METTL3 mediates m6A modification of lncRNA CRNDE to promote ATG10 expression and improve brain ischemia/reperfusion injury through YTHDC1.

IF 5.7 2区生物学 Q1 BIOLOGY

Biology Direct Pub Date : 2024-10-16 DOI:10.1186/s13062-024-00536-4

Zhengtao Yu, Ying Xia, Jiameng Li, Junwen Jiang, You Li, Youjun Li, Liu Wang

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引用次数: 0

Abstract

Background: Ischemia/reperfusion (I/R) injury is a severe brain disorder with currently limited effective treatments. This study aims to explore the role of N6-methyladenosine (m6A) modification and associated regulatory factors in I/R to identify potential therapeutic targets.

Methods: We utilized a middle cerebral artery occlusion (MCAO) rat model and SH-SY5Y cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to assess m6A levels and investigate the impact of METTL3 overexpression on long non-coding RNA (lncRNA) CRNDE expression. The effects of silencing lncRNA CRNDE on the interaction between YTHDC1 and ATG10 mRNA, as well as the stability of ATG10 mRNA, were evaluated. Additionally, apoptosis rates, pro-inflammatory and anti-inflammatory factor levels, ATG10 expression, and autophagic activity were analyzed to determine the effects of METTL3. The reverse effects of YTHDC1 overexpression were also examined.

Results: MCAO rats and OGD/R-treated SH-SY5Y cells exhibited reduced m6A levels. METTL3 overexpression significantly inhibited lncRNA CRNDE expression. Silencing lncRNA CRNDE mitigated OGD/R-induced apoptosis and inflammation in SH-SY5Y cells, while enhancing autophagy and stabilizing ATG10 mRNA. METTL3 overexpression decreased cell apoptosis, reduced the levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and increased IL-10 secretion. Furthermore, METTL3 overexpression upregulated ATG10 expression and promoted autophagy. Conversely, lncRNA CRNDE overexpression negated these effects.

Conclusion: The inhibition of lncRNA CRNDE affects the interaction between YTHDC1 and ATG10 mRNA and stabilizes ATG10 mRNA, mediated by METTL3 overexpression. These findings suggest that targeting lncRNA CRNDE to reduce apoptosis, inhibit inflammation, increase ATG10 expression, and enhance autophagy could offer new therapeutic strategies for I/R injury.

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METTL3通过YTHDC1介导lncRNA CRNDE的m6A修饰，促进ATG10的表达，改善脑缺血再灌注损伤。

背景：缺血再灌注（I/R）损伤是一种严重的脑部疾病，目前有效的治疗方法有限。本研究旨在探讨 N6-甲基腺苷（m6A）修饰及相关调控因子在 I/R 中的作用，从而确定潜在的治疗靶点：我们利用大脑中动脉闭塞（MCAO）大鼠模型和接受氧-葡萄糖剥夺/再氧合（OGD/R）的SH-SY5Y细胞来评估m6A水平，并研究METTL3过表达对长非编码RNA（lncRNA）CRNDE表达的影响。研究还评估了沉默lncRNA CRNDE对YTHDC1和ATG10 mRNA之间相互作用以及ATG10 mRNA稳定性的影响。此外，还分析了细胞凋亡率、促炎因子和抗炎因子水平、ATG10表达和自噬活性，以确定METTL3的影响。此外，还研究了 YTHDC1 过表达的反向效应：结果：MCAO大鼠和OGD/R处理的SH-SY5Y细胞的m6A水平降低。METTL3的过表达明显抑制了lncRNA CRNDE的表达。沉默lncRNA CRNDE可减轻OGD/R诱导的SH-SY5Y细胞凋亡和炎症，同时增强自噬和稳定ATG10 mRNA。METTL3过表达可减少细胞凋亡，降低促炎细胞因子TNF-α、IL-1β和IL-6的水平，并增加IL-10的分泌。此外，METTL3 过表达可上调 ATG10 的表达并促进自噬。相反，lncRNA CRNDE过表达则会抵消这些作用：结论：抑制lncRNA CRNDE会影响YTHDC1和ATG10 mRNA之间的相互作用，并在METTL3过表达的介导下稳定ATG10 mRNA。这些研究结果表明，以lncRNA CRNDE为靶点减少细胞凋亡、抑制炎症、增加ATG10表达和增强自噬，可为I/R损伤提供新的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biology Direct 生物-生物学

CiteScore

6.40

自引率

10.90%

发文量

审稿时长

7 months

期刊介绍： Biology Direct serves the life science research community as an open access, peer-reviewed online journal, providing authors and readers with an alternative to the traditional model of peer review. Biology Direct considers original research articles, hypotheses, comments, discovery notes and reviews in subject areas currently identified as those most conducive to the open review approach, primarily those with a significant non-experimental component.