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Nanog maintains pluripotency of mouse embryonic stem cells by inhibiting NFκB and cooperating with Stat3

Nature Cell Biology volume 10, pages 194201 (2008) | Download Citation

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Abstract

Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of blastocysts. Self-renewal of mouse ES cells depends on activation of Stat3 by leukaemia inhibitory factor (LIF) in collaboration with bone morphogenetic protein signalling1,2,3. The transcription factor Nanog is essential in maintaining pluripotency4,5 but the mechanisms involved are poorly understood. Here we examine the functional interactions of Nanog with the Stat3 and NFκB pathways. Nanog and Stat3 were found to bind to and synergistically activate Stat3-dependent promoters. We also found that Nanog binds to NFκB proteins; however, Nanog binding inhibited transcriptional activity of NFκB proteins. Endogenous NFκB activity and target-gene expression increased during differentiation of ES cells. Overexpression of NFκB proteins promoted differentiation, whereas inhibition of NFκB signalling, either by genetic ablation of the Ikbkg gene or overexpression of the IκBα super-repressor, increased expression of pluripotency markers. We conclude that Nanog represses the pro-differentiation activities of NFκB and cooperates with Stat3 to maintain pluripotency.

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Acknowledgements

We thank T. W. Mak, M. Gassmann, A. Smith, I. Chambers, T. Hirano, T. Fukada, F. Ventura, T. López-Rovira, I. Kerr, J. C. Lacall and S. Aznar-Benith for sharing reagents, Lisa Sevilla for helpful discussions and Héctor Pálmer for advice about transcriptional assays. We are indebted to Lola Martínez and Phil East from the London Research Institute, Cancer Research UK (CRUK) for their help with the flow cytometric and ChIP analyses. This work was supported by CRUK, the Wellcome Trust and EuroStemCell. J.T. was the recipient of a FEBS postdoctoral fellowship.

Author information

Affiliations

  1. Wellcome Trust Centre for Stem Cell Research, Tennis Court Road, Cambridge CB2 1QR, UK.

    • Josema Torres
    •  & Fiona M. Watt
  2. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.

    • Fiona M. Watt

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Contributions

J. T. carried out the exerimental work, J. T. and F. M. W. contributed to the project planning, data analysis and writing of the manuscript.

Corresponding author

Correspondence to Fiona M. Watt.

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    Supplementary figures S1, S2, S3, Supplementary table S1

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DOI

https://doi.org/10.1038/ncb1680

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