基因启动子甲基化在癫痫的研究进展_Journal of Epilepsy

Authors：

黎银潮 ¹ , 秦家明 ² , 林婉蓉 ¹ , 赵怡然 ¹ , 陈傲寒 ¹ ,  周列民 ¹

1. ;
2. ;

Corresponding author：

周列民, Email: lmzhou56@163.com

Keywords：

启动子; DNA 甲基化; 表观遗传学; 癫痫; 研究进展

DOI：

10.7507/2096-0247.20200071

Video：

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DNA 甲基化是人类发现最早的表观遗传学修饰之一，具有多种调控功能，参与机体发育过程中干细胞生长、细胞增殖、器官发育、衰老和肿瘤发生等多个生物学过程，而且在突触重塑、神经细胞分化等神经生物过程中也具有重要作用。近年来，越来越多的研究表明 DNA 甲基化修饰与癫痫的发病机制密切相关，特别是基因启动子的甲基化改变逐渐受到关注。文章主要对表观遗传中基因启动子区的甲基化在癫痫发生发展中的研究进展进行综述。

Citation： 黎银潮, 秦家明, 林婉蓉, 赵怡然, 陈傲寒, 周列民. 基因启动子甲基化在癫痫的研究进展. Journal of Epilepsy, 2020, 6(5): 431-435. doi: 10.7507/2096-0247.20200071 Copy

