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Cell. 2015 Jul 30;162(3):564-79. doi: 10.1016/j.cell.2015.07.001.

Deterministic Restriction on Pluripotent State Dissolution by Cell-Cycle Pathways.

Author information

1
Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore.
2
Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
3
Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 639798, Singapore.
4
Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597.
5
Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
6
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 639798, Singapore.
7
National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
8
Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597; Institute of Molecular and Cellular Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
9
Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 639798, Singapore. Electronic address: nghh@gis.a-star.edu.sg.

Abstract

During differentiation, human embryonic stem cells (hESCs) shut down the regulatory network conferring pluripotency in a process we designated pluripotent state dissolution (PSD). In a high-throughput RNAi screen using an inclusive set of differentiation conditions, we identify centrally important and context-dependent processes regulating PSD in hESCs, including histone acetylation, chromatin remodeling, RNA splicing, and signaling pathways. Strikingly, we detected a strong and specific enrichment of cell-cycle genes involved in DNA replication and G2 phase progression. Genetic and chemical perturbation studies demonstrate that the S and G2 phases attenuate PSD because they possess an intrinsic propensity toward the pluripotent state that is independent of G1 phase. Our data therefore functionally establish that pluripotency control is hardwired to the cell-cycle machinery, where S and G2 phase-specific pathways deterministically restrict PSD, whereas the absence of such pathways in G1 phase potentially permits the initiation of differentiation.

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PMID:
26232226
DOI:
10.1016/j.cell.2015.07.001
[Indexed for MEDLINE]
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