Epilepsy is a common and devastating neurological disorder characterized by recurrent and unprovoked spontaneous seizures. One leading hypothesis for the development and progression of epilepsy is that large-scale changes in gene transcription and protein expression contribute to aberrant network restructuring and hyperexcitability, resulting in the genesis of repeated seizures. Current research shows that epigenetic mechanisms, including posttranslational alterations to the proteins around which DNA is coiled, chemical modifications to DNA, and the activity of various noncoding RNA molecules exert important influences on these gene networks in experimental epilepsy. Key findings from animal models have been replicated in humans using brain tissue obtained from living patients at the time of neurosurgical resection for pharmacoresistant epilepsy. These findings have spurred efforts to target epigenetic processes to disrupt or modify epilepsy in experimental models with varying degrees of success. In this review, we will (1) summarize the epigenetic mechanisms implicated in epileptogenesis and epilepsy, (2) explore the influence of metabolic factors on epigenetic mechanisms, and (3) assess the potential of using epigenetic markers to support diagnosis and prognosis. Translation of these findings may guide the development of molecular biomarkers and novel therapeutics for prevention or modification of epileptic disorders.
AizawaSYamamuroY.2015. Valproate administration to mice increases hippocampal p21 expression by altering genomic DNA methylation. Neuroreport26(15):915–20.
2.
AlbrightBDhaherRWangHHarbRLeeTWZaveriH, and others. 2016. Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition. Exp Neurol288:122–33.
3.
BarryGBriggsJAHwangDWNaylerSPFortunaPRJonkhoutN, and others. 2017. The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states. Sci Rep7:40127.
4.
BelhediNPerroudNKaregeFVessazMMalafosseASalzmannA.2014. Increased CPA6 promoter methylation in focal epilepsy and in febrile seizures. Epilepsy Res108(1):144–8.
5.
BergerSLSassone-CorsiP.2016. Metabolic signaling to chromatin. Cold Spring Harb Perspect Biol8(11):a019463. doi:10.1101/cshperspect.a019463.
6.
BernardDPrasanthKVTripathiVColasseSNakamuraTXuanZ, and others. 2010. A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J29(18):3082–93.
7.
BlumckeIThomMAronicaEArmstrongDDBartolomeiFBernasconiA, and others. 2013. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia54(7):1315–29.
8.
BoisonD. 2016. Adenosinergic signaling in epilepsy. Neuropharmacology104:131–9.
9.
ButlerAAWebbWMLubinFD. 2016. Regulatory RNAs and control of epigenetic mechanisms: expectations for cognition and cognitive dysfunction. Epigenomics8(1):135–51.
10.
CampbellPNWorkTSMellanbyE.1951. The isolation of a toxic substance from agenized wheat flour. Biochem J48(1):106–13.
11.
CloixJFHevorT.2009. Epilepsy, regulation of brain energy metabolism and neurotransmission. Curr Med Chem16(7):841–53.
12.
CrosioCHeitzEAllisCDBorrelliESassone-CorsiP.2003. Chromatin remodeling and neuronal response: multiple signaling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons. J Cell Sci116(Pt 24):4905–14.
13.
DebskiKJPitkanenAPuhakkaNBotAMKhuranaIHarikrishnanKN, and others. 2016. Etiology matters—genomic DNA methylation patterns in three rat models of acquired epilepsy. Sci Rep6:25668.
14.
DetichNBovenziVSzyfM.2003. Valproate induces replication-independent active DNA demethylation. J Biol Chem278(30):27586–92.
15.
DhaherRWangHGruenbaumSETuNLeeTSZaveriHP, and others. 2015. Effects of site-specific infusions of methionine sulfoximine on the temporal progression of seizures in a rat model of mesial temporal lobe epilepsy. Epilepsy Res115:45–54.
16.
DhediyaRMJoshiSSGajbhiyeSVJalgaonkarSVBiswasM.2016. Evaluation of antiepileptic effect of S-adenosyl methionine and its role in memory impairment in pentylenetetrazole-induced kindling model in rats. Epilepsy Behav61:153–7.
17.
FalconerMA. 1974. Mesial temporal (Ammon’s horn) sclerosis as a common cause of epilepsy. Aetiology, treatment, and prevention. Lancet2(7883):767–70.
18.
FernándezEGregerBHousePAArandaIBotellaCAlbisuaJ and others. 2014. Acute human brain responses to intracortical microelectrode arrays: challenges and future prospects. Front Neuroeng7:24.
19.
GottlicherMMinucciSZhuPKramerOHSchimpfAGiavaraS, and others. 2001. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J20(24):6969–78.
20.
GrossCYaoXEngelTTiwariDXingLRowleyS, and others. 2016. MicroRNA-mediated downregulation of the potassium channel Kv4.2 contributes to seizure onset. Cell Rep17(1):37–45.
Gupta-AgarwalSFranklinAVDeramusTWheelockMDavisRLMcMahonLL, and others. 2012. G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. J Neurosci32(16):5440–53.
23.
HenshallDCHamerHMPasterkampRJGoldsteinDBKjemsJPrehnJH, and others. 2016. MicroRNAs in epilepsy: pathophysiology and clinical utility. Lancet Neurol15(13):1368–76.
24.
HoffmannKCzappMLoscherW.2008. Increase in antiepileptic efficacy during prolonged treatment with valproic acid: role of inhibition of histone deacetylases?Epilepsy Res81(2-3):107–13.
25.
HsiaoJYuanTYTsaiMSLuCYLinYCLeeML, and others. 2016. Upregulation of haploinsufficient gene expression in the brain by targeting a long non-coding RNA improves seizure phenotype in a model of Dravet syndrome. EBioMedicine9:257–77.
26.
HuangYDohertyJJDingledineR.2002. Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus. J Neurosci22(19):8422–8.
27.
HuangYPastorWAShenYTahilianiMLiuDRRaoA.2010. The behaviour of 5-hydroxymethylcytosine in bisulfite sequencing. PLoS One5(1):e8888.
28.
IoriVIyerAMRavizzaTBeltrameLParacchiniLMarchiniS and others. 2017. Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol Dis99:12–23.
29.
Jimenez-MateosEMArribas-BlazquezMSanz-RodriguezAConcannonCOlivos-OreLAReschkeCR, and others. 2015a. microRNA targeting of the P2X7 purinoceptor opposes a contralateral epileptogenic focus in the hippocampus. Sci Rep5:17486.
30.
Jimenez-MateosEMEngelTMerino-SerraisPFernaud-EspinosaIRodriguez-AlvarezNReynoldsJ, and others. 2015b. Antagomirs targeting microRNA-134 increase hippocampal pyramidal neuron spine volume in vivo and protect against pilocarpine-induced status epilepticus. Brain Struct Funct220(4):2387–99.
31.
JinS-GKadamSPfeiferGP. 2010. Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosine. Nucleic Acids Res38(11):e125.
32.
KaasGAZhongCEasonDERossDLVachhaniRVMingGL, and others. 2013. TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron79(6):1086–93.
33.
KawamuraMJrRuskinDNGeigerJDBoisonDMasinoSA. 2014. Ketogenic diet sensitizes glucose control of hippocampal excitability. J Lipid Res55(11):2254–60.
34.
KawamuraMJRuskinDNMasinoSA. 2016. Metabolic therapy for temporal lobe epilepsy in a dish: investigating mechanisms of ketogenic diet using electrophysiological recordings in hippocampal slices. Front Mol Neurosci9:112.
35.
KlepperJSchefferHLeiendeckerBGertsenEBinderSLeferinkM, and others. 2005. Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics36(5):302–8.
36.
KobowKEl-OstaABlümckeI.2013a. The methylation hypothesis of pharmacoresistance in epilepsy. Epilepsia54:41–7.
37.
KobowKJeskeIHildebrandtMHaukeJHahnenEBusleiR, and others. 2009. Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy. J Neuropathol Exp Neurol68(4):356–64.
38.
KobowKKaspiAHarikrishnanKNKieseKZiemannMKhuranaI, and others. 2013b. Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol126(5):741–56.
39.
KriaucionisSHeintzN.2009. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science324(5929):929–30.
40.
KundakovicMChenYCostaEGraysonDR. 2007. DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes. Mol Pharmacol71(3):644–53.
41.
KwanPBrodieMJ. 2000. Early identification of refractory epilepsy. N Engl J Med342(5):314–9.
42.
LeeDYMoonJLeeSTJungKHParkDKYooJS, and others. 2015. Dysregulation of long non-coding RNAs in mouse models of localization-related epilepsy. Biochem Biophys Res Commun462(4):433–40.
43.
LeeSTJeonDChuKJungKHMoonJSunwooJ, and others. 2016. Inhibition of miR-203 reduces spontaneous recurrent seizures in mice. Mol Neurobiol. May10, Epub ahead of print. doi:10.1007/s12035-016-9901-7.
44.
LiHJWanRPTangLJLiuSJZhaoQHGaoMM, and others. 2015. Alteration of Scn3a expression is mediated via CpG methylation and MBD2 in mouse hippocampus during postnatal development and seizure condition. Biochim Biophys Acta1849(1):1–9.
45.
LiTRenGLusardiTWilzALanJQIwasatoT, and others. 2008. Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice. J Clin Invest118(2):571–82.
46.
