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

Cell stem cell | 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 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.

Pubmed ID: 23850245 RIS Download

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Associated grants

  • Agency: Wellcome Trust, United Kingdom
    Id: 095645
  • Agency: Medical Research Council, United Kingdom
    Id: G0801727
  • Agency: Biotechnology and Biological Sciences Research Council, United Kingdom
    Id: BBS/E/B/0000C199
  • Agency: Biotechnology and Biological Sciences Research Council, United Kingdom
    Id: BBS/E/B/000C0417
  • Agency: Worldwide Cancer Research, United Kingdom
    Id: 12-1259
  • Agency: Cancer Research UK, United Kingdom
    Id: 14867
  • Agency: Medical Research Council, United Kingdom
    Id: G0801156
  • Agency: Biotechnology and Biological Sciences Research Council, United Kingdom
    Id: BBS/E/B/000C0419

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