通过 YTHDF1 依赖性 PIEZO2 mRNA m6A 修饰对心脏纤维化的外转录组调控

IF 10.2 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Ji-Fei Ding, Bin Tu, Kai Song, Zhen-Yu Liu, Li-Chan Lin, Zhi-Yan Liu, Yan Shi, Jing-Jing Yang, Jian-Yuan Zhao, Hui Tao
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引用次数: 0

摘要

背景:机械敏感性离子通道在心脏发育、生理和疾病中发挥着关键作用。然而,人们对机械敏感性非选择性阳离子通道 Piezo 家族在心脏纤维化中的分子机制知之甚少:用 ISO/Ang-II/TAC 处理小鼠以诱导心脏纤维化。将携带 POSTN 启动子驱动的靶向 YTHDF1 和 Piezo2 的小发夹 RNA 的 AAV9 注射给 ISO 小鼠,以研究它们在心脏纤维化中的作用。为了确定YTHDF1在心脏纤维化中调控Piezo2表达的机制,研究人员进行了RNA-seq、单细胞测序以及组织学和生化分析。在YTHDF1缺陷的心脏成纤维细胞和小鼠心脏中重组了Piezo2,以研究其对心脏成纤维细胞自噬和纤维化的影响。在实验性心脏纤维化和TGF-β1诱导的心脏成纤维细胞中,Piezo2而非Piezo1的表达增加。成纤维细胞特异性Piezo2缺乏症可改善成纤维细胞活化和自噬,并抑制心脏纤维化。从机理上讲,Piezo2 的上调与 m6A mRNA 水平的升高有关。峰值_26355的位点特异性m6A修饰对于调节YTHDF1与Piezo2 mRNA的结合以及诱导Piezo2翻译至关重要。值得注意的是,Piezo2表转录抑制改善了实验性心脏纤维化:我们证明了一种新的表转录组学机制,通过该机制,YTHDF1 可识别 Piezo2 并通过 m6A 依赖性调控来控制心成纤维细胞的自噬和纤维化。我们的发现为开发心脏纤维化的预防措施提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Epitranscriptomic regulation of cardiac fibrosis via YTHDF1-dependent PIEZO2 mRNA m6A modification.

Background: Mechanosensitive ion channels play a key role in heart development, physiology, and disease. However, little is known about the molecular mechanisms of the mechanosensitive nonselective cationic channel Piezo family in cardiac fibrosis.

Methods and results: Mice were treated with ISO/Ang-II/TAC to induce cardiac fibrosis. AAV9 carrying POSTN promoter-driven small hairpin RNA targeting YTHDF1, and Piezo2 were administered to ISO mice to investigate their roles in cardiac fibrosis. RNA-seq, single-cell sequencing, and histological and biochemical analyses were performed to determine the mechanism by which YTHDF1 regulates Piezo2 expression in cardiac fibrosis. Piezo2 was reconstituted in YTHDF1-deficient cardiac fibroblasts and mouse hearts to study its effects on cardiac fibroblast autophagy and fibrosis. Piezo2 but not Piezo1 expression increased in experimental cardiac fibrosis and TGF-β1-induced cardiac fibroblasts. Fibroblast-specific Piezo2 deficiency ameliorated fibroblast activation and autophagy and inhibited cardiac fibrosis. Mechanistically, Piezo2 upregulation was associated with elevated m6A mRNA levels. Site-specific m6A modifications at peak_26355 were crucial for regulating the binding of YTHDF1 to Piezo2 mRNA and inducing Piezo2 translation. Notably, Piezo2 epitranscriptomic repression ameliorated experimental cardiac fibrosis.

Conclusions: We demonstrated a novel epitranscriptomic mechanism through which YTHDF1 recognizes Piezo2 and controls cardiac fibroblast autophagy and fibrosis through m6A-dependent modulation. Our findings provide new insights for the development of preventive measures for cardiac fibrosis.

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来源期刊
Cardiovascular Research
Cardiovascular Research 医学-心血管系统
CiteScore
21.50
自引率
3.70%
发文量
547
审稿时长
1 months
期刊介绍: Cardiovascular Research Journal Overview: International journal of the European Society of Cardiology Focuses on basic and translational research in cardiology and cardiovascular biology Aims to enhance insight into cardiovascular disease mechanisms and innovation prospects Submission Criteria: Welcomes papers covering molecular, sub-cellular, cellular, organ, and organism levels Accepts clinical proof-of-concept and translational studies Manuscripts expected to provide significant contribution to cardiovascular biology and diseases
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