Article | Published:

C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence

Nature Cell Biology volume 15, pages 385394 (2013) | Download Citation

Abstract

In blood, the transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver haematopoietic stem cells (HSCs). However, its function in adult HSCs has remained unknown. Here, using an inducible knockout model we found that C/EBPa-deficient adult HSCs underwent a pronounced increase in number with enhanced proliferation, characteristics resembling fetal liver HSCs. Consistently, transcription profiling of C/EBPa-deficient HSCs revealed a gene expression program similar to fetal liver HSCs. Moreover, we observed that age-specific Cebpa expression correlated with its inhibitory effect on the HSC cell cycle. Mechanistically we identified N-Myc as a downstream target of C/EBPa, and loss of C/EBPa resulted in de-repression of N-Myc. Our data establish C/EBPa as a central determinant in the switch from fetal to adult HSCs.

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Acknowledgements

This study was supported by the National Institutes of Health grant HL 56745 and the Harvard Stem Cell Institute grant DP-0086-10-00. G.A. was supported by the Collegio Ghislieri Fellowship Program. E.L. was supported by FAMRI YCSA and CIA grants. P.B.S. was supported by the Austrian Research Foundation and the European Union. D.G.T. is supported by the Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award. We thank all members of the Tenen laboratory for helpful discussions; R. Welner, C. Bach, H. Xie, M. Stadtfeld, T. Graf and X. Guo for careful reading of the manuscript and suggestions; J. LaVecchio and G. Buruzula from the Harvard Stem Cell Institute/Joslin Diabetes Center flow cytometry facility for their expertise during cell sorting; and A. T. Lay Keng and L. M. Hui from the NUS-Duke genomic facility in Singapore for their expertise in microarray analysis.

Author information

Author notes

    • Min Ye
    •  & Hong Zhang

    These authors contributed equally to this work

Affiliations

  1. Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Min Ye
    • , Hong Zhang
    • , Giovanni Amabile
    • , Philipp B. Staber
    • , Elena Levantini
    • , Meritxell Alberich-Jordà
    •  & Daniel G. Tenen
  2. Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA

    • Min Ye
    • , Hong Zhang
    • , Giovanni Amabile
    • , Philipp B. Staber
    • , Pu Zhang
    • , Elena Levantini
    • , Meritxell Alberich-Jordà
    •  & Junyan Zhang
  3. Cancer Science Institute, National University of Singapore, 117599, Singapore

    • Henry Yang
    • , Akira Kawasaki
    •  & Daniel G. Tenen
  4. Division of Hematology, Medical University Graz, 8036 Graz, Austria

    • Philipp B. Staber
  5. Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria

    • Philipp B. Staber
  6. Institute of Biomedical Technologies, National Research Council, 56124, Italy

    • Elena Levantini
  7. Center for Life Sciences, 3 Blackfan Circle, Room 437, Boston, Massachusetts 02115, USA

    • Daniel G. Tenen

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Contributions

M.Y. and D.G.T. designed the study; M.Y., H.Z., G.A., H.Y., P.Z., E.L., P.B.S., J.Z. and M.A.J. performed research; M.Y., H.Z., H.Y. and P.Z. analysed data; M.Y., H.Z. and D.G.T. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Daniel G. Tenen.

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DOI

https://doi.org/10.1038/ncb2698

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