Skip to main content


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

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.

Author information

Correspondence to Wolf Reik.

Rights and permissions

Reprints and Permissions

About this article


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