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EGR1-Driven METTL3 Activation Curtails VIM-Mediated Neuron Injury in Epilepsy

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Abstract

Uncovering mechanisms underlying epileptogenesis aids in preventing further epilepsy progression and to lessen seizure severity and frequency. The purpose of this study is to explore the antiepileptogenic and neuroprotective mechanisms of EGR1 in neuron injuries encountered in epilepsy. Bioinformatics analysis was conducted to identify the key genes related to epilepsy. The mice were rendered epileptic using the kainic acid protocol, followed by measurement of seizure severity, high amplitude and frequency, pathological changes of hippocampal tissues and neuron apoptosis. Furthermore, an in vitro epilepsy model was constructed in the neurons isolated from newborn mice, which was then subjected to loss- and gain-of-function investigations, followed by neuron injury and apoptosis assessment. Interactions among EGR1, METTL3, and VIM were analyzed by a series of mechanistic experiments. In the mouse and cell models of epilepsy, VIM was robustly induced. However, its knockdown reduced hippocampal neuron injury and apoptosis. Meanwhile, VIM knockdown decreased inflammatory response and neuron apoptosis in vivo. Mechanistic investigations indicated that EGR1 transcriptionally activated METTL3, which in turn downregulated VIM expression through m6A modification. EGR1 activated METTL3 and reduced VIM expression, thereby impairing hippocampal neuron injury and apoptosis, preventing epilepsy progression. Taken together, this study demonstrates that EGR1 alleviates neuron injuries in epilepsy by inducing METTL3-mediated inhibition of VIM, which provides clues for the development of novel antiepileptic treatments.

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Data Availability

The data that supports the findings of this study are available on request from the corresponding author.

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Acknowledgements

Not applicable.

Funding

This study was supported by The Natural Science Foundation of Guangdong Province (Grant No. 2021A1515220116), Science and Technology Program of Guangzhou (Grant No. 202201010071, 2023A03J0960) and National Natural Science Foundation of China (Grant No. 82001370).

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  1. Zhaofei Dong, Fuli Min and Sai Zhang: Co-first authors.

Authors and Affiliations

  1. Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, People’s Republic of China

    Zhaofei Dong

  2. Department of Neurology, School of Medicine, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou, 510180, Guangdong Province, People’s Republic of China

    Fuli Min, Sai Zhang, Huili Zhang & Tao Zeng

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  1. Zhaofei Dong
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  2. Fuli Min
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Contributions

ZD, FM and SZ wrote the paper and conceived and designed the experiments; HZ and TZ analyzed the data; ZD and FM collected and provided the sample for this study. All authors have read and approved the final submitted manuscript.

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Correspondence to Tao Zeng.

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The current study was performed with the approval of the Institutional Animal Care and Use Committee(IACUC), Sun Yat-Sen University and performed according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (SYSU-IACUC-2020-B0178).

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Dong, Z., Min, F., Zhang, S. et al. EGR1-Driven METTL3 Activation Curtails VIM-Mediated Neuron Injury in Epilepsy. Neurochem Res 48, 3349–3362 (2023). https://doi.org/10.1007/s11064-023-03950-8

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