LiuXOuSXuTLiuSYuanJHuangH, and others. 2016. New differentially expressed genes and differential DNA methylation underlying refractory epilepsy. Oncotarget7(52):87402–16.
47.
LongHYFengLKangJLuoZHXiaoWBLongLL, and others. 2017. Blood DNA methylation pattern is altered in mesial temporal lobe epilepsy. Sci Rep7:43810.
48.
LubinFD. 2012. Epileptogenesis: can the science of epigenetics give us answers?Epilepsy Curr12(3):105–10.
49.
LubinFDRothTLSweattJD. 2008. Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci28(42):10576–86.
50.
LystMJBirdA.2015. Rett syndrome: a complex disorder with simple roots. Nat Rev Genet16(5):261–75.
51.
MaDKJangM-HGuoJUKitabatakeYChangM-LPow-AnpongkulN, and others. 2009. Neuronal activity–induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science323(5917):1074–7.
52.
MachnesZMHuangTCChangPKGillRReistNDezsiG, and others. 2013. DNA methylation mediates persistent epileptiform activity in vitro and in vivo. PLoS One8(10):e76299.
53.
Martinez-LevyGARochaLLubinFDAlonso-VanegasMANaniABuentello-GarciaRM, and others. 2016. Increased expression of BDNF transcript with exon VI in hippocampi of patients with pharmaco-resistant temporal lobe epilepsy. Neuroscience314:12–21.
54.
MellenMAyataPDewellSKriaucionisSHeintzN.2012. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell151(7):1417–30.
55.
Miller-DelaneySFBryanKDasSMcKiernanRCBrayIMReynoldsJP, and others. 2015. Differential DNA methylation profiles of coding and non-coding genes define hippocampal sclerosis in human temporal lobe epilepsy. Brain 138(Pt 3):616–31.
56.
Miller-DelaneySFCDasSSanoTJimenez-MateosEMBryanKBuckleyPG, and others. 2012. Differential DNA methylation patterns define status epilepticus and epileptic tolerance. J Neurosci32(5):1577–88.
57.
MilutinovicSD’AlessioACDetichNSzyfM.2007. Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis28(3):560–71.
58.
MooneyCBeckerBARaoofRHenshallDC. 2016. EpimiRBase: a comprehensive database of microRNA-epilepsy associations.Bioinformatics32(9):1436–8.
59.
MunzelMGlobischDBrucklTWagnerMWelzmillerVMichalakisS, and others. 2010. Quantification of the sixth DNA base hydroxymethylcytosine in the brain. Angew Chem Int Ed Engl49(31):5375–7.
60.
NgugiAKBottomleyCKleinschmidtISanderJWNewtonCR. 2010. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia51(5):883–90.
61.
OkanoMBellDWHaberDALiE.1999. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell99(3):247–57.
62.
OlsenGMSonnewaldU.2015. Glutamate: where does it come from and where does it go?Neurochem Int88:47–52.
63.
ParrishRAlbertsonAJBuckinghamSCHablitzJJMasciaKLDavis HaseldenW, and others. 2013. Status epilepticus triggers early and late alterations in brain-derived neurotrophic factor and NMDA glutamate receptor Grin2b DNA methylation levels in the hippocampus. Neuroscience248:602–19.
64.
ParrishRRBuckinghamSCMasciaKLJohnsonJJMatyjasikMMLockhartRM, and others. 2015. Methionine increases BDNF DNA methylation and improves memory in epilepsy. Ann Clin Transl Neurol2(4):401–16.
65.
PerrineKHermannBPMeadorKJVickreyBGCramerJAHaysRD, and others. 1995. The relationship of neuropsychological functioning to quality of life in epilepsy. Arch Neurol52(10):997–1003.
66.
RajanISavelievaKVYeG-LWangC-YMalbariMMFriddleC, and others. 2009. Loss of the putative catalytic domain of HDAC4 leads to reduced thermal nociception and seizures while allowing normal bone development. PLoS One4(8):e6612.
67.
ReschkeCRSilvaLFANorwoodBASenthilkumarKMorrisGSanz-RodriguezA, and others. 2017. Potent anti-seizure effects of locked nucleic acid antagomirs targeting miR-134 in multiple mouse and rat models of epilepsy. Mol Ther Nucleic Acids6:45–56.
68.
RichardOHevorT.1995. Methionine sulfoximine increases acetylcholine level in the rat brain: no relation with epileptogenesis. Neuroreport6(15):2027–32.
69.
SngJCTaniuraHYonedaY.2006. Histone modifications in kainate-induced status epilepticus. Eur J Neurosci23(5):1269–82.
70.
SpainEJimenez-MateosEMRaoofRElNaggarHDelantyNForsterRJ, and others. 2015. Direct, non-amplified detection of microRNA-134 in plasma from epilepsy patients. RSC Adv5(109):90071–8.
