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Initiation of stem cell differentiation involves cell cycle-dependent regulation of developmental genes by Cyclin D.

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Pauklin, Siim 
Bertero, Alessandro 


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.



Cyclin D, cell cycle, differentiation, endoderm, hESCs, neuroectoderm, Cell Cycle, Cell Differentiation, Chromatin, Cyclin D, Embryonic Stem Cells, Endoderm, Epigenesis, Genetic, Gene Expression Regulation, Developmental, Genome-Wide Association Study, Neural Plate, Phosphorylation, Protein Binding

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Genes Dev

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Cold Spring Harbor Laboratory
Medical Research Council (G1000847)
Medical Research Council (G0800784)
Medical Research Council (MC_PC_12009)
This work was supported by the European Research Council grant Relieve IMDs and the Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V.). A.B. was funded by the British Heart Foundation Ph.D. Studentship. S.P. was funded by a Federation of European Biochemical Societies long-term fellowship and a InnovaLiv EuFP7 grant. S.P. and L.V. conceived the research and wrote the manuscript. S.P. and A.B. performed the experiments. P.M. performed bioinformatic analyses.