Oncotarget

Research Papers:

Association of RASgrf1 methylation with epileptic seizures

Xiaoni Chen, Xi Peng, Liang Wang, Xinwei Fu, Ji Xiu Zhou, Binglin Zhu, Jing Luo, Xuefeng Wang and Zheng Xiao _

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Oncotarget. 2017; 8:46286-46297. https://doi.org/10.18632/oncotarget.18000

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Abstract

Xiaoni Chen1,2,*, Xi Peng3,*, Liang Wang1,*, Xinwei Fu1,4, Ji Xiu Zhou1, Binglin Zhu1, Jing Luo1, Xuefeng Wang1 and Zheng Xiao1

1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

2Department of Neurology, Xi’an Third Hospital, Shanxi 710000, China

3Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

4Department of Neurology, The Third Hospital of Mianyang, Sichuan 621000, China

*These authors contributed equally to this work

Correspondence to:

Zheng Xiao, email: [email protected]

Keywords: RASgrf1, DNA methylation, RG108, epilepsy

Received: February 14, 2017     Accepted: April 11, 2017     Published: May 19, 2017

ABSTRACT

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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