Abstract |
Hypoxia benefits undifferentiated pluripotent stem cell renewal, and 2-oxoglutarate (2OG) dioxygenases have been implicated in pluripotent stem cell induction and renewal. We show in human embryonic stem cells (hESC) that an ambient oxygen-induced oxidative stress response elicited by culture in a hypoxic atmosphere (0.5% O2) correlates with the expression of 2OG dioxygenases, which oxidise DNA (TET1, 2, 3) and histone H3 (KDM4C), the former reflected by elevation in genomic 5-hydroxymethylcytosine (5hmC). siRNA-mediated targeting of KDM4C and TET1-3 induces hESC differentiation. Under ambient atmospheric oxygen (21% O2), exposure to a low inhibitory concentration of sodium arsenite (NaAsO2, IC10), as a model of chemically-induced oxidative stress, suppresses antioxidant gene expression, reduces mitochondrial membrane potential and induces hESC differentiation. Co-administration of the antioxidant N-acetyl-L-cysteine promoted anti-oxidant, pluripotency and 2OG dioxygenase gene expression, elevated genomic hydroxymethylation and blocked induction of differentiation. Transient ectopic expression of KDM4C or TET1 in ambient atmospheric oxygen achieved the same. Our study substantiates a role for 2OG-dependent dioxygenases in hypoxia's promotion of undifferentiated hESC self-renewal.
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Authors | Eirini Koutsouraki, Steve Pells, Paul A De Sousa |
Journal | Stem cell research
(Stem Cell Res)
Vol. 34
Pg. 101358
(01 2019)
ISSN: 1876-7753 [Electronic] England |
PMID | 30640062
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved. |
Chemical References |
- Arsenites
- KDM4C protein, human
- Ketoglutaric Acids
- Proto-Oncogene Proteins
- Sodium Compounds
- sodium arsenite
- Dioxygenases
- Jumonji Domain-Containing Histone Demethylases
- Oxygen
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Topics |
- Arsenites
(toxicity)
- Cell Differentiation
(drug effects)
- Cell Line
- Dioxygenases
(metabolism)
- Human Embryonic Stem Cells
(cytology, drug effects)
- Humans
- Jumonji Domain-Containing Histone Demethylases
(metabolism)
- Ketoglutaric Acids
(metabolism)
- Oxidative Stress
(drug effects)
- Oxygen
(pharmacology)
- Phenotype
- Proto-Oncogene Proteins
(metabolism)
- Sodium Compounds
(toxicity)
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