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

Article metrics

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

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

  2. 2

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

  3. 3

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

  4. 4

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

  5. 5

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

  6. 6

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

  7. 7

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

  8. 8

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

  9. 9

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

  10. 10

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

  11. 11

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

  12. 12

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

  13. 13

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

  14. 14

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

  15. 15

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

  16. 16

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

  17. 17

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

  18. 18

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

  19. 19

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

  20. 20

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

  21. 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).

  22. 22

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

  23. 23

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

  24. 24

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

  25. 25

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

  26. 26

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

  27. 27

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

  28. 28

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

  29. 29

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

Download references

Author information

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) doi:10.1038/375318a0

Download citation

Further reading

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.