Abstract
Dnmt2/Trdmt1 is a methyltransferase, which has been shown to methylate tRNAs. Deficient mutants were reported to exhibit various, seemingly unrelated, defects in development and RNA-mediated epigenetic heredity. Here we report a role in a distinct developmental regulation effected by a noncoding RNA. We show that Dnmt2-deficiency in mice results in cardiac hypertrophy. Echocardiographic measurements revealed that cardiac function is preserved notwithstanding the increased dimensions of the organ due to cardiomyocyte enlargement. Mechanistically, activation of the P-TEFb complex, a critical step for cardiac growth, results from increased dissociation of the negatively regulating Rn7sk non-coding RNA component in Dnmt2-deficient cells. Our data suggest that Dnmt2 plays an unexpected role for regulation of cardiac growth by modulating activity of the P-TEFb complex.
MeSH terms
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Animals
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Cells, Cultured
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DNA (Cytosine-5-)-Methyltransferases / physiology*
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Embryo, Mammalian
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Female
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Gene Expression Regulation, Developmental
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Heart / embryology*
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Heart / growth & development
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Organogenesis / genetics*
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Positive Transcriptional Elongation Factor B / metabolism
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RNA Polymerase II / metabolism*
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Trans-Activators / physiology
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Transcription, Genetic* / genetics
Substances
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Trans-Activators
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Dnmt2 protein, mouse
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DNA (Cytosine-5-)-Methyltransferases
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Positive Transcriptional Elongation Factor B
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RNA Polymerase II
Grants and funding
This work was supported by the French Government (National Research Agency, ANR) through the "Investments for the Future" LABEX SIGNALIFE program (reference ANR-11-LABX-0028-01), the Association pour la Recherche sur le Cancer and Fondation de France (KDW), the Ligue Nationale Contre le Cancer and Agence Nationale de la Recherche France (ANR-08-GENOPAT-011 Epipath-Parapath) (MR). HG was the recipient of a scholarship from Shahid Beheshti University of Medical Sciences, Iran.