Dataset Information

Genomic Integrity Safeguards Self-Renewal in Embryonic Stem Cells.

ABSTRACT: A multitude of signals are coordinated to maintain self-renewal in embryonic stem cells (ESCs). To unravel the essential internal and external signals required for sustaining the ESC state, we expand upon a set of ESC pluripotency-associated phosphoregulators (PRs) identified previously by short hairpin RNA (shRNA) screening. In addition to the previously described Aurka, we identify 4 additional PRs (Bub1b, Chek1, Ppm1g, and Ppp2r1b) whose depletion compromises self-renewal and leads to consequent differentiation. Global gene expression profiling and computational analyses reveal that knockdown of the 5 PRs leads to DNA damage/genome instability, activating p53 and culminating in ESC differentiation. Similarly, depletion of genome integrity-associated genes involved in DNA replication and checkpoint, mRNA processing, and Charcot-Marie-Tooth disease lead to compromise of ESC self-renewal via an increase in p53 activity. Our studies demonstrate an essential link between genomic integrity and developmental cell fate regulation in ESCs.

SUBMITTER: Su J

PROVIDER: S-EPMC6708277 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Genomic Integrity Safeguards Self-Renewal in Embryonic Stem Cells.

Su Jie J Zhu Dandan D Huo Zijun Z Gingold Julian A JA Ang Yen-Sin YS Tu Jian J Zhou Ruoji R Lin Yu Y Luo Haidan H Yang Huiling H Zhao Ruiying R Schaniel Christoph C Moore Kateri A KA Lemischka Ihor R IR Lee Dung-Fang DF

Cell reports 20190801 6

A multitude of signals are coordinated to maintain self-renewal in embryonic stem cells (ESCs). To unravel the essential internal and external signals required for sustaining the ESC state, we expand upon a set of ESC pluripotency-associated phosphoregulators (PRs) identified previously by short hairpin RNA (shRNA) screening. In addition to the previously described Aurka, we identify 4 additional PRs (Bub1b, Chek1, Ppm1g, and Ppp2r1b) whose depletion compromises self-renewal and leads to consequ ...[more]

PMID: 31390555

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Project description:Embryonic stem (ES) cells and germ cells have the potential to give rise to an entire organism. A common requirement is that both must have very robust mechanisms to preserve the integrity of their genomes. This is particularly true since somatic cells have very high mutation frequencies approaching 10-4 in vivo that would lead to unacceptable levels of fetal lethality and congenital defects. Notably, between 70% and 80% of mutational events monitored at a heterozygous endogenous selectable marker were loss of heterozygosity due to mitotic recombination, a mechanism that affects multiple heterozygous loci between the reporter gene and the site of crossing over. This chapter examines three mechanisms by which mouse embryonic stem cells preserve their genomic integrity. The first entails suppression of mutation and recombination between chromosome homologues by two orders of magnitude when compared with isogenic mouse embryo fibroblasts which had a mutation frequency similar to that seen in adult somatic cells. The second renders mouse ES cells hypersensitive to environmental challenge and eliminates damaged cells from the self-renewing population. Mouse ES cells lack a G1 checkpoint so that cells damaged by exogenous insult such as ionizing radiation do not arrest at the G1/S phase checkpoint but progress into the S phase where the damaged DNA is replicated, the damage exacerbated and the cells driven to apoptosis. The third mechanism examines how mouse ES cells repair double strand DNA breaks. Somatic cells predominantly utilize error prone nonhomologous end joining which, from a teleological perspective, would be disadvantageous for ES cells since it would promote accumulation of mutations. When ES cells were tested for the preferred pathway of double strand DNA break repair, they predominantly utilized the high fidelity homology-mediated repair pathway, thereby minimizing the incurrence of mutations during the repair process. When mouse ES cells are induced to differentiate, the predominant repair pathway switches from homology-mediated repair to nonhomologous end joining that is characteristic of somatic cells.

Dataset Information

Genomic Integrity Safeguards Self-Renewal in Embryonic Stem Cells.

Publications

Genomic Integrity Safeguards Self-Renewal in Embryonic Stem Cells.

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