癫表观遗传学研究进展
|
摘要
癫是临床最常见的神经系统疾病,临床表现和病因多样,受遗传因素和环境因素的共同影响。传统遗传学机制不能完全解释癫的发生机制,因此环境因素影响基因表达可能成为癫发生机制研究的新方向。表观遗传学是研究环境因素或其他非DNA序列改变对基因表达的影响。本文拟对癫表观遗传学研究进展进行简要概述,以为癫发生机制和治疗提供新的视角。
Epilepsy is one of the most common neurological disorders with complex manifestationsand etiologies. It is widely influenced by hereditary and environmental elements. Traditional geneticmechanism can not well explain the reason that epilepsy occurs. Therefore, epigenetics, which explores theeffects of environment or non DNA sequential changes on gene expression, may provide a new perspectiveto unravel the underlying cause. This article intends to discuss recent research progress of epigenetics,which is likely to provide a new perspective to explain why epilepsy occurs and how to treat epilepsy inclinical practice.
Epilepsy is one of the most common neurological disorders with complex manifestationsand etiologies. It is widely influenced by hereditary and environmental elements. Traditional geneticmechanism can not well explain the reason that epilepsy occurs. Therefore, epigenetics, which explores theeffects of environment or non DNA sequential changes on gene expression, may provide a new perspectiveto unravel the underlying cause. This article intends to discuss recent research progress of epigenetics,which is likely to provide a new perspective to explain why epilepsy occurs and how to treat epilepsy inclinical practice.
引文
[1]Wang WZ,Wu JZ,Wang DS,Dai XY,Yang B,Wang TP,Yuan CL,Scott RA,Prilipko LL,de Boer HM,Sander JW.The prevalence and treatment gap in epilepsy in China:an ILAE/IBE/WHO study[J].Neurology,2003,60:1544-1545.
[2]Alhusaini S,Whelan CD,Sisodiya SM,Thompson PM.Quantitative magnetic resonance imaging traits as endophenotypes for genetic mapping in epilepsy[J].Neuroimage Clin,2016,12:526-534.
[3]Graff J,Tsai LH.Histone acetylation:molecular mnemonics on the chromatin[J].Nat Rev Neurosci,2013,14:97-111.
[4]Jones PA.Functions of DNA methylation:islands,start sites,gene bodies and beyond[J].Nat Rev Genet,2012,13:484-492.
[5]Kobow K,El-Osta A,Blümcke I.The methylation hypothesis of pharmacoresistance in epilepsy[J].Epilepsia,2013,54 Suppl 2:41-47.
[6]Bestor TH.The DNA methyltransferases of mammals[J].Hum Mol Genet,2000,9:2395-2402.
[7]Feng J,Zhou Y,Campbell SL,Le T,Li E,Sweatt JD,Silva AJ,Fan G.Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons[J].Nat Neurosci,2010,13:423-430.
[8]Urdinguio RG,Sanchez-Mut JV,Esteller M.Epigenetic mechanisms in neurological diseases:genes,syndromes,and therapies[J].Lancet Neurol,2009,8:1056-1072.
[9]Zhou Z,Hong EJ,Cohen S,Zhao WN,Ho HY,Schmidt L,Chen WG,Lin Y,Savner E,Griffith EC,Hu L,Steen JA,Weitz CJ,Greenberg ME.Brain-specific phosphorylation of Me CP2regulates activity-dependent Bdnf transcription,dendritic growth,and spine maturation[J].Neuron,2006,52:255-269.
[10]Kobow K,Jeske I,Hildebrandt M,Hauke J,Hahnen E,Buslei R,Buchfelder M,Weigel D,Stefan H,Kasper B,Pauli E,Blümcke I.Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy[J].J Neuropathol Exp Neurol,2009,68:356-364.
[11]Zhu Q,Wang L,Zhang Y,Zhao FH,Luo J,Xiao Z,Chen GJ,Wang XF.Increased expression of DNA methyltransferase 1and 3a in human temporal lobe epilepsy[J].J Mol Neurosci,2012,46:420-426.
[12]Long HY,Feng L,Kang J,Luo ZH,Xiao WB,Long LL,Yan XX,Zhou L,Xiao B.Blood DNA methylation pattern is altered in mesial temporal lobe epilepsy[J].Sci Rep,2017,7:43810.
[13]Kobow K,Kaspi A,Harikrishnan KN,Kiese K,Ziemann M,Khurana I,Fritzsche I,Hauke J,Hahnen E,Coras R,Muhlebner A,El-Osta A,Blümcke I.Deep sequencing reveals increased DNA methylation in chronic rat epilepsy[J].Acta Neuropathol,2013,126:741-756.
[14]Miller-Delaney SF,Bryan K,Das S,Mc Kiernan RC,Bray IM,Reynolds JP,Gwinn R,Stallings RL,Henshall DC.Differential DNA methylation profiles of coding and non-coding genes define hippocampal sclerosis in human temporal lobe epilepsy[J].Brain,2015,138(Pt 3):616-631.
[15]He L,Hannon GJ.Micro RNAs:small RNAs with a big role in gene regulation[J].Nat Rev Genet,2004,5:522-531.
[16]Kim VN,Han J,Siomi MC.Biogenesis of small RNAs in animals[J].Nat Rev Mol Cell Biol,2009,10:126-139.
[17]Djuranovic S,Nahvi A,Green R.mi RNA-mediated gene silencing by translational repression followed by m RNAdeadenylation and decay[J].Science,2012,336:237-240.
[18]Sun AX,Crabtree GR,Yoo AS.Micro RNAs:regulators of neuronal fate[J].Curr Opin Cell Biol,2013,25:215-221.
[19]Alsharafi WA,Xiao B,Abuhamed MM,Luo Z.mi RNAs:biological and clinical determinants in epilepsy[J].Front Mol Neurosci,2015,8:59.
[20]Jimenez-Mateos EM,Engel T,Merino-Serrais P,Mc Kiernan RC,Tanaka K,Mouri G,Sano T,O'Tuathaigh C,Waddington JL,Prenter S,Delanty N,Farrell MA,O'Brien DF,Conroy RM,Stallings RL,De Felipe J,Henshall DC.Silencing micro RNA-134 produces neuroprotective and prolonged seizure-suppressive effects[J].Nat Med,2012,18:1087-1094.
[21]Henshall DC.Micro RNAs in the pathophysiology and treatment of status epilepticus[J].Front Mol Neurosci,2013,6:37.
[22]Brennan GP,Henshall DC.micro RNAs in the pathophysiology of epilepsy[J].Neurosci Lett,2018,667:47-52.
[23]Wang J,Yu JT,Tan L,Tian Y,Ma J,Tan CC,Wang HF,Liu Y,Tan MS,Jiang T,Tan L.Genome-wide circulating micro RNA expression profiling indicates biomarkers for epilepsy[J].Sci Rep,2015,5:9522.
[24]Wang J,Tan L,Tan L,Tian Y,Ma J,Tan CC,Wang HF,Liu Y,Tan MS,Jiang T,Yu JT.Circulating micro RNAs are promising novel biomarkers for drug-resistant epilepsy[J].Sci Rep,2015,5:10201.
[25]Cui P,Lin Q,Ding F,Xin C,Gong W,Zhang L,Geng J,Zhang B,Yu X,Yang J,Hu S,Yu J.A comparison between ribominus RNA-sequencing and poly A-selected RNA-sequencing[J].Genomics,2010,96:259-265.
[26]Roberts TC,Morris KV,Wood MJ.The role of long non-coding RNAs in neurodevelopment,brain function and neurological disease[J].Philos Trans R Soc Lond B Biol Sci,2014,369:1652.
[27]Bond AM,Vangompel MJ,Sametsky EA,Clark MF,Savage JC,Disterhoft JF,Kohtz JD.Balanced gene regulation by an embryonic brain nc RNA is critical for adult hippocampal GABA circuitry[J].Nat Neurosci,2009,12:1020-1027.
[28]Lipovich L,Dachet F,Cai J,Bagla S,Balan K,Jia H,Loeb JA.Activity-dependent human brain coding/noncoding gene regulatory networks[J].Genetics,2012,192:1133-1148.
[29]Ruthenburg AJ,Li H,Patel DJ,Allis CD.Multivalent engagement of chromatin modifications by linked binding modules[J].Nat Rev Mol Cell Biol,2007,8:983-994.
[30]Jagirdar R,Drexel M,Bukovac A,Tasan RO,Sperk G.Expression of classⅡHDACs in two mouse models of temporal lobe epilepsy[J].J Neurochem,2015[.Epub ahead of print]
[31]Huang Y,Doherty JJ,Dingledine R.Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus[J].JNeurosci,2002,22:8422-8428.
[32]Tsankova NM,Kumar A,Nestler EJ.Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures[J].J Neurosci,2004,24:5603-5610.
[33]Crosio C,Heitz E,Allis CD,Borrelli E,Sassone-Corsi P.Chromatin remodeling and neuronal response:multiple signaling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons[J].J Cell Sci,2003,116(Pt 24):4905-4914.
[34]Sng JC,Taniura H,Yoneda Y.Histone modifications in kainateinduced status epilepticus[J].Eur J Neurosci,2006,23:1269-1282.
[35]Huang Y,Zhao F,Wang L,Yin H,Zhou C,Wang X.Increased expression of histone deacetylases 2 in temporal lobe epilepsy:a study of epileptic patients and rat models[J].Synapse,2012,66:151-159.
[36]Park HG,Yu HS,Park S,Ahn YM,Kim YS,Kim SH.Repeated treatment with electroconvulsive seizures induces HDAC2 expression and down-regulation of NMDA receptorrelated genes through histone deacetylation in the rat frontal cortex[J].Int J Neuropsychopharmacol,2014,17:1487-1500.
[37]Kobow K,Blümcke I.Epigenetic mechanisms in epilepsy[J].Pro Brain Res,2014,213:279-316.
[38]Kleefstra T,Brunner HG,Amiel J,Oudakker AR,Nillesen WM,Magee A,Genevieve D,Cormier-Daire V,van Esch H,Fryns JP,Hamel BC,Sistermans EA,de Vries BB,van Bokhoven H.Loss-of-function mutations in euchromatin histone methyl transferase 1(EHMT1)cause the 9q34 subtelomeric deletion syndrome[J].Am J Hum Genet,2006,79:370-377.
[39]Kleefstra T,Kramer JM,Neveling K,Willemsen MH,Koemans TS,Vissers LE,Wissink-Lindhout W,Fenckova M,van den Akker WM,Kasri NN,Nillesen WM,Prescott T,Clark RD,Devriendt K,van Reeuwijk J,de Brouwer AP,Gilissen C,Zhou H,Brunner HG,Veltman JA,Schenck A,van Bokhoven H.Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability[J].Am J Hum Genet,2012,91:73-82.
[40]Iwase S,Lan F,Bayliss P,de la Torre-Ubieta L,Huarte M,Qi HH,Whetstine JR,Bonni A,Roberts TM,Shi Y.The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases[J].Cell,2007,128:1077-1088.
[41]Shoubridge C,Fullston T,Gécz J.ARX spectrum disorders:making inroads into the molecular pathology[J].Hum Mutat,2010,31:889-900.
[42]Poeta L,Fusco F,Drongitis D,Shoubridge C,Manganelli G,Filosa S,Paciolla M,Courtney M,Collombat P,Lioi MB,Gecz J,Ursini MV,Miano MG.A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX[J].Am J Hum Genet,2013,92:114-125.
[43]Türkmen S,Gillessen-Kaesbach G,Meinecke P,Albrecht B,Neumann LM,Hesse V,Palanduz S,Balg S,Majewski F,Fuchs S,Zschieschang P,Greiwe M,Mennicke K,Kreuz FR,Dehmel HJ,Rodeck B,Kunze J,Tinschert S,Mundlos S,Horn D.Mutations in NSD1 are responsible for Sotos syndrome,but are not a frequent finding in other overgrowth phenotypes[J].Eur JHum Genet,2003,11:858-865.
[44]Blanco S,Dietmann S,Flores JV,Hussain S,Kutter C,Humphreys P,Lukk M,Lombard P,Treps L,Popis M,Kellner S,H?lter SM,Garrett L,Wurst W,Becker L,Klopstock T,Fuchs H,Gailus-Durner V,Hrabe DA,Karadottir RT,Helm M,Ule J,Gleeson JG,Odom DT,Frye M.Aberrant methylation of t RNAs links cellular stress to neuro-developmental disorders[J].EMBO J,2014,33:2020-2039.
[45]Fawcett KA,Barroso I.The genetics of obesity:FTO leads the way[J].Trends Genet,2010,26:266-274.
[46]Reitz C,Tosto G,Mayeux R,Luchsinger JA;NIA-LOAD/NCRAD Family Study Group,Alzheimer's Disease Neuroimaging Initiative.Genetic variants in the Fat and Obesity Associated(FTO)gene and risk of Alzheimer's disease[J].PLo S One,2012,7:E50354.
[47]Rowles J,Wong M,Powers R,Olsen M.FTO,RNA epigenetics and epilepsy[J].Epigenetics,2012,7:1094-1097.
[48]Li Y,Zhang Y,Li S,Lu J,Chen J,Wang Y,Li Y,Xu J,Li X.Genome-wide DNA methylome analysis reveals epigenetically dysregulated non-coding RNAs in human breast cancer[J].Sci Rep,2015,5:8790.
[49]Xiao W,Cao Y,Long H,Luo Z,Li S,Deng N,Wang J,Lu X,Wang T,Ning S,Wang L,Xiao B.Genome-wide DNAmethylation patterns analysis of noncoding RNAs in temporal lobe epilepsy patients[J].Mol Neurobiol,2017,55:793-803.
[50]Alexander RP,Fang G,Rozowsky J,Snyder M,Gerstein MB.Annotating non-coding regions of the genome[J].Nat Rev Genet,2010,11:559-571.
[51]Seba R,Booth SA.Polymorphisms affecting mi RNA regulation:a new level of genetic variation affecting disorders and diseases of the human CNS[J].Future Neurol,2013,8:411-431.
[52]Sethupathy P,Collins FS.Micro RNA target site polymorphisms and human disease[J].Trends Genet,2008,24:489-497.
[53]Aronica E,Fluiter K,Iyer A,Zurolo E,Vreijling J,van Vliet EA,Baayen JC,Gorter JA.Expression pattern of mi R-146a,an inflammation-associated micro RNA,in experimental and human temporal lobe epilepsy[J].Eur J Neurosci,2010,31:1100-1107.
[54]Cui L,Tao H,Wang Y,Liu Z,Xu Z,Zhou H,Cai Y,Yao L,Chen B,Liang W,Liu Y,Cheng W,Liu T,Ma G,Li Y,Zhao B,Li K.A functional polymorphism of the micro RNA-146a gene is associated with susceptibility to drug-resistant epilepsy and seizures frequency[J].Seizure,2015,27:60-65.
[2]Alhusaini S,Whelan CD,Sisodiya SM,Thompson PM.Quantitative magnetic resonance imaging traits as endophenotypes for genetic mapping in epilepsy[J].Neuroimage Clin,2016,12:526-534.
[3]Graff J,Tsai LH.Histone acetylation:molecular mnemonics on the chromatin[J].Nat Rev Neurosci,2013,14:97-111.
[4]Jones PA.Functions of DNA methylation:islands,start sites,gene bodies and beyond[J].Nat Rev Genet,2012,13:484-492.
[5]Kobow K,El-Osta A,Blümcke I.The methylation hypothesis of pharmacoresistance in epilepsy[J].Epilepsia,2013,54 Suppl 2:41-47.
[6]Bestor TH.The DNA methyltransferases of mammals[J].Hum Mol Genet,2000,9:2395-2402.
[7]Feng J,Zhou Y,Campbell SL,Le T,Li E,Sweatt JD,Silva AJ,Fan G.Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons[J].Nat Neurosci,2010,13:423-430.
[8]Urdinguio RG,Sanchez-Mut JV,Esteller M.Epigenetic mechanisms in neurological diseases:genes,syndromes,and therapies[J].Lancet Neurol,2009,8:1056-1072.
[9]Zhou Z,Hong EJ,Cohen S,Zhao WN,Ho HY,Schmidt L,Chen WG,Lin Y,Savner E,Griffith EC,Hu L,Steen JA,Weitz CJ,Greenberg ME.Brain-specific phosphorylation of Me CP2regulates activity-dependent Bdnf transcription,dendritic growth,and spine maturation[J].Neuron,2006,52:255-269.
[10]Kobow K,Jeske I,Hildebrandt M,Hauke J,Hahnen E,Buslei R,Buchfelder M,Weigel D,Stefan H,Kasper B,Pauli E,Blümcke I.Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy[J].J Neuropathol Exp Neurol,2009,68:356-364.
[11]Zhu Q,Wang L,Zhang Y,Zhao FH,Luo J,Xiao Z,Chen GJ,Wang XF.Increased expression of DNA methyltransferase 1and 3a in human temporal lobe epilepsy[J].J Mol Neurosci,2012,46:420-426.
[12]Long HY,Feng L,Kang J,Luo ZH,Xiao WB,Long LL,Yan XX,Zhou L,Xiao B.Blood DNA methylation pattern is altered in mesial temporal lobe epilepsy[J].Sci Rep,2017,7:43810.
[13]Kobow K,Kaspi A,Harikrishnan KN,Kiese K,Ziemann M,Khurana I,Fritzsche I,Hauke J,Hahnen E,Coras R,Muhlebner A,El-Osta A,Blümcke I.Deep sequencing reveals increased DNA methylation in chronic rat epilepsy[J].Acta Neuropathol,2013,126:741-756.
[14]Miller-Delaney SF,Bryan K,Das S,Mc Kiernan RC,Bray IM,Reynolds JP,Gwinn R,Stallings RL,Henshall DC.Differential DNA methylation profiles of coding and non-coding genes define hippocampal sclerosis in human temporal lobe epilepsy[J].Brain,2015,138(Pt 3):616-631.
[15]He L,Hannon GJ.Micro RNAs:small RNAs with a big role in gene regulation[J].Nat Rev Genet,2004,5:522-531.
[16]Kim VN,Han J,Siomi MC.Biogenesis of small RNAs in animals[J].Nat Rev Mol Cell Biol,2009,10:126-139.
[17]Djuranovic S,Nahvi A,Green R.mi RNA-mediated gene silencing by translational repression followed by m RNAdeadenylation and decay[J].Science,2012,336:237-240.
[18]Sun AX,Crabtree GR,Yoo AS.Micro RNAs:regulators of neuronal fate[J].Curr Opin Cell Biol,2013,25:215-221.
[19]Alsharafi WA,Xiao B,Abuhamed MM,Luo Z.mi RNAs:biological and clinical determinants in epilepsy[J].Front Mol Neurosci,2015,8:59.
[20]Jimenez-Mateos EM,Engel T,Merino-Serrais P,Mc Kiernan RC,Tanaka K,Mouri G,Sano T,O'Tuathaigh C,Waddington JL,Prenter S,Delanty N,Farrell MA,O'Brien DF,Conroy RM,Stallings RL,De Felipe J,Henshall DC.Silencing micro RNA-134 produces neuroprotective and prolonged seizure-suppressive effects[J].Nat Med,2012,18:1087-1094.
[21]Henshall DC.Micro RNAs in the pathophysiology and treatment of status epilepticus[J].Front Mol Neurosci,2013,6:37.
[22]Brennan GP,Henshall DC.micro RNAs in the pathophysiology of epilepsy[J].Neurosci Lett,2018,667:47-52.
[23]Wang J,Yu JT,Tan L,Tian Y,Ma J,Tan CC,Wang HF,Liu Y,Tan MS,Jiang T,Tan L.Genome-wide circulating micro RNA expression profiling indicates biomarkers for epilepsy[J].Sci Rep,2015,5:9522.
[24]Wang J,Tan L,Tan L,Tian Y,Ma J,Tan CC,Wang HF,Liu Y,Tan MS,Jiang T,Yu JT.Circulating micro RNAs are promising novel biomarkers for drug-resistant epilepsy[J].Sci Rep,2015,5:10201.
[25]Cui P,Lin Q,Ding F,Xin C,Gong W,Zhang L,Geng J,Zhang B,Yu X,Yang J,Hu S,Yu J.A comparison between ribominus RNA-sequencing and poly A-selected RNA-sequencing[J].Genomics,2010,96:259-265.
[26]Roberts TC,Morris KV,Wood MJ.The role of long non-coding RNAs in neurodevelopment,brain function and neurological disease[J].Philos Trans R Soc Lond B Biol Sci,2014,369:1652.
[27]Bond AM,Vangompel MJ,Sametsky EA,Clark MF,Savage JC,Disterhoft JF,Kohtz JD.Balanced gene regulation by an embryonic brain nc RNA is critical for adult hippocampal GABA circuitry[J].Nat Neurosci,2009,12:1020-1027.
[28]Lipovich L,Dachet F,Cai J,Bagla S,Balan K,Jia H,Loeb JA.Activity-dependent human brain coding/noncoding gene regulatory networks[J].Genetics,2012,192:1133-1148.
[29]Ruthenburg AJ,Li H,Patel DJ,Allis CD.Multivalent engagement of chromatin modifications by linked binding modules[J].Nat Rev Mol Cell Biol,2007,8:983-994.
[30]Jagirdar R,Drexel M,Bukovac A,Tasan RO,Sperk G.Expression of classⅡHDACs in two mouse models of temporal lobe epilepsy[J].J Neurochem,2015[.Epub ahead of print]
[31]Huang Y,Doherty JJ,Dingledine R.Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus[J].JNeurosci,2002,22:8422-8428.
[32]Tsankova NM,Kumar A,Nestler EJ.Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures[J].J Neurosci,2004,24:5603-5610.
[33]Crosio C,Heitz E,Allis CD,Borrelli E,Sassone-Corsi P.Chromatin remodeling and neuronal response:multiple signaling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons[J].J Cell Sci,2003,116(Pt 24):4905-4914.
[34]Sng JC,Taniura H,Yoneda Y.Histone modifications in kainateinduced status epilepticus[J].Eur J Neurosci,2006,23:1269-1282.
[35]Huang Y,Zhao F,Wang L,Yin H,Zhou C,Wang X.Increased expression of histone deacetylases 2 in temporal lobe epilepsy:a study of epileptic patients and rat models[J].Synapse,2012,66:151-159.
[36]Park HG,Yu HS,Park S,Ahn YM,Kim YS,Kim SH.Repeated treatment with electroconvulsive seizures induces HDAC2 expression and down-regulation of NMDA receptorrelated genes through histone deacetylation in the rat frontal cortex[J].Int J Neuropsychopharmacol,2014,17:1487-1500.
[37]Kobow K,Blümcke I.Epigenetic mechanisms in epilepsy[J].Pro Brain Res,2014,213:279-316.
[38]Kleefstra T,Brunner HG,Amiel J,Oudakker AR,Nillesen WM,Magee A,Genevieve D,Cormier-Daire V,van Esch H,Fryns JP,Hamel BC,Sistermans EA,de Vries BB,van Bokhoven H.Loss-of-function mutations in euchromatin histone methyl transferase 1(EHMT1)cause the 9q34 subtelomeric deletion syndrome[J].Am J Hum Genet,2006,79:370-377.
[39]Kleefstra T,Kramer JM,Neveling K,Willemsen MH,Koemans TS,Vissers LE,Wissink-Lindhout W,Fenckova M,van den Akker WM,Kasri NN,Nillesen WM,Prescott T,Clark RD,Devriendt K,van Reeuwijk J,de Brouwer AP,Gilissen C,Zhou H,Brunner HG,Veltman JA,Schenck A,van Bokhoven H.Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability[J].Am J Hum Genet,2012,91:73-82.
[40]Iwase S,Lan F,Bayliss P,de la Torre-Ubieta L,Huarte M,Qi HH,Whetstine JR,Bonni A,Roberts TM,Shi Y.The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases[J].Cell,2007,128:1077-1088.
