• Junfen Fan, Liyuan Zhong, Feng Yan, Xue Li, Lingzhi Li, Haiping Zhao, Ziping Han, Rongliang Wang, Zhen Tao, Yangmin Zheng, Qingfeng Ma, and Yumin Luo.
• Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing 100053, China; Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing 100053, China. Electronic address: fanjunfen@xwhosp.org.
• Neuroscience. 2024 Aug 16; 553: 567356-73.

BackgroundN6-methyladenosine (m6A) is one of the most extensive RNA methylation modifications in eukaryotes and participates in the pathogenesis of numerous diseases including ischemic stroke. Peripheral blood neutrophils are forerunners after ischemic brain injury and exert crucial functions. This study aims to explore the transcriptional profiles of m6A modification in neutrophils of patients with ischemic stroke.ResultsWe found that the expression levels of m6A regulators FTO and YTHDC1 were notably decreased in the neutrophils following ischemic stroke, and FTO expression was negatively correlated with neutrophil counts and neutrophil-to-lymphocyte ratio (NLR). The m6A mRNA&lncRNA epigenetic transcriptome microarray identified 416 significantly upregulated and 500 significantly downregulated mRNA peaks in neutrophils of ischemic stroke patients. Moreover, 48 mRNAs and 18 lncRNAs were hypermethylated, and 115 mRNAs and 29 lncRNAs were hypomethylated after cerebral ischemia. Gene ontology (GO) analysis identified that these m6A-modified mRNAs were primarily enriched in calcium ion transport, long-term synaptic potentiation, and base-excision repair. The signaling pathways involved were EGFR tyrosine kinase inhibitor resistance, ErbB, and base excision repair signaling pathway. MeRIP-qPCR validation results showed that NRG1 and GDPD1 were significantly hypermethylated, and LIG1, CHRND, lncRNA RP11-442J17.2, and lncRNA RP11-600P1.2 were significantly hypomethylated after cerebral ischemia. Moreover, the expression levels of major m6A regulators Mettl3, Fto, Ythdf1, and Ythdf3 were obviously declined in the brain and leukocytes of post-stroke mouse models.ConclusionThis study explored the RNA m6A methylation pattern in the neutrophils of ischemic stroke patients, indicating that it is an intervention target of epigenetic regulation in ischemic stroke.Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.

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