71.
SpruijtCGGnerlichFSmitsAHPfaffenederTJansenPWBauerC, and others. 2013. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell152(5):1146–59.
72.
St LaurentGWahlestedtCKapranovP. 2015. The landscape of long non-coding RNA classification. Trends Genet31(5):239–51.
73.
StafstromCEOckulyJCMurphreeLValleyMTRoopraASutulaTP. 2009. Anticonvulsant and antiepileptic actions of 2-deoxy-d-glucose in epilepsy models. Ann Neurol65(4):435–47.
74.
StafstromCERoopraASutulaTP. 2008. Seizure suppression via glycolysis inhibition with 2-deoxy-d-glucose (2DG). Epilepsia49(Suppl 8):97–100.
75.
TahilianiMKohKPShenYPastorWABandukwalaHBrudnoY, and others. 2009. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science324(5929):930–5.
76.
TaniuraHSngJCYonedaY.2006. Histone modifications in status epilepticus induced by kainate. Histol Histopathol21(7):785–91.
77.
ThomasRHBerkovicSF. 2014. The hidden genetics of epilepsy-a clinically important new paradigm. Nat Rev Neurol10(5):283–92.
78.
van GassenKLvan der HelWSHakvoortTBLamersWHde GraanPN. 2009. Haploinsufficiency of glutamine synthetase increases susceptibility to experimental febrile seizures. Genes Brain Behav8(3):290–5.
79.
WangDLiZZhangYWangGWeiMHuY and others. 2016a. Targeting of microRNA-199a-5p protects against pilocarpine-induced status epilepticus and seizure damage via SIRT1-p53 cascade. Epilepsia57(5):706–16.
80.
WangJTanLTanLTianYMaJTanCC, and others. 2015. Circulating microRNAs are promising novel biomarkers for drug-resistant epilepsy. Sci Rep5:10201.
81.
WangLFuXPengXXiaoZLiZChenG, and others. 2016b. DNA methylation profiling reveals correlation of differential methylation patterns with gene expression in human epilepsy. J Mol Neurosci59(1):68–77.
82.
WangWWangXChenLZhangYXuZLiuJ, and others. 2016c. The microRNA miR-124 suppresses seizure activity and regulates CREB1 activity. Expert Rev Mol Med18:e4.
83.
WangXSunYTanZCheNJiALuoX, and others. 2016d. Serum microRNA-4521 is a potential biomarker for focal cortical dysplasia with refractory epilepsy. Neurochem Res41(4):905–12.
84.
WenLLiXYanLTanYLiRZhaoY, and others. 2014. Previously considered to be a stable mark, it is now known that DNA methylation is dynamic, and methyl groups can be modified or removed from DNA residues through the activity of certain enzymes. Genome Biol15(3):R49.
85.
WiebeSBlumeWTGirvinJPEliasziwM.2001. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med345(5):311–8.
86.
Williams-KarneskyRLSandauUSLusardiTALytleNKFarrellJMPritchardEM, and others. 2013. Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Invest123(8):3552–63.
87.
WuHD’AlessioACItoSWangZCuiKZhaoK, and others. 2011. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev25(7):679–84.
88.
XiaoWCaoYLongHLuoZLiSDengN, and others. 2017. Genome-wide DNA methylation patterns analysis of noncoding RNAs in temporal lobe epilepsy patients. Mol Neurobiol. Jan5, Epub ahead of print. doi:10.1007/s12035-016-0353-x.
89.
XuWWangFYuZXinF.2016. Epigenetics and cellular metabolism. Genet Epigenet8:43–51.
90.
ZhanLYaoYFuHLiZWangFZhangX, and others. 2016. Protective role of miR-23b-3p in kainic acid–induced seizure. Neuroreport27(10):764–8.
91.
ZhengHTangRYaoYJiZCaoYLiuZ, and others. 2016. MiR-219 protects against seizure in the kainic acid model of epilepsy. Mol Neurobiol53(1):1–7.
92.
ZhongJChuangSCBianchiRZhaoWLeeHFentonAA, and others. 2009. BC1 regulation of metabotropic glutamate receptor-mediated neuronal excitability. J Neurosci29(32):9977–86.
93.
ZhuQWangLZhangYZhaoFHLuoJXiaoZ, and others. 2012. Increased expression of DNA methyltransferase 1 and 3a in human temporal lobe epilepsy. J Mol Neurosci46(2):420–6.
94.
Zybura-BrodaKAmborskaRAmbrozek-LateckaMWilemskaJBoguszABuckoJ, and others. 2016. Epigenetics of epileptogenesis-evoked upregulation of matrix metalloproteinase-9 in hippocampus. PLoS One11(8):e0159745.
