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Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells near-final version
Siqin Bao1,4, Fuchou Tang1,4, Xihe Li2, Katsuhiko Hayashi1,5, Astrid Gillich1, Kaiqin Lao3 & M. Azim Surani1
1 Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
2 College of Life Science, Inner Mongolia University/Mengniu RB CO. Ltd., West No. 1 Daxue Road, Huhhot, Inner Mongolia 010021, China
3 Molecular Cell Biology, Applied Biosystems, 850 Lincoln Centre Drive, Foster City, California 94404, USA
4 These authors contributed equally to this work.
5 Present address: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-Cho, Sako-Ku, Kyoto 606-8501, Japan.
Correspondence to: M. Azim Surani1 Correspondence and requests for materials should be addressed to M.A.S.
The pluripotent state, which is first established in the primitive ectoderm cells of blastocysts, is lost progressively and irreversibly during subsequent development1. For example, development of post-implantation epiblast cells from primitive ectoderm involves significant transcriptional and epigenetic changes, including DNA methylation and X chromosome inactivation2, which create a robust epigenetic barrier and prevent their reversion to a primitive-ectoderm-like state. Epiblast cells are refractory to leukaemia inhibitory factor (LIF)–STAT3 signalling, but they respond to activin/basic fibroblast growth factor to form self-renewing epiblast stem cells (EpiSCs), which exhibit essential properties of epiblast cells3, 4 and that differ from embryonic stem (ES) cells derived from primitive ectoderm5. Here we show reprogramming of advanced epiblast cells from embryonic day 5.5–7.5 mouse embryos with uniform expression of N-cadherin and inactive X chromosome to ES-cell-like cells (rESCs) in response to LIF–STAT3 signalling. Cultured epiblast cells overcome the epigenetic barrier progressively as they proceed with the erasure of key properties of epiblast cells, resulting in DNA demethylation, X reactivation and expression of E-cadherin. The accompanying changes in the transcriptome result in a loss of phenotypic and epigenetic memory of epiblast cells. Using this approach, we report reversion of established EpiSCs to rESCs. Moreover, unlike epiblast and EpiSCs, rESCs contribute to somatic tissues and germ cells in chimaeras. Further studies may reveal how signalling-induced epigenetic reprogramming may promote reacquisition of pluripotency.
