CHAPIR z-bo 2020-11-02 503

　　Chronic myocardial hypertrophy and its related myocardial remodeling are the main factors in the development of cardiac dysfunction, leading to severe heart failure and death. The mechanism of RNA m6A methylation/demethylation is closely related to the physiological and pathological processes of the heart. However, the molecular mechanism of m6A modification involved in cardiac hypertrophy is still unclear. Non-coding RNA (ncRNA), especially the heart-specific expression of ncRNA, has unique regulatory functions in both physiological and pathological cardiac hypertrophy. In the process of cardiac hypertrophy, a large amount of non-coding RNA is expressed, and this ncRNA can interact with PIWI protein, called piRNA, but their function and molecular mechanism in cardiac hypertrophy are still unknown.

　　Recently, the team of Professor Wang Kun from the Institute of Translational Medicine of Qingdao University published an article entitled "The piRNA CHAPIR regulates cardiac hypertrophy by controlling METTL3-dependent N6-methyladenosine methylation of Parp10 mRNA" on Nature Cell Biology, revealing that piRNA-mediated The RNA epigenetic mechanism is involved in the regulation of cardiac hypertrophy. Targeting the CHAPIR–METTL3–PARP10–NFATC4 signal transduction axis can treat pathological hypertrophy and maladaptive heart remodeling.

　　In order to systematically study the potential role of piRNA and identify specific piRNAs that play a role in cardiac hypertrophy, the researchers performed transected aortic constriction (TAC) surgery on adult mice, and examined the overall expression of piRNA in left ventricular samples 4 weeks later . The results of the study showed that three of the piRNAs with significant changes in expression levels are related to myocardial hypertrophy, so the researchers tested the expression levels of these three piRNAs in different tissues and found that compared with other organs, DQ726659 is highly expressed in the heart, so Researchers speculate that DQ726659 has a potential regulatory role in cardiac hypertrophy, and call this uncharacterized piRNA associated with cardiac hypertrophy (CHAPIR).

　　Next, the researchers assessed the functional correlation between CHAPIR and pathological myocardial hypertrophy using CHAPIR gene knockout mice (constructed by Saiye Biology). The results show that the lack of CHAPIR can prevent the development of pathological cardiac hypertrophy, and the administration of CHAPIR mimics can enhance the pathological hypertrophy of mice with cardiac hypertrophy caused by pressure overload. In order to explore whether CHAPIR regulates cardiomyocyte hypertrophy, the researchers used an in vitro model of hypertrophy induced by angiotensin II (Ang II). The results indicate that CHAPIR plays an important role in regulating cardiac hypertrophy.

　　Finally, the researchers studied the molecular mechanism of CHAPIR regulating cardiomyocyte hypertrophy, and found that the CHAPIR–PIWIL4 complex directly interacts with METTL3 and blocks the m6A modification of Parp10 mRNA transcripts, thereby up-regulating the expression of PARP10, thereby inhibiting the activity of GSK3β kinase, and Increase the accumulation and activity of nuclear transcription factor NFATC4, which is a transcription factor involved in the expression of myocardial hypertrophy genes.

　　In conclusion, this study proves that CHAPIR plays an important role in cardiac hypertrophy. It affects the function of anti-cardiac hypertrophy molecules (such as GSK3β) by regulating RNA epigenetic activity and up-regulating PARP10 (a factor affecting cardiac hypertrophy). In addition, in mice lacking CHAPIR, the significant improvement in cardiac function and the significant reduction in fibrotic response indicate that targeting CHAPIR may be a useful treatment strategy.