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miR-29a and miR-30c negatively regulate DNMT 3a in cardiac ischemic tissues: implications for cardiac remodelling

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Gambacciani C., Kusmic C., Chiavacci E., Meghini F., Rizzo M., Mariani L., Pitto L.

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Recent evidences indicate that epigenetic changes play an important role in the transcriptional reprogramming of gene expression that characterizes cardiac hypertrophy and failure and may dictate response to therapy. Several data demonstrate that microRNAs (miRNAs) play critical roles both in normal cardiac function and under pathological conditions. Here we assessed, in in vivo rat models of myocardial infarction (MI) and ischemia-reperfusion (IR), the relationship between two miRNAs (miR-29a and miR-30c) and de novo methyltransferase (DNMT3a) which, altering the chromatin accessibility for transcription factors, deeply impacts gene expression. We showed that the levels of members of miR-29 and miR- 30 families were down regulated in ischemic tissues whilst the protein levels of DNMT3a were increased, such a relation was not present in healthy tissues. Furthermore, by an in vitro assay, we demonstrated that both miRNAs are able to down regulate DNMT3a by directly interacting with DNMT3a 3’UTR and that miR-29a or miR-30c overexpression in the cardiac HL1 cell line causes decrease of DNMT3a enzyme both at the mRNA and protein levels. Our data, besides confirming the down regulation of the miR-29a and miR-30c in infarcted tissues, envisage a cross-talk between microRNAs and chromatin modifying enzymes suggesting a new mechanism that might generate the alterations of DNA methylation often observed in myocardial pathophysiology.

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1 microRNA Diagnostics and Therapeutics

1 2014

1 Chiavacci E.

1 Gambacciani C.

1 Kusmic C.

1 Mariani L.

1 Meghini F.

1 Pitto L.

1 Rizzo M.

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miR-29a and miR-30c negatively regulate DNMT 3a in cardiac ischemic tissues: implications for cardiac remodelling