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The piRNA CHAPIR regulates cardiac hypertrophy by controlling METTL3-dependent N 6 -methyladenosine methylation of Parp10 mRNA
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-10-05 , DOI: 10.1038/s41556-020-0576-y
Xiang-Qian Gao 1 , Yu-Hui Zhang 2 , Fang Liu 3 , Murugavel Ponnusamy 1 , Xue-Mei Zhao 2 , Lu-Yu Zhou 1 , Mei Zhai 2 , Cui-Yun Liu 1 , Xin-Min Li 1 , Man Wang 1 , Chan Shan 1 , Pei-Pei Shan 1 , Yin Wang 1 , Yan-Han Dong 1 , Li-Li Qian 1 , Tao Yu 1 , Jie Ju 1 , Tao Wang 1 , Kai Wang 1 , Xin-Zhe Chen 1 , Yun-Hong Wang 2 , Jian Zhang 2 , Pei-Feng Li 1 , Kun Wang 1
Affiliation  

PIWI-interacting RNAs (piRNAs) are abundantly expressed during cardiac hypertrophy. However, their functions and molecular mechanisms remain unknown. Here, we identified a cardiac-hypertrophy-associated piRNA (CHAPIR) that promotes pathological hypertrophy and cardiac remodelling by targeting METTL3-mediated N6-methyladenosine (m6A) methylation of Parp10 mRNA transcripts. CHAPIR deletion markedly attenuates cardiac hypertrophy and restores heart function, while administration of a CHAPIR mimic enhances the pathological hypertrophic response in pressure-overloaded mice. Mechanistically, CHAPIR–PIWIL4 complexes directly interact with METTL3 and block the m6A methylation of Parp10 mRNA transcripts, which upregulates PARP10 expression. The CHAPIR-dependent increase in PARP10 promotes the mono-ADP-ribosylation of GSK3β and inhibits its kinase activity, which results in the accumulation of nuclear NFATC4 and the progression of pathological hypertrophy. Hence, our findings reveal that a piRNA-mediated RNA epigenetic mechanism is involved in the regulation of cardiac hypertrophy and that the CHAPIR–METTL3–PARP10–NFATC4 signalling axis could be therapeutically targeted for treating pathological hypertrophy and maladaptive cardiac remodelling.



中文翻译:

piRNA CHAPIR 通过控制 Parp10 mRNA 的 METTL3 依赖性 N 6 -甲基腺苷甲基化来调节心脏肥大

PIWI 相互作用的 RNA (piRNA) 在心脏肥大期间大量表达。然而,它们的功能和分子机制仍然未知。在这里,我们鉴定了一种心脏肥大相关的 piRNA (CHAPIR),它通过靶向 METTL3 介导的Parp10 mRNA 转录本的N 6 -甲基腺苷(m 6 A) 甲基化来促进病理性肥大和心脏重塑。CHAPIR 缺失显着减轻心脏肥大并恢复心脏功能,而 CHAPIR 模拟物的给药可增强压力超负荷小鼠的病理性肥大反应。机械地,CHAPIR-PIWIL4络合物直接交互与METTL3并阻断米6的甲基化PARP10mRNA 转录本,上调 PARP10 表达。PARP10 的 CHAPIR 依赖性增加促进 GSK3β 的单 ADP 核糖基化并抑制其激酶活性,从而导致核 NFATC4 的积累和病理性肥大的进展。因此,我们的研究结果表明,piRNA 介导的 RNA 表观遗传机制参与了心脏肥大的调节,并且 CHAPIR-METTL3-PARP10-NFATC4 信号轴可以在治疗上成为治疗病理性肥大和适应不良的心脏重塑的目标。

更新日期:2020-10-05
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