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. 1991 Jul;11(7):3786–3794. doi: 10.1128/mcb.11.7.3786

Human alpha-globin genes demonstrate autonomous developmental regulation in transgenic mice.

M Albitar 1, M Katsumata 1, S A Liebhaber 1
PMCID: PMC361149  PMID: 1710771

Abstract

Recent studies have demonstrated that transcriptional activation of the human adult beta-globin transgene in mice by coinsertion of the beta-globin cluster locus control region (beta-LCR) results in loss of its adult restricted pattern of expression. Normal developmental control is reestablished by coinsertion of the fetal gamma-globin transgene in cis to the adult beta-globin gene. To test the generality of this interdependence of two globin genes for their proper developmental control, we generated transgenic mice in which the human adult alpha-globin genes are transcriptionally activated by the beta-LCR either alone or in cis to their corresponding embryonic zeta-globin gene. In both cases, the human globin transgenes were expressed at the appropriate developmental period. In contrast to the beta-globin gene, developmental control of the human adult alpha-globin transgenes appears to be autonomous and maintained even when activated by an adjacent locus control region.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albitar M., Peschle C., Liebhaber S. A. Theta, zeta, and epsilon globin messenger RNAs are expressed in adults. Blood. 1989 Aug 1;74(2):629–637. [PubMed] [Google Scholar]
  2. Alter B. P. The G gamma:A gamma composition of fetal hemoglobin in fetuses and newborns. Blood. 1979 Nov;54(5):1158–1163. [PubMed] [Google Scholar]
  3. Behringer R. R., Hammer R. E., Brinster R. L., Palmiter R. D., Townes T. M. Two 3' sequences direct adult erythroid-specific expression of human beta-globin genes in transgenic mice. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7056–7060. doi: 10.1073/pnas.84.20.7056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Behringer R. R., Ryan T. M., Palmiter R. D., Brinster R. L., Townes T. M. Human gamma- to beta-globin gene switching in transgenic mice. Genes Dev. 1990 Mar;4(3):380–389. doi: 10.1101/gad.4.3.380. [DOI] [PubMed] [Google Scholar]
  5. Behringer R. R., Ryan T. M., Reilly M. P., Asakura T., Palmiter R. D., Brinster R. L., Townes T. M. Synthesis of functional human hemoglobin in transgenic mice. Science. 1989 Sep 1;245(4921):971–973. doi: 10.1126/science.2772649. [DOI] [PubMed] [Google Scholar]
  6. Blom van Assendelft G., Hanscombe O., Grosveld F., Greaves D. R. The beta-globin dominant control region activates homologous and heterologous promoters in a tissue-specific manner. Cell. 1989 Mar 24;56(6):969–977. doi: 10.1016/0092-8674(89)90630-2. [DOI] [PubMed] [Google Scholar]
  7. Brinster R. L., Chen H. Y., Trumbauer M. E., Yagle M. K., Palmiter R. D. Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4438–4442. doi: 10.1073/pnas.82.13.4438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chada K., Magram J., Costantini F. An embryonic pattern of expression of a human fetal globin gene in transgenic mice. Nature. 1986 Feb 20;319(6055):685–689. doi: 10.1038/319685a0. [DOI] [PubMed] [Google Scholar]
  9. Choi O. R., Engel J. D. Developmental regulation of beta-globin gene switching. Cell. 1988 Oct 7;55(1):17–26. doi: 10.1016/0092-8674(88)90005-0. [DOI] [PubMed] [Google Scholar]
  10. Chui D. H., Mentzer W. C., Patterson M., Iarocci T. A., Embury S. H., Perrine S. P., Mibashan R. S., Higgs D. R. Human embryonic zeta-globin chains in fetal and newborn blood. Blood. 1989 Sep;74(4):1409–1414. [PubMed] [Google Scholar]
