Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1 (original) (raw)

Nature Cell Biology volume 8, pages 1114–1123 (2006)Cite this article

Abstract

Embryonic stem (ES) cells are pluripotent cells that can self-renew or differentiate into many cell types. A unique network of transcription factors and signalling molecules are essential for maintaining this capability. Here, we report that a spalt family member, Sall4, is required for the pluripotency of ES cells. Similarly to Oct4, a reduction in Sall4 levels in mouse ES cells results in respecification, under the appropriate culture conditions, of ES cells to the trophoblast lineage. Sall4 regulates transcription of Pou5f1 which encodes Oct4. Sall4 binds to the highly conserved regulatory region of the Pou5f1 distal enhancer and activates Pou5f1 expression in vivo and in vitro. Microinjection of Sall4 small interfering (si) RNA into mouse zygotes resulted in reduction of Sall4 and Oct4 mRNAs in preimplantation embryos and significant expansion of Cdx2 expression into the inner cell mass. These results demonstrate that Sall4 is a transcriptional activator of Pou5f1 and has a critical role in the maintenance of ES cell pluripotency by modulating Oct4 expression. The data also indicates that Sall4 is important for early embryonic cell-fate decisions.

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Acknowledgements

This work is supported by the Agency for Science, Technology and Research (Singapore). W.L.T. is a recipient of the A*STAR graduate scholarship. The work is also partially supported by National Institutes of Health (NIH) grants to B.L. (DK04763 and AI54973), Y.M. (K08 CA097185 and P20 RR016464) and L.C. (K08 DK063220). We are grateful to colleagues in the Genome Institute of Singapore for helpful discussions and J. Buhlman for critical reading of the manuscript.

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Author notes

  1. Jinqiu Zhang, Wai-Leong Tam and Guo Qing Tong: These authors contributed equally to this work.

Authors and Affiliations

  1. Stem Cell and Developmental Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore, 138672
    Jinqiu Zhang, Wai-Leong Tam, Guo Qing Tong, Hsiao-Yun Chan, Boon-Seng Soh, Yuefei Lou, Thomas Lufkin, Paul Robson & Bing Lim
  2. NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 117456
    Wai-Leong Tam
  3. Gene Regulation Laboratory, Genome Institute of Singapore, 60 Biopolis Street, Singapore, 138672
    Qiang Wu & Huck-Hui Ng
  4. Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, 89135, NV, USA
    Jianchang Yang & Yupo Ma
  5. The Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA
    Li Chai
  6. Department of Biological Sciences, National University of Singapore, Singapore, 117543
    Huck-Hui Ng, Thomas Lufkin & Paul Robson
  7. Harvard Institutes of Medicine, Harvard Medical School, Boston, 02115, MA, USA
    Bing Lim

Authors

  1. Jinqiu Zhang
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  2. Wai-Leong Tam
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  3. Guo Qing Tong
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  4. Qiang Wu
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  5. Hsiao-Yun Chan
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  6. Boon-Seng Soh
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  7. Yuefei Lou
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  8. Jianchang Yang
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  9. Yupo Ma
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  10. Li Chai
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  11. Huck-Hui Ng
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  12. Thomas Lufkin
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  13. Paul Robson
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  14. Bing Lim
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Contributions

J.Z., W.L.T. and B.L. were involved in project planning, experimental work, data analysis and manuscript preparation; G.Q.T. and H.Y.C. performed the embryo work; Q.W. performed chromatin immunoprecipitations; B.S.S. performed human ES cell culture; J.Y., Y.M. and L.C. generated knockout ES cells; and H.H.N., T.L. and P.R. were involved in project planning and manuscript preparation.

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Correspondence toBing Lim.

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Zhang, J., Tam, WL., Tong, G. et al. Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1.Nat Cell Biol 8, 1114–1123 (2006). https://doi.org/10.1038/ncb1481

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