title: MicroRNAs in the Myocyte Enhancer Factor 2 (MEF2)-regulated Gtl2-Dio3 Noncoding RNA Locus Promote Cardiomyocyte Proliferation by Targeting the Transcriptional Coactivator Cited2.
abstract: Understanding cell cycle regulation in postmitotic cardiomyocytes may lead to new therapeutic approaches to regenerate damaged cardiac tissue. We have demonstrated previously that microRNAs encoded by the Gtl2-Dio3 noncoding RNA locus function downstream of the MEF2A transcription factor in skeletal muscle regeneration. We have also reported expression of these miRNAs in the heart. Here we investigated the role of two Gtl2-Dio3 miRNAs, miR-410 and miR-495, in cardiac muscle. Overexpression of miR-410 and miR-495 robustly stimulated cardiomyocyte DNA synthesis and proliferation. Interestingly, unlike our findings in skeletal muscle, these miRNAs did not modulate the activity of the WNT signaling pathway. Instead, these miRNAs targeted Cited2, a coactivator required for proper cardiac development. Consistent with miR-410 and miR-495 overexpression, siRNA knockdown of Cited2 in neonatal cardiomyocytes resulted in robust proliferation. This phenotype was associated with reduced expression of Cdkn1c/p57/Kip2, a cell cycle inhibitor, and increased expression of VEGFA, a growth factor with proliferation-promoting effects. Therefore, miR-410 and miR-495 are among a growing number of miRNAs that have the ability to potently stimulate neonatal cardiomyocyte proliferation.
authors.affiliation: From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Clark
authors.affiliation: From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215 fnaya@bu.edu.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Naya
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci / Q000502:physiology*; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062085:RNA, Long Noncoding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: C517260:CITED2 protein, rat; C493965:Cdkn1c protein, mouse; C110087:Cited2 protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D064326:MEF2 Transcription Factors; C578037:MEF2A protein, rat; C422882:MEG3 non-coding RNA, mouse; C547683:MIRN495 microRNA, mouse; C578036:Mef2a protein, mouse; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C467498:vascular endothelial growth factor A, rat
keywords: MEF2; cardiomyocyte; heart; microRNA (miRNA); proliferation; transcriptional coactivator