE commission on therapeutic strategies","volume":"51","author":"Kwan","year":"2010","journal-title":"Epilepsia."},{"key":"B21","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.eplepsyres.2006.06.018","article-title":"Incidence of epilepsy in a racially diverse, community-dwelling, elderly cohort: results from the Einstein aging study","volume":"71","author":"Hussain","year":"2006","journal-title":"Epilep Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1111\/ene.13005","article-title":"Long-term prognosis of epilepsy, prognostic patterns and drug resistance: a population-based study","volume":"23","author":"Giussani","year":"2016","journal-title":"Europ J Neurol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/S0074-7742(08)00002-0","article-title":"Epidemiology and classification of epilepsy: gender comparisons","volume":"83","author":"McHugh","year":"2008","journal-title":"Int Rev Neurob."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.2147\/NDT.S84852","article-title":"Managing drug-resistant epilepsy: challenges and solutions","volume":"12","author":"Dalic","year":"2016","journal-title":"Neuropsych Dis Treat."},{"key":"B25","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1074\/mcp.M113.035600","article-title":"Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics","volume":"13","author":"Fagerberg","year":"2014","journal-title":"Mol Cell Proteom."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.692412\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T14:26:43Z","timestamp":1627568803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.692412\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,29]]},"references-count":25,"alternative-id":["10.3389\/fneur.2021.692412"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2021.692412","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,29]]},"article-number":"692412"}}