期刊
CELL STEM CELL
卷 13, 期 3, 页码 351-359出版社
CELL PRESS
DOI: 10.1016/j.stem.2013.06.004
关键词
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资金
- Wellcome Trust
- BBSRC
- MRC
- EU NoE Epigenesys
- EU BLUEPRINT
- Human Frontier Science Program
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000H334, BBS/E/B/0000S266, BBS/E/B/000C0419, BBS/E/B/0000C199, BBS/E/B/000C0417] Funding Source: researchfish
- Cancer Research UK [14867] Funding Source: researchfish
- Medical Research Council [G0801156, G0801727] Funding Source: researchfish
- Worldwide Cancer Research [12-1259] Funding Source: researchfish
- BBSRC [BBS/E/B/000C0419, BBS/E/B/000C0417, BBS/E/B/0000S266, BBS/E/B/0000H334] Funding Source: UKRI
- MRC [G0801727, G0801156] Funding Source: UKRI
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 Gsk3 beta 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.
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