1.	Dalic L, Cook MJ. Managing drug-resistant epilepsy: challenges and solutions. Neuropsychiatr Dis Treat, 2016, 12: 2605-2616.
2.	Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states. Science, 2010, 330(6004): 612-616.
3.	包翌, 肖争. DNA 甲基化在癫痫中的研究进展. 癫痫杂志, 2018, 4(3): 238-241.
4.	Lerche H, Vezzani A, Beck H, <italic>et al</italic>. New developments in epileptogenesis and therapeutic perspectives. Nervenarzt, 2011, 82(8): 978-985.
5.	Aronica E, Fluiter K, Iyer A, <italic>et al</italic>. Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Eur J Neurosci, 2010, 31(6): 1100-1107.
6.	Omran A, Peng J, Zhang C, <italic>et al</italic>. Interleukin-1beta and microRNA-146a in an immature rat model and children with mesial temporal lobe epilepsy. Epilepsia, 2012, 53(7): 1215-1224.
7.	Dogini DB, Avansini SH, Vieira AS, <italic>et al</italic>. MicroRNA regulation and dysregulation in epilepsy. Front Cell Neurosci, 2013, 7: 172.
8.	Vo N, Klein ME, Varlamova O, <italic>et al</italic>. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc Natl Acad Sci U S A, 2005, 102(45): 16426-16431.
9.	Jimenez-Mateos EM, Engel T, Merino-Serrais P, <italic>et al</italic>. Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat Med, 2012, 18(7): 1087-1094.
10.	Liu DZ, Tian Y, Ander BP, <italic>et al</italic>. Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab, 2010, 30(1): 92-101.
11.	Sano T, Reynolds JP, Jimenez-Mateos EM, <italic>et al</italic>. MicroRNA-34a upregulation during seizure-induced neuronal death. Cell Death Dis, 2012, 3: e287.
12.	Risbud RM, Porter BE. Changes in microRNA expression in the whole hippocampus and hippocampal synaptoneurosome fraction following pilocarpine induced status epilepticus. PLoS One, 2013, 8(1): e53464.
13.	Jang Y, Moon J, Lee ST, <italic>et al</italic>. Dysregulated long non-coding RNAs in the temporal lobe epilepsy mouse model. Seizure, 2018, 58: 110-119.
14.	Mazzuferi M, Palma E, Martinello K, <italic>et al</italic>. Enhancement of GABA(A)-current run-down in the hippocampus occurs at the first spontaneous seizure in a model of temporal lobe epilepsy. Proc Natl Acad Sci U S A, 2010, 107(7): 3180-3185.
15.	Nightingale KP, Wellinger RE, Sogo JM, <italic>et al</italic>. Histone acetylation facilitates RNA polymerase Ⅱ transcription of the Drosophila hsp26 gene in chromatin. EMBO J, 1998, 17(10): 2865-2876.
16.	Huang Y, Zhao F, Wang L, <italic>et al</italic>. Increased expression of histone deacetylases 2 in temporal lobe epilepsy: a study of epileptic patients and rat models. Synapse, 2012, 66(2): 151-159.
17.	Robertson KD, Jones PA. DNA methylation: past, present and future directions. Carcinogenesis, 2000, 21(3): 461-467.
18.	Kim JK, Samaranayake M, Pradhan S. Epigenetic mechanisms in mammals. Cell Mol Life Sci, 2009, 66(4): 596-612.
19.	Meilinger D, Fellinger K, Bultmann S, <italic>et al</italic>. Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells. EMBO Rep, 2009, 10(11): 1259-1264.
20.	Kobow K, Kaspi A, Harikrishnan KN, <italic>et al</italic>. Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol, 2013, 126(5): 741-756.
21.	Unal Y, Kara M, Genc F, <italic>et al</italic>. The methylation status of NKCC1 and KCC2 in the patients with refractory temporal lobe epilepsy. Ideggyogy Sz, 2019, 72(5-6): 181-186.
22.	Xiao W, Cao Y, Long H, <italic>et al</italic>. Genome-wide DNA methylation patterns analysis of noncoding RNAs in temporal lobe epilepsy patients. Mol Neurobiol, 2018, 55(1): 793-803.
23.	Ryley Parrish R, Albertson AJ, <italic>et al</italic>. 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: 602-619.
24.	Machnes ZM, Huang TC, Chang PK, <italic>et al</italic>. DNA methylation mediates persistent epileptiform activity in vitro and in vivo. PLoS One, 2013, 8(10): e76299.
25.	Wang L, Fu X, Peng X, <italic>et al</italic>. DNA methylation profiling reveals correlation of differential methylation patterns with gene expression in human epilepsy. J Mol Neurosci, 2016, 59(1): 68-77.
26.	Miller-Delaney SF, Bryan K, Das S, <italic>et al</italic>. Differential DNA methylation profiles of coding and non-coding genes define hippocampal sclerosis in human temporal lobe epilepsy. Brain, 2015, 138(Pt 3): 616-631.
