Volume 5 Supplement 1

Proceedings of the Birmingham Cancer Epigenetics Conference; Translational Opportunities

Open Access

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

  • Gabriella Ficz1,
  • Timothy A Hore1,
  • Fatima Santos1,
  • Heather J Lee1,
  • Wendy Dean1,
  • Julia Arand2,
  • Felix Krueger3,
  • David Oxley4,
  • Yu-Lee Paul1,
  • Jörn Walter2,
  • Simon J Cook5,
  • Simon Andrews3,
  • Miguel R Branco1, 6 and
  • Wolf Reik1, 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: 19 August 2013

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
(2)
Department of Biological Sciences, Institute of Genetics/Epigenetics, University of Saarland
(3)
Bioinformatics Group, Babraham Institute
(4)
Proteomics Research Group, Babraham Institute
(5)
Signalling Programme, The Babraham Institute
(6)
Centre for Trophoblast Research, University of Cambridge
(7)
Wellcome Trust Sanger Institute

Copyright

© Ficz et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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