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通过依赖m6A-YTHDF2的机制抑制NOVA2,METTL14可以逆转肝纤维化
Xiaoxue Hou1, Yuwen Li2, Jiali Song1
1Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Hepatology communications
|August 3, 2023
概括
该研究显示,降低METTL14水平通过减少N6-甲基氨酸 (m6A) 修饰,促进HSC激活和NOVA2mRNA降解来恶化肝纤维化. 恢复METTL14或NOVA2可以治疗肝纤维化.
科学领域:
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 肝病学 肝病学是一种肝病学.
背景情况:
- N6-甲基氨酸 (m6A) 是一种关键的RNA修饰,参与各种生理和病理过程.
- 通过METTL14介导的m6A修饰在肝纤维化 (LF) 病原发生中的作用在很大程度上仍未被探索.
研究的目的:
- 为了调查METTL14诱导的m6A修饰在肝纤维化中的参与.
- 阐明METTL14影响肝星细胞 (HSC) 激活和LF进展的潜在分子机制.
主要方法:
- 在体外研究中使用具有METTL14倒置/过度表达的HSC细胞系来评估增殖,细胞周期和迁移.
- 使用MeRIP-seq和RNA-seq来识别METTL14下游目标.
- 在体内实验中使用AAV介导的METTL14敲击在LF的小鼠模型.
主要成果:
- 在LF患者的肝组织中,METTL14表达和m6A修饰水平降低.
- 在HSC中抑制METTL14促进了它们的激活,扩散和迁移,加剧了LF.
- METTL14耗尽减少了NOVA2mRNA的m6A修饰,导致其通过YTHDF2路径降解.
结论:
- 在肝纤维化中,METTL14作为瘤抑制剂,通过m6A修饰维持NOVA2的表达.
- 缺乏METTL14会加剧LF,而NOVA2则表现出抗纤维的作用.
- 准METTL14-m6A-NOVA2轴为肝纤维化提供了一个潜在的治疗策略.
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