27.	Miller-Delaney SF, Das S, Sano T, <italic>et al</italic>. Differential DNA methylation patterns define status epilepticus and epileptic tolerance. J Neurosci, 2012, 32(5): 1577-1588.
28.	Martinez-Levy GA, Rocha L, Lubin FD. Increased expression of BDNF transcript with exon VI in hippocampi of patients with pharmaco-resistant temporal lobe epilepsy. Neuroscience, 2016, 314: 12-21.
29.	Sulewska A, Niklinska W, Kozlowski M, <italic>et al</italic>. DNA methylation in states of cell physiology and pathology. Folia Histochem Cytobiol, 2007, 45(3): 149-158.
30.	Bender J. DNA methylation and epigenetics. Annu Rev Plant Biol, 2004, 55: 41-68.
31.	Kobow K, Jeske I, Hildebrandt M, a l. Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy. J Neuropathol Exp Neurol, 2009, 68(4): 3563-64.
32.	Long HY, Feng L, Kang J,. Blood DNA methylation pattern is altered in mesial temporal lobe epilepsy. Sci Rep, 2017, 7: 43810.
33.	Tan NN, Tang HL, Lin GW. Epigenetic downregulation of scn3a expression by valproate: a possible role in its anticonvulsant activity. Mol Neurobiol, 2017, 54(4): 2831-2842.
34.	Li HJ, Wan RP, Tang LJ, <italic>et al</italic>. Alteration of Scn3a expression is mediated via CpG methylation and MBD2 in mouse hippocampus during postnatal development and seizure condition. Biochim Biophys Acta, 2015, 1849(1): 1-9.
35.	Aizawa S, Yamamuro Y. Valproate administration to mice increases hippocampal p21 expression by altering genomic DNA methylation. Neuroreport, 2015, 26(15): 915-920.
36.	Kohno S, Kohno T, Nakano Y, <italic>et al</italic>. Mechanism and significance of specific proteolytic cleavage of Reelin. Biochem Biophys Res Commun, 2009, 380(1): 93-97.
37.	Muller MC, Osswald M, Tinnes S, <italic>et al</italic>. Exogenous reelin prevents granule cell dispersion in experimental epilepsy. Exp Neurol, 2009, 216(2): 390-397.
38.	Meisler MH, Kearney JA. Sodium channel mutations in epilepsy and other neurological disorders. J Clin Invest, 2005, 115(8): 2010-2017.
39.	Goldin AL. Diversity of mammalian voltage-gated sodium channels. Ann N Y Acad Sci, 1999, 868: 38-50.
40.	Haris PI, Ramesh B, Sansom MS, <italic>et al</italic>. Studies of the pore-forming domain of a voltage-gated potassium channel protein. Protein Eng, 1994, 7(2): 255-262.
41.	Schade SD, Brown GB. Identifying the promoter region of the human brain sodium channel subtype Ⅱ gene (SCN2A). Brain Res Mol Brain Res, 2000, 81(1-2): 187-190.
42.	Drews VL, Lieberman AP, Meisler MH. Multiple transcripts of sodium channel SCN8A (Na(V)1.6) with alternative 5'- and 3'-untranslated regions and initial characterization of the SCN8A promoter. Genomics, 2005, 85(2): 245-257.
43.	Long YS, Zhao QH, Su T, <italic>et al</italic>. Identification of the promoter region and the 5'-untranslated exons of the human voltage-gated sodium channel Nav1.1 gene (SCN1A) and enhancement of gene expression by the 5'-untranslated exon. J Neurosci Res, 2008, 86(15): 3375-3381.
44.	Martin MS, Tang B, Ta N, <italic>et al</italic>. Characterization of 5' untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncoding sequences. Genomics, 2007, 90(2): 225-235.
45.	Krapivinsky G, Krapivinsky L, Manasian Y, <italic>et al</italic>. The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron, 2003, 40(4): 775-784.
46.	Zhu Q, Wang L, Xiao Z, <italic>et al</italic>. Decreased expression of Ras-GRF1 in the brain tissue of the intractable epilepsy patients and experimental rats. Brain Res, 2013, 1493: 99-109.
47.	Chen X, Peng X, Wang L, <italic>et al</italic>. Association of RASgrf1 methylation with epileptic seizures. Oncotarget, 2017, 8(28): 46286-46297.
48.	Bao Y, Chen X, Wang L, <italic>et al</italic>. RASgrf1, a potential methylatic mediator of anti-epileptogenesis? Neurochem Res, 2018, 43(10): 2000-2007.
49.	Lv Y, Zheng X, Shi M, <italic>et al</italic>. Different EPHX1 methylation levels in promoter area between carbamazepine-resistant epilepsy group and carbamazepine-sensitive epilepsy group in Chinese population. BMC Neurol, 2019, 19(1): 114.
50.	Belhedi N, Perroud N, Karege F, <italic>et al</italic>. Increased CPA6 promoter methylation in focal epilepsy and in febrile seizures. Epilepsy Res, 2014, 108(1): 144-148.

