MicroRNA-20a constrains p300-driven myocardial angiogenic transcription by direct targeting of p300

Lina A. Shehadeh, Salil Sharma, Mônica Pessanha, Jian Qin Wei, Jing Liu, Huijun Yuan, Claudia O. Rodrigues, Michaela Scherr, Nicholas F. Tsinoremas, Nanette H. Bishopric

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Abstract

Objective: To characterize downstream effectors of p300 acetyltransferase in the myocardium. Background: Acetyltransferase p300 is a central driver of the hypertrophic response to increased workload, but its biological targets and downstream effectors are incompletely known. Methods and Results: Mice expressing a myocyte-restricted transgene encoding acetyltransferase p300, previously shown to develop spontaneous hypertrophy, were observed to undergo robust compensatory blood vessel growth together with increased angiogenic gene expression. Chromatin immunoprecipitation demonstrated binding of p300 to the enhancers of the angiogenic regulators Angpt1 and Egln3. Interestingly, p300 overexpression in vivo was also associated with relative upregulation of several members of the anti-angiogenic miR-17∼92 cluster in vivo. Confirming this finding, both miR-17-3p and miR-20a were upregulated in neonatal rat ventricular myocytes following adenoviral transduction of p300. Relative expression of most members of the 17∼92 cluster was similar in all 4 cardiac chambers and in other organs, however, significant downregulation of miR-17-3p and miR-20a occurred between 1 and 8 months of age in both wt and tg mice. The decline in expression of these microRNAs was associated with increased expression of VEGFA, a validated miR-20a target. In addition, miR-20a was demonstrated to directly repress p300 expression through a consensus binding site in the p300 3′UTR. In vivo transduction of p300 resulted in repression both of p300 and of p300-induced angiogenic transcripts. Conclusion: p300 drives an angiogenic transcription program during hypertrophy that is fine-tuned in part through direct repression of p300 by miR-20a.

Original languageEnglish (US)
Article numbere79133
JournalPloS one
Volume8
Issue number11
DOIs
StatePublished - Nov 13 2013

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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