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


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.


CONCLUSIONS
p300 drives an angiogenic transcription program during hypertrophy that is fine-tuned in part through direct repression of p300 by miR-20a.
Department of Medicine, Division of Cardiology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
Lina A
LA
Shehadeh
Salil
S
Sharma
Mônica
M
Pessanha
Jian Qin
JQ
Wei
Jing
J
Liu
Huijun
H
Yuan
Claudia O
CO
Rodrigues
Michaela
M
Scherr
Nicholas F
NF
Tsinoremas
Nanette H
NH
Bishopric
D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000502:physiology*; D050881:E1A-Associated p300 Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018919:Neovascularization, Physiologic; D034622:RNA Interference; D051381:Rats
D042501:Angiogenic Proteins; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human