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Nature. 2017 Aug 10;548(7666):219-223. doi: 10.1038/nature23274. Epub 2017 Jul 26.

Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells.

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Massachusetts General Hospital Department of Molecular Biology, Boston, Massachusetts 02114, USA.
Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, Massachusetts 02114, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, Massachusetts 02138, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Department of Genetics, Yale University School of Medicine, 10 Amistad Street, New Haven, Connecticut 06519, USA.
New York University Langone Medical Center, New York 10016, USA.
Center for Integrative Medical Sciences, RIKEN National Research and Development Agency, 1-7-22 Suehiuro-cho, Tsurumi-ku, Yokohama-shi, Kanagawa-ken 230-0045, Japan.
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
Centre de recherche sur le cancer de l'Université Laval, CRCHU de Québec, L'Hôtel-Dieu de Québec, 9, rue McMahon, Quebec G1R 2J6, Canada.


Concomitant activation of the Wnt pathway and suppression of Mapk signalling by two small molecule inhibitors (2i) in the presence of leukaemia inhibitory factor (LIF) (hereafter termed 2i/L) induces a naive state in mouse embryonic stem (ES) cells that resembles the inner cell mass (ICM) of the pre-implantation embryo. Since the ICM exists only transiently in vivo, it remains unclear how sustained propagation of naive ES cells in vitro affects their stability and functionality. Here we show that prolonged culture of male mouse ES cells in 2i/L results in irreversible epigenetic and genomic changes that impair their developmental potential. Furthermore, we find that female ES cells cultured in conventional serum plus LIF medium phenocopy male ES cells cultured in 2i/L. Mechanistically, we demonstrate that the inhibition of Mek1/2 is predominantly responsible for these effects, in part through the downregulation of DNA methyltransferases and their cofactors. Finally, we show that replacement of the Mek1/2 inhibitor with a Src inhibitor preserves the epigenetic and genomic integrity as well as the developmental potential of ES cells. Taken together, our data suggest that, although short-term suppression of Mek1/2 in ES cells helps to maintain an ICM-like epigenetic state, prolonged suppression results in irreversible changes that compromise their developmental potential.

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