1. Dalic L, Cook MJ. Managing drug-resistant epilepsy: challenges and solutions. Neuropsychiatr Dis Treat, 2016, 12: 2605-2616.
2. Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states. Science, 2010, 330(6004): 612-616.
3. 包翌, 肖争. DNA 甲基化在癫痫中的研究进展. 癫痫杂志, 2018, 4(3): 238-241.
4. Lerche H, Vezzani A, Beck H, <italic>et al</italic>. New developments in epileptogenesis and therapeutic perspectives. Nervenarzt, 2011, 82(8): 978-985.
5. Aronica E, Fluiter K, Iyer A, <italic>et al</italic>. Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Eur J Neurosci, 2010, 31(6): 1100-1107.
6. Omran A, Peng J, Zhang C, <italic>et al</italic>. Interleukin-1beta and microRNA-146a in an immature rat model and children with mesial temporal lobe epilepsy. Epilepsia, 2012, 53(7): 1215-1224.
7. Dogini DB, Avansini SH, Vieira AS, <italic>et al</italic>. MicroRNA regulation and dysregulation in epilepsy. Front Cell Neurosci, 2013, 7: 172.
8. Vo N, Klein ME, Varlamova O, <italic>et al</italic>. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc Natl Acad Sci U S A, 2005, 102(45): 16426-16431.
9. Jimenez-Mateos EM, Engel T, Merino-Serrais P, <italic>et al</italic>. Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat Med, 2012, 18(7): 1087-1094.
10. Liu DZ, Tian Y, Ander BP, <italic>et al</italic>. Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab, 2010, 30(1): 92-101.
11. Sano T, Reynolds JP, Jimenez-Mateos EM, <italic>et al</italic>. MicroRNA-34a upregulation during seizure-induced neuronal death. Cell Death Dis, 2012, 3: e287.
12. Risbud RM, Porter BE. Changes in microRNA expression in the whole hippocampus and hippocampal synaptoneurosome fraction following pilocarpine induced status epilepticus. PLoS One, 2013, 8(1): e53464.
13. Jang Y, Moon J, Lee ST, <italic>et al</italic>. Dysregulated long non-coding RNAs in the temporal lobe epilepsy mouse model. Seizure, 2018, 58: 110-119.
14. Mazzuferi M, Palma E, Martinello K, <italic>et al</italic>. Enhancement of GABA(A)-current run-down in the hippocampus occurs at the first spontaneous seizure in a model of temporal lobe epilepsy. Proc Natl Acad Sci U S A, 2010, 107(7): 3180-3185.
15. Nightingale KP, Wellinger RE, Sogo JM, <italic>et al</italic>. Histone acetylation facilitates RNA polymerase Ⅱ transcription of the Drosophila hsp26 gene in chromatin. EMBO J, 1998, 17(10): 2865-2876.
16. Huang Y, Zhao F, Wang L, <italic>et al</italic>. Increased expression of histone deacetylases 2 in temporal lobe epilepsy: a study of epileptic patients and rat models. Synapse, 2012, 66(2): 151-159.
17. Robertson KD, Jones PA. DNA methylation: past, present and future directions. Carcinogenesis, 2000, 21(3): 461-467.
18. Kim JK, Samaranayake M, Pradhan S. Epigenetic mechanisms in mammals. Cell Mol Life Sci, 2009, 66(4): 596-612.
19. Meilinger D, Fellinger K, Bultmann S, <italic>et al</italic>. Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells. EMBO Rep, 2009, 10(11): 1259-1264.
20. Kobow K, Kaspi A, Harikrishnan KN, <italic>et al</italic>. Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol, 2013, 126(5): 741-756.
21. Unal Y, Kara M, Genc F, <italic>et al</italic>. The methylation status of NKCC1 and KCC2 in the patients with refractory temporal lobe epilepsy. Ideggyogy Sz, 2019, 72(5-6): 181-186.
22. Xiao W, Cao Y, Long H, <italic>et al</italic>. Genome-wide DNA methylation patterns analysis of noncoding RNAs in temporal lobe epilepsy patients. Mol Neurobiol, 2018, 55(1): 793-803.
23. Ryley Parrish R, Albertson AJ, <italic>et al</italic>. 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: 602-619.
24. Machnes ZM, Huang TC, Chang PK, <italic>et al</italic>. DNA methylation mediates persistent epileptiform activity in vitro and in vivo. PLoS One, 2013, 8(10): e76299.
25. Wang L, Fu X, Peng X, <italic>et al</italic>. DNA methylation profiling reveals correlation of differential methylation patterns with gene expression in human epilepsy. J Mol Neurosci, 2016, 59(1): 68-77.
26. Miller-Delaney SF, Bryan K, Das S, <italic>et al</italic>. Differential DNA methylation profiles of coding and non-coding genes define hippocampal sclerosis in human temporal lobe epilepsy. Brain, 2015, 138(Pt 3): 616-631.
