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FGF signalling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency
Open accessAbstract
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 signalling 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, Dnmt3b) and Dnmt3L. We identify a Prdm14 and Nanog binding cis-acting regulatory region in Dnmt3b that is highly responsive to signalling. These insights provide a novel framework for understanding how signalling pathways regulate reprogramming to an epigenetic ground state of pluripotency.
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Cited by
Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity
Smallwood, S. A., Lee, H. J., Angermueller, C., Krueger, F., Saadeh, H., Peat, J., Andrews, S. R., Stegle, O., Reik, W., & Kelsey, G. (2014) · Nature Methods · doi:10.1038/nmeth.3035 · Cited by 1,125
Self-citationReversing DNA Methylation: Mechanisms, Genomics, and Biological Functions
Wu, H., & Zhang, Y. (2014) · Cell · doi:10.1016/j.cell.2013.12.019 · Cited by 1,065
Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells
Carey, B. W., Finley, L. W. S., Cross, J. R., Allis, C. D., & Thompson, C. B. (2015) · Nature · doi:10.1038/nature13981 · Cited by 1,007
Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity
Angermueller, C., Clark, S. J., Lee, H. J., Macaulay, I. C., Teng, M. J., Hu, T. X., Krueger, F., Smallwood, S. A., Ponting, C. P., Voet, T., et al. (2016) · Nature Methods · doi:10.1038/nmeth.3728 · Cited by 717
Self-citationSingle Cell RNA-Sequencing of Pluripotent States Unlocks Modular Transcriptional Variation
Kolodziejczyk, A. A., Kim, J. K., Tsang, J. C. H., Ilicic, T., Henriksson, J., Natarajan, K. N., Tuck, A. C., Gao, X., Bühler, M., Liu, P., et al. (2015) · Cell Stem Cell · doi:10.1016/j.stem.2015.09.011 · Cited by 570
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
- Clinical Epigenetics
- Published
- 2013-08
- Volume
- 5
- Issue
- S1
- ISSN
- 1868-7075 (ISSN-L)
- 1868-7083
- OpenAlex
- W64811814
- Cited by
- 164
- References
- 0
- FWCI
- 10.09
- Type
- journal article
- Language
- en
- Open access
- gold
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- CoChat. (2026). Citation check: FGF signalling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. https://app.cochat.ai/papers/10.1186/1868-7083-5-s1-s2
- The paper
- 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 signalling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Clinical Epigenetics. https://doi.org/10.1186/1868-7083-5-s1-s2
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