Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine / analogs & derivatives*
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Adenosine / metabolism
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Animals
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Cells, Cultured
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Disease Models, Animal
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Gene Expression Regulation, Enzymologic
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Glycogen Synthase Kinase 3 beta / genetics
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Glycogen Synthase Kinase 3 beta / metabolism
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Heart Ventricles / enzymology*
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Heart Ventricles / pathology
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Hypertrophy, Left Ventricular / enzymology*
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Hypertrophy, Left Ventricular / genetics
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Hypertrophy, Left Ventricular / pathology
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Hypertrophy, Left Ventricular / physiopathology
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Male
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Methylation
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Methyltransferases / genetics
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Methyltransferases / metabolism*
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Mice, Inbred C57BL
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Mice, Knockout
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Myocytes, Cardiac / enzymology*
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Myocytes, Cardiac / pathology
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / metabolism
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA Stability
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RNA, Messenger / genetics
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RNA, Messenger / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism*
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Signal Transduction
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Ventricular Function, Left*
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Ventricular Remodeling
Substances
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NFATC Transcription Factors
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Nfatc4 protein, mouse
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Small Interfering
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N-methyladenosine
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Methyltransferases
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Mettl3 protein, mouse
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Parp10 protein, mouse
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Poly(ADP-ribose) Polymerases
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Adenosine