Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Lethal β-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF

Nature volume 375, pages 318–322 (1995)Cite this article

Abstract

GLOBIN genes are regulated in a tissue-specific and developmental stage-specific manner, with the β-globin gene being the last to be activated in the β-gene cluster1. CACCC-nucleotide sequences, which bind multiple nuclear proteins, including ubiquitously expressed Spl and erythroid Krüppel-like factor (EKLF), are among the cis-regulatory sequences critical for transcription of globin and non-globin erythroid-expressed genes2-5. To determine the function of EKLF in vivo, we created mice deficient in EKLF by gene targeting6. These embryos die of anaemia during fetal liver erythropoiesis and show the molecular and haematological features of β-globin deficiency, found in β-thalassaemia. Although it is expressed at all stages, EKLF is not required for yolk sac erythropoiesis, erythroid commitment or expression of other potential target genes. Its stage-specific and β-globin-gene-specific requirement suggests that EKLF may facilitate completion of the fetal-to-adult (haemoglobin α to β) switch in humans.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Crossley, M. & Orkin, S. H. Curr. Opin. Genet. Dev. 3, 232–237 (1993).

    Article  CAS  Google Scholar 

  2. Treisman, R., Orkin, S. H. & Maniatis, T. Nature 302, 591–596 (1983).

    Article  ADS  CAS  Google Scholar 

  3. Myers, R. M., Tilly, K. & Maniatis, T. Science 232, 613–618 (1986).

    Article  ADS  CAS  Google Scholar 

  4. Miller, I. J. & Bieker, J. J. Molec. cell. Biol. 13, 2776–2786 (1993).

    Article  CAS  Google Scholar 

  5. Hartzog, G. A. & Myers, R. M. Molec. cell. Biol. 13, 44–56 (1993).

    Article  CAS  Google Scholar 

  6. Capecchi, M. R. Science 244, 1288–1292 (1989).

    Article  ADS  CAS  Google Scholar 

  7. Nathan, D. G. & Gunn, R. B. Am. J. Med. 41, 815–830 (1966).

    Article  CAS  Google Scholar 

  8. Tsai, S.-F. et al. Nature 339, 446–451 (1989).

    Article  ADS  CAS  Google Scholar 

  9. Tsai, S.-F., Strauss, E. & Orkin, S. H. Genes Dev. 5, 919–931 (1991).

    Article  CAS  Google Scholar 

  10. Youssoufian, H., Zon, L., Orkin, S. H., D'Andrea, A. D. & Lodish, H. F. Molec. cell. Biol. 10, 3675–3682 (1990).

    Article  CAS  Google Scholar 

  11. Porcher, C. et al. J. biol. Chem. 266, 10562–10569 (1991).

    CAS  PubMed  Google Scholar 

  12. Feng, W. C., Southwood, C. M. & Bieker, J. J. J. biol. Chem. 269, 1493–1500 (1994).

    CAS  PubMed  Google Scholar 

  13. Brotherton, T. W., Chui, D. H. K., Gauldie, J. & Patterson, M. Proc. natn. Acad. Sci. U.S.A. 76, 2853–2857 (1979).

    Article  ADS  CAS  Google Scholar 

  14. Thien, S. L., Wood, W. G., Wickramasinghe, S. N. & Galvin, M. C. Blood 82, 961–967 (1993).

    Google Scholar 

  15. Orkin, S. H. et al. Nature 296, 627–631 (1982).

    Article  ADS  CAS  Google Scholar 

  16. Pevny, L. et al. Nature 349, 257–260 (1991).

    Article  ADS  CAS  Google Scholar 

  17. Shivdasani, R., Mayer, E. & Orkin, S. H. Nature 373, 432–434 (1995).

    Article  ADS  CAS  Google Scholar 

  18. Dillon, N. & Grosveld, F. Nature 350, 252–254 (1991).

    Article  ADS  CAS  Google Scholar 

  19. Lloyd, J. A., Krakowsky, J. M., Crable, S. C. & Lingrel, J. B. Molec. cell. Biol. 12, 1561–1567 (1992).

    Article  CAS  Google Scholar 

  20. Stamatoyannopoulos, G., Josephson, B., Zhang, J.-W. & Li, Q. Molec. cell. Biol. 13, 7636–7644 (1993).

    Article  CAS  Google Scholar 

  21. McDonagh, K. T. & Nienhuis, A. W. in Hematology of Infancy and Childhood 4th Edn (eds Nathan, D. G. & Oski, F. A.) 783–879 (Saunders, Philadelphia, 1992).

    Google Scholar 

  22. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual 2nd edn (Cold Spring Harbor Laboratory Press, New York, 1989).

    Google Scholar 

  23. Mansour, S., Thomas, K. & Capecchi, M. Nature 336, 348–352 (1988).

    Article  ADS  CAS  Google Scholar 

  24. Li, E., Bestor, T. H. & Jaenisch, R. Cell 69, 915–926 (1992).

    Article  CAS  Google Scholar 

  25. Baron, M. H. & Maniatis, T. Cell 46, 591–602 (1986).

    Article  CAS  Google Scholar 

  26. Chomczynski, P. & Sacchi, N. Analyt. Biochem. 162, 156–159 (1987).

    Article  CAS  Google Scholar 

  27. Weiss, M. J., Keller, G. & Orkin, S. H. Genes Dev. 8, 1184–1197 (1994).

    Article  CAS  Google Scholar 

  28. Alter, B. P. & Campbell, A. S. Hemoglobin 6, 517–522 (1982).

    Article  CAS  Google Scholar 

  29. Andrews, N. C. & Faller, D. V. Nucleic Acids Res. 19, 2499 (1991).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Pediatrics, Children's Hospital and the Dana Farber Cancer Institute,

    Andrew C. Parkins & Stuart H. Orkin

  2. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Arlene H. Sharpe

  3. Howard Hughes Medical Institute, Boston, Massachusetts, 02115, USA

    Stuart H. Orkin

Authors
  1. Andrew C. Parkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arlene H. Sharpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stuart H. Orkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Parkins, A., Sharpe, A. & Orkin, S. Lethal β-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF. Nature 375, 318–322 (1995). https://doi.org/10.1038/375318a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/375318a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing