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Association of RASgrf1 methylation with epileptic seizures

DNA methylation, one of the mechanisms of epigenetic regulation, has been suggested to be related with epilepsy. RASgrf1 is a paternally imprinted gene and has a differentially methylated region (DMR) at the promoter that can silence gene expression. We have previously observed the down-regulation o...

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Autores principales: Chen, Xiaoni, Peng, Xi, Wang, Liang, Fu, Xinwei, Zhou, Ji Xiu, Zhu, Binglin, Luo, Jing, Wang, Xuefeng, Xiao, Zheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542267/
https://www.ncbi.nlm.nih.gov/pubmed/28611277
http://dx.doi.org/10.18632/oncotarget.18000
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author Chen, Xiaoni
Peng, Xi
Wang, Liang
Fu, Xinwei
Zhou, Ji Xiu
Zhu, Binglin
Luo, Jing
Wang, Xuefeng
Xiao, Zheng
author_facet Chen, Xiaoni
Peng, Xi
Wang, Liang
Fu, Xinwei
Zhou, Ji Xiu
Zhu, Binglin
Luo, Jing
Wang, Xuefeng
Xiao, Zheng
author_sort Chen, Xiaoni
collection PubMed
description DNA methylation, one of the mechanisms of epigenetic regulation, has been suggested to be related with epilepsy. RASgrf1 is a paternally imprinted gene and has a differentially methylated region (DMR) at the promoter that can silence gene expression. We have previously observed the down-regulation of RASgrf1 in the temporal neocortex of epilepsy patients and in the hippocampus of epileptic animals. Here, we further explored the dynamic change (1-day acute period, 10-day latent period and 45-day chronic phase) of DNA methylation and RASgrf1 expression after acute epileptic seizures in kainic acid (KA)-treated mice, and we observed the impact of N-phthalyl-L-tryptophan (RG108), a DNA methyltransferase (DNMT) inhibitor, on an acute epileptic model by polymerase chain reaction (PCR), western blotting, and bisulfite sequencing PCR (BSP). The results directly showed that the methylation of the RASgrf1 promoter gradually increased and reached a maximal level at the latent period, with subsequent suppression of RASgrf1 mRNA and protein expression levels, which reached a minimum level in the chronic phase. RG108 inhibited the increased methylation of the RASgrf1 gene, with significant inhibition occurring at the latent period, and restored RASgrf1 expression levels in the chronic phase. In addition, we demonstrated that RG108 could suppress acute epileptic seizures in KA-treated mice and epileptic discharges in 4-aminopyridine (4-AP)-treated hippocampal slices. These findings demonstrate that RASgrf1 is closely associated with epilepsy via the aberrant methylation of RASgrf1, and regulating the methylation status of relevant genes might be an intriguing topic in future research on epilepsy.
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spelling pubmed-55422672017-08-07 Association of RASgrf1 methylation with epileptic seizures Chen, Xiaoni Peng, Xi Wang, Liang Fu, Xinwei Zhou, Ji Xiu Zhu, Binglin Luo, Jing Wang, Xuefeng Xiao, Zheng Oncotarget Research Paper DNA methylation, one of the mechanisms of epigenetic regulation, has been suggested to be related with epilepsy. RASgrf1 is a paternally imprinted gene and has a differentially methylated region (DMR) at the promoter that can silence gene expression. We have previously observed the down-regulation of RASgrf1 in the temporal neocortex of epilepsy patients and in the hippocampus of epileptic animals. Here, we further explored the dynamic change (1-day acute period, 10-day latent period and 45-day chronic phase) of DNA methylation and RASgrf1 expression after acute epileptic seizures in kainic acid (KA)-treated mice, and we observed the impact of N-phthalyl-L-tryptophan (RG108), a DNA methyltransferase (DNMT) inhibitor, on an acute epileptic model by polymerase chain reaction (PCR), western blotting, and bisulfite sequencing PCR (BSP). The results directly showed that the methylation of the RASgrf1 promoter gradually increased and reached a maximal level at the latent period, with subsequent suppression of RASgrf1 mRNA and protein expression levels, which reached a minimum level in the chronic phase. RG108 inhibited the increased methylation of the RASgrf1 gene, with significant inhibition occurring at the latent period, and restored RASgrf1 expression levels in the chronic phase. In addition, we demonstrated that RG108 could suppress acute epileptic seizures in KA-treated mice and epileptic discharges in 4-aminopyridine (4-AP)-treated hippocampal slices. These findings demonstrate that RASgrf1 is closely associated with epilepsy via the aberrant methylation of RASgrf1, and regulating the methylation status of relevant genes might be an intriguing topic in future research on epilepsy. Impact Journals LLC 2017-05-19 /pmc/articles/PMC5542267/ /pubmed/28611277 http://dx.doi.org/10.18632/oncotarget.18000 Text en Copyright: © 2017 Chen et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Chen, Xiaoni
Peng, Xi
Wang, Liang
Fu, Xinwei
Zhou, Ji Xiu
Zhu, Binglin
Luo, Jing
Wang, Xuefeng
Xiao, Zheng
Association of RASgrf1 methylation with epileptic seizures
title Association of RASgrf1 methylation with epileptic seizures
title_full Association of RASgrf1 methylation with epileptic seizures
title_fullStr Association of RASgrf1 methylation with epileptic seizures
title_full_unstemmed Association of RASgrf1 methylation with epileptic seizures
title_short Association of RASgrf1 methylation with epileptic seizures
title_sort association of rasgrf1 methylation with epileptic seizures
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542267/
https://www.ncbi.nlm.nih.gov/pubmed/28611277
http://dx.doi.org/10.18632/oncotarget.18000
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