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FGF Signaling Inhibition in ESCs Drives Rapid Genome-wide Demethylation to the Epigenetic Ground State of Pluripotency

Open access
Ficz, Gabriella, Hore, Timothy A., Santos, Fátima, Lee, Heather J., Dean, Wendy, Arand, Julia, Krueger, Felix, Oxley, David, Paul, Yu-Lee, Walter, Jörn, Cook, Simon J., Andrews, Simon, Branco, Miguel R., Reik, Wolf·2013·Cell Stem Cell

Abstract

Genome-wide erasure of DNA methylation takes place in primordial germ cells (PGCs) and early embryos and is linked with pluripotency. Inhibition of Erk1/2 and Gsk3β signaling in mouse embryonic stem cells (ESCs) by small-molecule inhibitors (called 2i) has recently been shown to induce hypomethylation. We show by whole-genome bisulphite sequencing that 2i induces rapid and genome-wide demethylation on a scale and pattern similar to that in migratory PGCs and early embryos. Major satellites, intracisternal A particles (IAPs), and imprinted genes remain relatively resistant to erasure. Demethylation involves oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), impaired maintenance of 5mC and 5hmC, and repression of the de novo methyltransferases (Dnmt3a and Dnmt3b) and Dnmt3L. We identify a Prdm14- and Nanog-binding cis-acting regulatory region in Dnmt3b that is highly responsive to signaling. These insights provide a framework for understanding how signaling pathways regulate reprogramming to an epigenetic ground state of pluripotency.

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Metadata

Authors
Ficz, G., Hore, T. A., Santos, F., Lee, H. J., Dean, W., Arand, J., Krueger, F., Oxley, D., Paul, Y.-L., Walter, J., Cook, S. J., Andrews, S., Branco, M. R., & Reik, W.
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2013-09
Volume
13
Issue
3
Pages
351-359
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
OpenAlex
W2167010568
Cited by
395
References
4
FWCI
18.96
Type
journal article
Language
en
Open access
hybrid

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CoChat. (2026). Citation check: FGF Signaling Inhibition in ESCs Drives Rapid Genome-wide Demethylation to the Epigenetic Ground State of Pluripotency. https://app.cochat.ai/papers/10.1016/j.stem.2013.06.004
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Ficz, G., Hore, T. A., Santos, F., Lee, H. J., Dean, W., Arand, J., Krueger, F., Oxley, D., Paul, Y.-L., Walter, J., Cook, S. J., Andrews, S., Branco, M. R., & Reik, W. (2013). FGF Signaling Inhibition in ESCs Drives Rapid Genome-wide Demethylation to the Epigenetic Ground State of Pluripotency. Cell Stem Cell. https://doi.org/10.1016/j.stem.2013.06.004

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