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

Choi, J., Huebner, A. J., Clement, K., Walsh, R. M., Savol, A., Lin, K., et al. (2017). Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells. Nature, 548(7666), 219-223. doi:10.1038/nature23274.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-DD02-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-DD03-D
Genre: Journal Article

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 Creators:
Choi, Jiho, Author
Huebner, Aaron J., Author
Clement, Kendell, Author
Walsh, Ryan M. , Author
Savol, Andrej , Author
Lin, Kaixuan , Author
Gu, Hongcang, Author
Di Stefano, Bruno, Author
Brumbaugh, Justin , Author
Kim, Sang-Yong , Author
Sharif, Jafar , Author
Rose, Christopher M. , Author
Mohammad, Arman , Author
Odajima, Junko , Author
Charron, Jean , Author
Shioda, Toshi , Author
Gnirke, Andreas , Author
Gygi, Steven , Author
Koseki, Haruhiko , Author
Sadreyev, Ruslan I. , Author
Xiao, Andrew , AuthorMeissner, Alexander1, 2, 3, 4, Author              Hochedlinger, Konrad , Author more..
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA, ou_persistent22              
3Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, Massachusetts 02138, USA, ou_persistent22              
4Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA, ou_persistent22              

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 Abstract: 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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Language(s): eng - English
 Dates: 2017-07-262017-08-10
 Publication Status: Published in print
 Pages: 5
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/nature23274
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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 548 (7666) Sequence Number: - Start / End Page: 219 - 223 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238