| First Author | Gao XQ | Year | 2020 |
| Journal | Nat Cell Biol | Volume | 22 |
| Issue | 11 | Pages | 1319-1331 |
| PubMed ID | 33020597 | Mgi Jnum | J:310115 |
| Mgi Id | MGI:6709605 | Doi | 10.1038/s41556-020-0576-y |
| Citation | Gao XQ, et al. (2020) The piRNA CHAPIR regulates cardiac hypertrophy by controlling METTL3-dependent N(6)-methyladenosine methylation of Parp10 mRNA. Nat Cell Biol 22(11):1319-1331 |
| abstractText | 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 N(6)-methyladenosine (m(6)A) 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 m(6)A methylation of Parp10 mRNA transcripts, which upregulates PARP10 expression. The CHAPIR-dependent increase in PARP10 promotes the mono-ADP-ribosylation of GSK3beta 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. |