[41]Shoubridge C,Fullston T,Gécz J.ARX spectrum disorders:making inroads into the molecular pathology[J].Hum Mutat,2010,31:889-900.
[42]Poeta L,Fusco F,Drongitis D,Shoubridge C,Manganelli G,Filosa S,Paciolla M,Courtney M,Collombat P,Lioi MB,Gecz J,Ursini MV,Miano MG.A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX[J].Am J Hum Genet,2013,92:114-125.
[43]Türkmen S,Gillessen-Kaesbach G,Meinecke P,Albrecht B,Neumann LM,Hesse V,Palanduz S,Balg S,Majewski F,Fuchs S,Zschieschang P,Greiwe M,Mennicke K,Kreuz FR,Dehmel HJ,Rodeck B,Kunze J,Tinschert S,Mundlos S,Horn D.Mutations in NSD1 are responsible for Sotos syndrome,but are not a frequent finding in other overgrowth phenotypes[J].Eur JHum Genet,2003,11:858-865.
[44]Blanco S,Dietmann S,Flores JV,Hussain S,Kutter C,Humphreys P,Lukk M,Lombard P,Treps L,Popis M,Kellner S,H?lter SM,Garrett L,Wurst W,Becker L,Klopstock T,Fuchs H,Gailus-Durner V,Hrabe DA,Karadottir RT,Helm M,Ule J,Gleeson JG,Odom DT,Frye M.Aberrant methylation of t RNAs links cellular stress to neuro-developmental disorders[J].EMBO J,2014,33:2020-2039.
[45]Fawcett KA,Barroso I.The genetics of obesity:FTO leads the way[J].Trends Genet,2010,26:266-274.
[46]Reitz C,Tosto G,Mayeux R,Luchsinger JA;NIA-LOAD/NCRAD Family Study Group,Alzheimer's Disease Neuroimaging Initiative.Genetic variants in the Fat and Obesity Associated(FTO)gene and risk of Alzheimer's disease[J].PLo S One,2012,7:E50354.
[47]Rowles J,Wong M,Powers R,Olsen M.FTO,RNA epigenetics and epilepsy[J].Epigenetics,2012,7:1094-1097.
[48]Li Y,Zhang Y,Li S,Lu J,Chen J,Wang Y,Li Y,Xu J,Li X.Genome-wide DNA methylome analysis reveals epigenetically dysregulated non-coding RNAs in human breast cancer[J].Sci Rep,2015,5:8790.
[49]Xiao W,Cao Y,Long H,Luo Z,Li S,Deng N,Wang J,Lu X,Wang T,Ning S,Wang L,Xiao B.Genome-wide DNAmethylation patterns analysis of noncoding RNAs in temporal lobe epilepsy patients[J].Mol Neurobiol,2017,55:793-803.
[50]Alexander RP,Fang G,Rozowsky J,Snyder M,Gerstein MB.Annotating non-coding regions of the genome[J].Nat Rev Genet,2010,11:559-571.
[51]Seba R,Booth SA.Polymorphisms affecting mi RNA regulation:a new level of genetic variation affecting disorders and diseases of the human CNS[J].Future Neurol,2013,8:411-431.
[52]Sethupathy P,Collins FS.Micro RNA target site polymorphisms and human disease[J].Trends Genet,2008,24:489-497.
[53]Aronica E,Fluiter K,Iyer A,Zurolo E,Vreijling J,van Vliet EA,Baayen JC,Gorter JA.Expression pattern of mi R-146a,an inflammation-associated micro RNA,in experimental and human temporal lobe epilepsy[J].Eur J Neurosci,2010,31:1100-1107.
[54]Cui L,Tao H,Wang Y,Liu Z,Xu Z,Zhou H,Cai Y,Yao L,Chen B,Liang W,Liu Y,Cheng W,Liu T,Ma G,Li Y,Zhao B,Li K.A functional polymorphism of the micro RNA-146a gene is associated with susceptibility to drug-resistant epilepsy and seizures frequency[J].Seizure,2015,27:60-65.