Differential DNA Methylation Profiles of Coding and Non-coding Genes Define Hippocampal Sclerosis in Human Temporal Lobe Epilepsy

Overview

Journal Brain

Publisher Oxford University Press

Specialty Neurology

Date 2015 Jan 2

PMID 25552301

Citations 87

Authors

Suzanne F C Miller-Delaney

Kenneth Bryan

Sudipto Das

Ross C McKiernan

Isabella M Bray

James P Reynolds

Ryder Gwinn

Raymond L Stallings

David C Henshall

Affiliations

Soon will be listed here.

Abstract

Temporal lobe epilepsy is associated with large-scale, wide-ranging changes in gene expression in the hippocampus. Epigenetic changes to DNA are attractive mechanisms to explain the sustained hyperexcitability of chronic epilepsy. Here, through methylation analysis of all annotated C-phosphate-G islands and promoter regions in the human genome, we report a pilot study of the methylation profiles of temporal lobe epilepsy with or without hippocampal sclerosis. Furthermore, by comparative analysis of expression and promoter methylation, we identify methylation sensitive non-coding RNA in human temporal lobe epilepsy. A total of 146 protein-coding genes exhibited altered DNA methylation in temporal lobe epilepsy hippocampus (n = 9) when compared to control (n = 5), with 81.5% of the promoters of these genes displaying hypermethylation. Unique methylation profiles were evident in temporal lobe epilepsy with or without hippocampal sclerosis, in addition to a common methylation profile regardless of pathology grade. Gene ontology terms associated with development, neuron remodelling and neuron maturation were over-represented in the methylation profile of Watson Grade 1 samples (mild hippocampal sclerosis). In addition to genes associated with neuronal, neurotransmitter/synaptic transmission and cell death functions, differential hypermethylation of genes associated with transcriptional regulation was evident in temporal lobe epilepsy, but overall few genes previously associated with epilepsy were among the differentially methylated. Finally, a panel of 13, methylation-sensitive microRNA were identified in temporal lobe epilepsy including MIR27A, miR-193a-5p (MIR193A) and miR-876-3p (MIR876), and the differential methylation of long non-coding RNA documented for the first time. The present study therefore reports select, genome-wide DNA methylation changes in human temporal lobe epilepsy that may contribute to the molecular architecture of the epileptic brain.

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References

Wang J, Yang B, Han L, Li X, Tao H, Zhang S . Demethylation of miR-9-3 and miR-193a genes suppresses proliferation and promotes apoptosis in non-small cell lung cancer cell lines. Cell Physiol Biochem. 2013; 32(6):1707-19. DOI: 10.1159/000356605. View

Kin T, Ono Y . Idiographica: a general-purpose web application to build idiograms on-demand for human, mouse and rat. Bioinformatics. 2007; 23(21):2945-6. DOI: 10.1093/bioinformatics/btm455. View

Kan A, van Erp S, Derijck A, de Wit M, Hessel E, ODuibhir E . Genome-wide microRNA profiling of human temporal lobe epilepsy identifies modulators of the immune response. Cell Mol Life Sci. 2012; 69(18):3127-45. PMC: 3428527. DOI: 10.1007/s00018-012-0992-7. View

McKiernan R, Jimenez-Mateos E, Bray I, Engel T, Brennan G, Sano T . Reduced mature microRNA levels in association with dicer loss in human temporal lobe epilepsy with hippocampal sclerosis. PLoS One. 2012; 7(5):e35921. PMC: 3352899. DOI: 10.1371/journal.pone.0035921. View

Siegel G, Obernosterer G, Fiore R, Oehmen M, Bicker S, Christensen M . A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol. 2009; 11(6):705-16. PMC: 3595613. DOI: 10.1038/ncb1876. View

Miller C, Sweatt J . Covalent modification of DNA regulates memory formation. Neuron. 2007; 53(6):857-69. DOI: 10.1016/j.neuron.2007.02.022. View

Feng J, Zhou Y, Campbell S, Le T, Li E, Sweatt J . Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci. 2010; 13(4):423-30. PMC: 3060772. DOI: 10.1038/nn.2514. View

Parrish R, Albertson A, Buckingham S, Hablitz J, Mascia K, Davis Haselden W . Status epilepticus triggers early and late alterations in brain-derived neurotrophic factor and NMDA glutamate receptor Grin2b DNA methylation levels in the hippocampus. Neuroscience. 2013; 248:602-19. PMC: 3830613. DOI: 10.1016/j.neuroscience.2013.06.029. View

Robertson K . DNA methylation and human disease. Nat Rev Genet. 2005; 6(8):597-610. DOI: 10.1038/nrg1655. View

10.

Lemke J, Riesch E, Scheurenbrand T, Schubach M, Wilhelm C, Steiner I . Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia. 2012; 53(8):1387-98. DOI: 10.1111/j.1528-1167.2012.03516.x. View

11.

Buckley P, Das S, Bryan K, Watters K, Alcock L, Koster J . Genome-wide DNA methylation analysis of neuroblastic tumors reveals clinically relevant epigenetic events and large-scale epigenomic alterations localized to telomeric regions. Int J Cancer. 2010; 128(10):2296-305. DOI: 10.1002/ijc.25584. View

12.

Lubin F . Epileptogenesis: can the science of epigenetics give us answers?. Epilepsy Curr. 2012; 12(3):105-10. PMC: 3367416. DOI: 10.5698/1535-7511-12.3.105. View

13.

Kaas G, Zhong C, Eason D, Ross D, Vachhani R, Ming G . TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron. 2013; 79(6):1086-93. PMC: 3816951. DOI: 10.1016/j.neuron.2013.08.032. View

14.

Vezzani A, French J, Bartfai T, Baram T . The role of inflammation in epilepsy. Nat Rev Neurol. 2010; 7(1):31-40. PMC: 3378051. DOI: 10.1038/nrneurol.2010.178. View

15.

Wieser H . ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia. 2004; 45(6):695-714. DOI: 10.1111/j.0013-9580.2004.09004.x. View

16.

Lister R, Mukamel E, Nery J, Urich M, Puddifoot C, Johnson N . Global epigenomic reconfiguration during mammalian brain development. Science. 2013; 341(6146):1237905. PMC: 3785061. DOI: 10.1126/science.1237905. View

17.

Jimenez-Mateos E, Engel T, Merino-Serrais P, McKiernan R, Tanaka K, Mouri G . Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat Med. 2012; 18(7):1087-94. PMC: 3438344. DOI: 10.1038/nm.2834. View

18.

Grimson A, Farh K, Johnston W, Garrett-Engele P, Lim L, Bartel D . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007; 27(1):91-105. PMC: 3800283. DOI: 10.1016/j.molcel.2007.06.017. View

19.

Roopra A, Dingledine R, Hsieh J . Epigenetics and epilepsy. Epilepsia. 2012; 53 Suppl 9:2-10. PMC: 3531878. DOI: 10.1111/epi.12030. View

20.

Pitkanen A, Lukasiuk K . Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol. 2011; 10(2):173-86. DOI: 10.1016/S1474-4422(10)70310-0. View