title: Initiation of stem cell differentiation involves cell cycle-dependent regulation of developmental genes by Cyclin D.
abstract: Coordination of differentiation and cell cycle progression represents an essential process for embryonic development and adult tissue homeostasis. These mechanisms ultimately determine the quantities of specific cell types that are generated. Despite their importance, the precise molecular interplays between cell cycle machinery and master regulators of cell fate choice remain to be fully uncovered. Here, we demonstrate that cell cycle regulators Cyclin D1-3 control cell fate decisions in human pluripotent stem cells by recruiting transcriptional corepressors and coactivator complexes onto neuroectoderm, mesoderm, and endoderm genes. This activity results in blocking the core transcriptional network necessary for endoderm specification while promoting neuroectoderm factors. The genomic location of Cyclin Ds is determined by their interactions with the transcription factors SP1 and E2Fs, which result in the assembly of cell cycle-controlled transcriptional complexes. These results reveal how the cell cycle orchestrates transcriptional networks and epigenetic modifiers to instruct cell fate decisions.
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Madingley, Cambridge CB2 0SZ, United Kingdom;
authors.forename: Siim
authors.initials: S
authors.lastname: Pauklin
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Madingley, Cambridge CB2 0SZ, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Pedro
authors.initials: P
authors.lastname: Madrigal
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Madingley, Cambridge CB2 0SZ, United Kingdom;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertero
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Madingley, Cambridge CB2 0SZ, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D002843:Chromatin / Q000378:metabolism; D056741:Cyclin D / Q000235:genetics* / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology*; D004707:Endoderm / Q000166:cytology; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study; D054258:Neural Plate / Q000166:cytology; D010766:Phosphorylation; D011485:Protein Binding
chemical_list: D002843:Chromatin; D056741:Cyclin D
keywords: Cyclin D; cell cycle; differentiation; endoderm; hESCs; neuroectoderm