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  • Meeting abstract
  • Open Access

FGF signalling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency

  • 1,
  • 1,
  • 1,
  • 1,
  • 1,
  • 2,
  • 3,
  • 4,
  • 1,
  • 2,
  • 5,
  • 3,
  • 1, 6 and
  • 1, 6, 7Email author
Clinical EpigeneticsThe official journal of the Clinical Epigenetics Society20135 (Suppl 1) :S2

https://doi.org/10.1186/1868-7083-5-S1-S2

  • Published:

Keywords

  • Germ Cell
  • Embryonic Stem
  • Embryonic Stem Cell
  • Molecule Inhibitor
  • Small Molecule Inhibitor

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.

Authors’ Affiliations

(1)
Epigenetics Programme, The Babraham Institute, Cambridge, CB22 3AT, UK
(2)
Department of Biological Sciences, Institute of Genetics/Epigenetics, University of Saarland, Saarbrüken, Germany
(3)
Bioinformatics Group, Babraham Institute, Cambridge, CB22 3AT, UK
(4)
Proteomics Research Group, Babraham Institute, Cambridge, CB22 3AT, UK
(5)
Signalling Programme, The Babraham Institute, Cambridge, CB22 3AT, UK
(6)
Centre for Trophoblast Research, University of Cambridge, Cambridge, CB2 3EG, UK
(7)
Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK

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