title: MicroRNAs for Fine-Tuning of Mouse Embryonic Stem Cell Fate Decision through Regulation of TGF-β Signaling.
abstract: Over the past years, microRNAs (miRNAs) have emerged as crucial factors that regulate self-renewal and differentiation of embryonic stem cells (ESCs). Although much is known about their role in maintaining ESC pluripotency, the mechanisms by which they affect cell fate decisions remain poorly understood. By performing deep sequencing to profile miRNA expression in mouse ESCs (mESCs) and differentiated embryoid bodies (EBs), we identified four differentially expressed miRNAs. Among them, miR-191 and miR-16-1 are highly expressed in ESCs and repress Smad2, the most essential mediator of Activin-Nodal signaling, resulting in the inhibition of mesendoderm formation. miR-23a, which is also down-regulated in the differentiated state, suppresses differentiation toward the endoderm and ectoderm lineages. We further identified miR-421 as a differentiation-associated regulator through the direct repression of the core pluripotency transcription factor Oct4 and the bone morphogenetic protein (BMP)-signaling components, Smad5 and Id2. Collectively, our findings uncover a regulatory network between the studied miRNAs and both branches of TGF-β/BMP-signaling pathways, revealing their importance for ESC lineage decisions.
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas (FORTH), 70013 Heraklion, Crete, Greece; Department of Biology, University of Crete, 71409 Heraklion, Crete, Greece.
authors.forename: Christiana
authors.initials: C
authors.lastname: Hadjimichael
authors.affiliation: Department of Biology, University of Crete, 71409 Heraklion, Crete, Greece.
authors.forename: Christoforos
authors.initials: C
authors.lastname: Nikolaou
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas (FORTH), 70013 Heraklion, Crete, Greece; Department of Biology, University of Crete, 71409 Heraklion, Crete, Greece.
authors.forename: Joseph
authors.initials: J
authors.lastname: Papamatheakis
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas (FORTH), 70013 Heraklion, Crete, Greece. Electronic address: kretsova@imbb.forth.gr.
authors.forename: Androniki
authors.initials: A
authors.lastname: Kretsovali
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D016212:Transforming Growth Factor beta