27. Miller-Delaney SF, Das S, Sano T, <italic>et al</italic>. Differential DNA methylation patterns define status epilepticus and epileptic tolerance. J Neurosci, 2012, 32(5): 1577-1588.
28. Martinez-Levy GA, Rocha L, Lubin FD. Increased expression of BDNF transcript with exon VI in hippocampi of patients with pharmaco-resistant temporal lobe epilepsy. Neuroscience, 2016, 314: 12-21.
29. Sulewska A, Niklinska W, Kozlowski M, <italic>et al</italic>. DNA methylation in states of cell physiology and pathology. Folia Histochem Cytobiol, 2007, 45(3): 149-158.
30. Bender J. DNA methylation and epigenetics. Annu Rev Plant Biol, 2004, 55: 41-68.
31. Kobow K, Jeske I, Hildebrandt M, a l. Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy. J Neuropathol Exp Neurol, 2009, 68(4): 3563-64.
32. Long HY, Feng L, Kang J,. Blood DNA methylation pattern is altered in mesial temporal lobe epilepsy. Sci Rep, 2017, 7: 43810.
33. Tan NN, Tang HL, Lin GW. Epigenetic downregulation of scn3a expression by valproate: a possible role in its anticonvulsant activity. Mol Neurobiol, 2017, 54(4): 2831-2842.
34. Li HJ, Wan RP, Tang LJ, <italic>et al</italic>. Alteration of Scn3a expression is mediated via CpG methylation and MBD2 in mouse hippocampus during postnatal development and seizure condition. Biochim Biophys Acta, 2015, 1849(1): 1-9.
35. Aizawa S, Yamamuro Y. Valproate administration to mice increases hippocampal p21 expression by altering genomic DNA methylation. Neuroreport, 2015, 26(15): 915-920.
36. Kohno S, Kohno T, Nakano Y, <italic>et al</italic>. Mechanism and significance of specific proteolytic cleavage of Reelin. Biochem Biophys Res Commun, 2009, 380(1): 93-97.
37. Muller MC, Osswald M, Tinnes S, <italic>et al</italic>. Exogenous reelin prevents granule cell dispersion in experimental epilepsy. Exp Neurol, 2009, 216(2): 390-397.
38. Meisler MH, Kearney JA. Sodium channel mutations in epilepsy and other neurological disorders. J Clin Invest, 2005, 115(8): 2010-2017.
39. Goldin AL. Diversity of mammalian voltage-gated sodium channels. Ann N Y Acad Sci, 1999, 868: 38-50.
40. Haris PI, Ramesh B, Sansom MS, <italic>et al</italic>. Studies of the pore-forming domain of a voltage-gated potassium channel protein. Protein Eng, 1994, 7(2): 255-262.
41. Schade SD, Brown GB. Identifying the promoter region of the human brain sodium channel subtype Ⅱ gene (SCN2A). Brain Res Mol Brain Res, 2000, 81(1-2): 187-190.
42. Drews VL, Lieberman AP, Meisler MH. Multiple transcripts of sodium channel SCN8A (Na(V)1.6) with alternative 5'- and 3'-untranslated regions and initial characterization of the SCN8A promoter. Genomics, 2005, 85(2): 245-257.
43. Long YS, Zhao QH, Su T, <italic>et al</italic>. Identification of the promoter region and the 5'-untranslated exons of the human voltage-gated sodium channel Nav1.1 gene (SCN1A) and enhancement of gene expression by the 5'-untranslated exon. J Neurosci Res, 2008, 86(15): 3375-3381.
44. Martin MS, Tang B, Ta N, <italic>et al</italic>. Characterization of 5' untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncoding sequences. Genomics, 2007, 90(2): 225-235.
45. Krapivinsky G, Krapivinsky L, Manasian Y, <italic>et al</italic>. The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron, 2003, 40(4): 775-784.
46. Zhu Q, Wang L, Xiao Z, <italic>et al</italic>. Decreased expression of Ras-GRF1 in the brain tissue of the intractable epilepsy patients and experimental rats. Brain Res, 2013, 1493: 99-109.
47. Chen X, Peng X, Wang L, <italic>et al</italic>. Association of RASgrf1 methylation with epileptic seizures. Oncotarget, 2017, 8(28): 46286-46297.
48. Bao Y, Chen X, Wang L, <italic>et al</italic>. RASgrf1, a potential methylatic mediator of anti-epileptogenesis? Neurochem Res, 2018, 43(10): 2000-2007.
49. Lv Y, Zheng X, Shi M, <italic>et al</italic>. Different EPHX1 methylation levels in promoter area between carbamazepine-resistant epilepsy group and carbamazepine-sensitive epilepsy group in Chinese population. BMC Neurol, 2019, 19(1): 114.
50. Belhedi N, Perroud N, Karege F, <italic>et al</italic>. Increased CPA6 promoter methylation in focal epilepsy and in febrile seizures. Epilepsy Res, 2014, 108(1): 144-148.

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