Adult mammalian cardiomyocytes (CMs) have a very limited capacity to spontaneously proliferate or regenerate following injury or disease, restricting the possibility of cardiac repair after injury. CM gene expression in development and disease is tightly regulated by epigenetic modifications which covalently modify histones or DNA. In particular, the DNA is modified at the of 5’ cytosine by methylation (5-mC) or demethylation, the latter through hydroxymethylation (5-hmC) a process mediated by the ten-eleven translocation family protein (TET1,2,3). 5-mC is generally associated with inhibition of gene expression while 5-hmC with activation. It was previously found that in CMs 5-hmC marks not only active genes but also enhancers, modulating gene expression during development and adult myocardial stress conditions. Among the three TET isoforms, TET2 was found to be predominant in CMs. TET2 has been implied in hematopoietic tumors and somatic mutations are associated with clonal hematopoiesis of indetermined potential (CHIP). Whether TET2 controls CM cell cycle is still unknown. To answer this question, we generated a cardiomyocyte specific Tet2 knockout (KO) mouse line. Both in vivo and ex vivo assays revealed that neonatal Tet2 KO-CMs exhibited a higher proliferation rate compared to their wild-type (WT) counterparts. Echocardiographic evaluation of adult mice over time demonstrated that KO mice have improved cardiac function relative to WT mice. Consistent with these findings, isolated adult KO CMs showed enhanced contraction and relaxation phases compared to WT CMs. Lastly, the transcriptional profile of TET2 KO CMs exhibited significant differences compared to control. In summary, our results show that TET2 regulates CM cell cycle up to the neonatal phase. Its absence increases CM number, improving cardiac function during adulthood.

TET2 modulates neonatal cardiomyocyte proliferation and cardiac function in adult mice(2025 Jan 09).

TET2 modulates neonatal cardiomyocyte proliferation and cardiac function in adult mice

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2025-01-09

Abstract

Adult mammalian cardiomyocytes (CMs) have a very limited capacity to spontaneously proliferate or regenerate following injury or disease, restricting the possibility of cardiac repair after injury. CM gene expression in development and disease is tightly regulated by epigenetic modifications which covalently modify histones or DNA. In particular, the DNA is modified at the of 5’ cytosine by methylation (5-mC) or demethylation, the latter through hydroxymethylation (5-hmC) a process mediated by the ten-eleven translocation family protein (TET1,2,3). 5-mC is generally associated with inhibition of gene expression while 5-hmC with activation. It was previously found that in CMs 5-hmC marks not only active genes but also enhancers, modulating gene expression during development and adult myocardial stress conditions. Among the three TET isoforms, TET2 was found to be predominant in CMs. TET2 has been implied in hematopoietic tumors and somatic mutations are associated with clonal hematopoiesis of indetermined potential (CHIP). Whether TET2 controls CM cell cycle is still unknown. To answer this question, we generated a cardiomyocyte specific Tet2 knockout (KO) mouse line. Both in vivo and ex vivo assays revealed that neonatal Tet2 KO-CMs exhibited a higher proliferation rate compared to their wild-type (WT) counterparts. Echocardiographic evaluation of adult mice over time demonstrated that KO mice have improved cardiac function relative to WT mice. Consistent with these findings, isolated adult KO CMs showed enhanced contraction and relaxation phases compared to WT CMs. Lastly, the transcriptional profile of TET2 KO CMs exhibited significant differences compared to control. In summary, our results show that TET2 regulates CM cell cycle up to the neonatal phase. Its absence increases CM number, improving cardiac function during adulthood.
9-gen-2025
PASSARETTI, MAURO
TET2 modulates neonatal cardiomyocyte proliferation and cardiac function in adult mice(2025 Jan 09).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/97227
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