1. Deterministic Restriction on Pluripotent State Dissolution by Cell-Cycle Pathways.
- Author
-
Gonzales KA, Liang H, Lim YS, Chan YS, Yeo JC, Tan CP, Gao B, Le B, Tan ZY, Low KY, Liou YC, Bard F, and Ng HH
- Subjects
- Ataxia Telangiectasia Mutated Proteins metabolism, Cell Differentiation, Cyclin B2 metabolism, Embryonic Stem Cells metabolism, Epigenesis, Genetic, Humans, Pluripotent Stem Cells cytology, Pluripotent Stem Cells metabolism, Tumor Suppressor Protein p53 metabolism, Cell Cycle, Embryonic Stem Cells cytology, Gene Regulatory Networks
- 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., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF