title: Cardiomyogenesis is controlled by the miR-99a/let-7c cluster and epigenetic modifications.
abstract: Understanding the molecular basis of cardiomyocyte development is critical for understanding the pathogenesis of pre- and post-natal cardiac disease. MicroRNAs (miRNAs) are post-transcriptional modulators of gene expression that play an important role in many developmental processes. Here, we show that the miR-99a/let-7c cluster, mapping on human chromosome 21, is involved in the control of cardiomyogenesis by altering epigenetic factors. By perturbing miRNA expression in mouse embryonic stem cells, we find that let-7c promotes cardiomyogenesis by upregulating genes involved in mesoderm specification (T/Bra and Nodal) and cardiac differentiation (Mesp1, Nkx2.5 and Tbx5). The action of let-7c is restricted to the early phase of mesoderm formation at the expense of endoderm and its late activation redirects cells toward other mesodermal derivatives. The Polycomb complex group protein Ezh2 is a direct target of let-7c, which promotes cardiac differentiation by modifying the H3K27me3 marks from the promoters of crucial cardiac transcription factors (Nkx2.5, Mef2c, Tbx5). In contrast, miR-99a represses cardiac differentiation via the nucleosome-remodeling factor Smarca5, attenuating the Nodal/Smad2 signaling. We demonstrated that the identified targets are underexpressed in human Down syndrome fetal heart specimens. By perturbing the expression levels of these miRNAs in embryonic stem cells, we were able to demonstrate that these miRNAs control lineage- and stage-specific transcription factors, working in concert with chromatin modifiers to direct cardiomyogenesis.
authors.affiliation: Department of Biophysics, Biochemistry and General Pathology, Seconda Università di Napoli, 80138 Napoli, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Coppola
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), 80131 Napoli, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Romito
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Christelle
authors.initials: C
authors.lastname: Borel
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Gehrig
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Maryline
authors.initials: M
authors.lastname: Gagnebin
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Falconnet
authors.affiliation: Department of Molecular Medicine and Biotechnology, Università Federico II, 80131 Napoli, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Izzo
authors.affiliation: Department of Biophysics, Biochemistry and General Pathology, Seconda Università di Napoli, 80138 Napoli, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.affiliation: Department of Biophysics, Biochemistry and General Pathology, Seconda Università di Napoli, 80138 Napoli, Italy; Telethon Institute of Genetics and Medicine (TIGEM), 80131 Napoli, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Banfi
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.affiliation: Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131 Napoli, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Minchiotti
authors.affiliation: Department of Biophysics, Biochemistry and General Pathology, Seconda Università di Napoli, 80138 Napoli, Italy. Electronic address: g.cobellis@unina2.it.
authors.forename: Gilda
authors.initials: G
authors.lastname: Cobellis
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D044127:Epigenesis, Genetic; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
chemical_list: C561679:MIRN99 microRNA, human; D035683:MicroRNAs; C573158:Mirn99 microRNA, mouse; C487931:mirnlet7 microRNA, human; C542687:mirnlet7 microRNA, mouse