Abstract
IN man, a shift from γ- to β-globin gene expression in erythrob-lasts underlies a switch from fetal to adult haemoglobin during development1. In hereditary persistence of fetal haemoglobin (HPFH), inappropriately high γ-globin expression in adult life is associated with deletions in the β-globin cluster or with single-base changes upstream of the γ-globin genes. To account for enhanced γ-gene expression in HPFH of the non-deletion type, we tested the nuclear proteins of human erythroleukaemia cells2 that bind γ-promoter sequences in vitro by correlating specific mutations in their binding sites with promoter activity. An eryth-roid-specific factor (GF-1) binds as a single molecule to the –195 to –170 region and contacts two TATCT(AGATA) motifs, but not the conserved octamer (ATGCAAAT)3–8 that separates them. We observe that a single change (at –175, T→C ) found in HPFH9,10 leads to increased promoter activity only in erythroid cells. This effect is mediated by GF-1, the human counterpart of the chicken erythroid factor11 Eryf 1. The form of HPFH we studied here is an inherited disorder which can be ascribed to the action of a cell-specific DNA-binding factor on a mutant promoter.
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References
Stamatoyannopoulos, G. & Nienhuis, A. W. The Molecular Basis of Blood Diseases (ed. Stamatoyannopoulos, G., Nienhuis, A. W., Leder, P. & Majeru, P. W.) 66–105 (Saunders, Philadelphia, 1987).
Rutherford, T. R., Clegg, J. B., & Weatherall, D. J. Nature 280, 164–165 (1979).
Bark, C., Weller, P., Zabielski, J., Janson, L. & Pettersson, U. Nature 328, 356–358 (1987).
Fletcher, C., Heintz, N. & Roeder, R. G. Cell 51, 773–781 (1987).
Rosales, R. et al. EMBO J. 6, 3015–3025 (1987).
Scheidereit, C., Heguy, A. & Roeder, R. G. Cell 51, 783–793 (1987).
Staudt, L. M. et al. Nature 323, 640–643 (1986).
Wirth, T., Staudt, L. & Baltimore, D. Nature 329, 174–178 (1987).
Ottolenghi, S. et al. Blood 71, 815–817 (1988).
Surrey, S., Delgrosso, K., Malladi, P. & Schwartz, E. Blood 71, 807–810 (1988).
Evans, T., Reitman, M. & Felsenfeld, G. Proc. natn. Acad. Sci. U.S.A. 85, 5976–5980 (1988).
Lingrel, J. B., Weimer, J. & Menon, A. in Developmental Control of Globin Gene Expression (eds, Stamtoyannopoulos, G. & Nienhuis, A. W.) 251, 201–210 (1987).
Mantovani, R. et al. Nucleic Acids Res. 15, 9349–9364 (1987).
Lin, H. J., Anagnou, N. P., Rutherford, T. R., Shimada, T. & Nienhuis, A. W. J. clin. Invest. 80, 374–380 (1987).
Jones, K. A., Yamamoto, K. R. & Tjian, R. Cell 42, 559–572 (1985).
Siebenlist, U. & Gilbert, W. Proc. natn. Acad. Sci. U.S.A. 77, 122–126 (1980).
Mantovani, R. et al. Nucleic Acids Res. 16, 7783–7797 (1988).
Superti-Furga, G., Barberis, A., Schaffner, G. & Busslinger, M. EMBO J. 10, 3099–3107 (1988).
Shen, S., Slightom, J. L. & Smithies, O. Cell 26, 191–203 (1981).
Selden, R. F., Burke-Howie, K., Rowe, M. E., Goodman, H. M. & Moore, D. D. Molec. cell. Biol. 6, 3173–3179 (1986).
Tucker, K. A., Lilly, M. A., Heck, L. & Rado, T. A. Blood 70, 372–378 (1987).
Rutherford, T. & Niehhuis, A. W. Molec. cell. Biol. 7, 398–402 (1987).
Gumuchio, D. L. et al. Molec. cell. Biol. 8, 5310–5322 (1988).
Collins, F. S., Stoeckert, C., Serjeant, G., Forget, B. & Weissman, S. Proc. natn. Acad. Sci. U.S.A. 81, 4894–4898 (1984).
Ottolenghi, S. et al. Blood 69, 1058–1067 (1987).
Wall, L., deBoer, E. & Grosveld, F. Genes Dev. 2, 1089–1100 (1988).
Dignam, J. D., Martin, P. L., Shastry, B. S. & Roeder, R. G. Meth. Enzym. 101, 587–597 (1983).
Ausubel, F. M. et al. Current Protocols in Molecular Biology (Wiley, New York, 1987).
Fried, M. & Crothers, D. M. Nucleic Acids Res. 9, 6505–6523 (1981).
Strauss, F. & Varshovsky, A. Cell 37, 889–901 (1984).
Raymondjean, M., Cereghini, S. & Yaniv, M. Proc. natn. Acad. Sci. U.S.A. 85, 757–761 (1988).
Maxam, A. & Gilbert, W. Meth. Enzym. 65, 499–560 (1980).
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Martin, D., Tsai, SF. & Orkin, S. Increased γ-globin expression in a nondeletion HPFH mediated by an erythroid-specif ic DNA-binding factor. Nature 338, 435–438 (1989). https://doi.org/10.1038/338435a0
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DOI: https://doi.org/10.1038/338435a0
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