title: miR-300 mediates Bmi1 function and regulates differentiation in primitive cardiac progenitors.
abstract: B lymphoma Mo-MLV insertion region 1 (Bmi1) is a polycomb-family transcriptional factor critical for self-renewal in many adult stem cells and human neoplasia. We sought to identify microRNAs regulated by Bmi1 that could play a role in multipotent cardiac progenitor cell (CPC) decisions. We found that miR-300, a poorly characterized microRNA mapping in the Dlk1-Dio3 microRNA cluster, was positively regulated by Bmi1 in CPCs. Forced expression of miR-300 in CPCs promoted an improved stemness signature with a significant increase in Oct4 levels, a reduction in senescence progression and an enhanced proliferative status via p19 activation and inhibition of p16 accumulation. Endothelial and cardiogenic differentiation were clearly compromised by sustained miR-300 expression. Additionally, RNA and protein analysis revealed a significant reduction in key cardiac transcription factors, including Nkx2.5 and Tbx5. Collectively, these results suggest that some functions attributed to Bmi1 are due to induction of miR-300, which decreases the cardiogenic differentiation potential of multipotent CPCs in vitro and promotes self-renewal.
authors.affiliation: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: F M
authors.initials: FM
authors.lastname: Cruz
authors.affiliation: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.|Department of Immunology and Oncology, Spanish National Center for Biotechnology (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Tomé
authors.affiliation: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Bernal
authors.affiliation: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.|Department of Immunology and Oncology, Spanish National Center for Biotechnology (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Bernad
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism
chemical_list: C489421:Bmi1 protein, mouse; C000596512:MIRN300 microRNA, human; C000610600:MIRN300 microRNA, mouse; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D063150:Polycomb Repressive Complex 1