  11. Deisseroth A., Nienhuis A., Lawrence J., Giles R., Turner P., Ruddle F. H. Chromosomal localization of human beta globin gene on human chromosome 11 in somatic cell hybrids. Proc Natl Acad Sci U S A. 1978 Mar;75(3):1456–1460. doi: 10.1073/pnas.75.3.1456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Deisseroth A., Nienhuis A., Turner P., Velez R., Anderson W. F., Ruddle F., Lawrence J., Creagan R., Kucherlapati R. Localization of the human alpha-globin structural gene to chromosome 16 in somatic cell hybrids by molecular hybridization assay. Cell. 1977 Sep;12(1):205–218. doi: 10.1016/0092-8674(77)90198-2. [DOI] [PubMed] [Google Scholar]
  13. Driscoll M. C., Dobkin C. S., Alter B. P. Gamma delta beta-thalassemia due to a de novo mutation deleting the 5' beta-globin gene activation-region hypersensitive sites. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7470–7474. doi: 10.1073/pnas.86.19.7470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Enver T., Ebens A. J., Forrester W. C., Stamatoyannopoulos G. The human beta-globin locus activation region alters the developmental fate of a human fetal globin gene in transgenic mice. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7033–7037. doi: 10.1073/pnas.86.18.7033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Enver T., Raich N., Ebens A. J., Papayannopoulou T., Costantini F., Stamatoyannopoulos G. Developmental regulation of human fetal-to-adult globin gene switching in transgenic mice. Nature. 1990 Mar 22;344(6264):309–313. doi: 10.1038/344309a0. [DOI] [PubMed] [Google Scholar]
  16. Erhart M. A., Piller K., Weaver S. Polymorphism and gene conversion in mouse alpha-globin haplotypes. Genetics. 1987 Mar;115(3):511–519. doi: 10.1093/genetics/115.3.511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Greaves D. R., Fraser P., Vidal M. A., Hedges M. J., Ropers D., Luzzatto L., Grosveld F. A transgenic mouse model of sickle cell disorder. Nature. 1990 Jan 11;343(6254):183–185. doi: 10.1038/343183a0. [DOI] [PubMed] [Google Scholar]
  18. Grosveld F., van Assendelft G. B., Greaves D. R., Kollias G. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell. 1987 Dec 24;51(6):975–985. doi: 10.1016/0092-8674(87)90584-8. [DOI] [PubMed] [Google Scholar]
  19. Gusella J., Varsanyi-Breiner A., Kao F. T., Jones C., Puck T. T., Keys C., Orkin S., Housman D. Precise localization of human beta-globin gene complex on chromosome 11. Proc Natl Acad Sci U S A. 1979 Oct;76(10):5239–5242. doi: 10.1073/pnas.76.10.5239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hanscombe O., Vidal M., Kaeda J., Luzzatto L., Greaves D. R., Grosveld F. High-level, erythroid-specific expression of the human alpha-globin gene in transgenic mice and the production of human hemoglobin in murine erythrocytes. Genes Dev. 1989 Oct;3(10):1572–1581. doi: 10.1101/gad.3.10.1572. [DOI] [PubMed] [Google Scholar]
  21. Higgs D. R., Vickers M. A., Wilkie A. O., Pretorius I. M., Jarman A. P., Weatherall D. J. A review of the molecular genetics of the human alpha-globin gene cluster. Blood. 1989 Apr;73(5):1081–1104. [PubMed] [Google Scholar]
  22. Higgs D. R., Wood W. G., Jarman A. P., Sharpe J., Lida J., Pretorius I. M., Ayyub H. A major positive regulatory region located far upstream of the human alpha-globin gene locus. Genes Dev. 1990 Sep;4(9):1588–1601. doi: 10.1101/gad.4.9.1588. [DOI] [PubMed] [Google Scholar]
  23. Kazazian H. H., Jr, Woodhead A. P. Hemoglobin A synthesis in the developing fetus. N Engl J Med. 1973 Jul 12;289(2):58–62. doi: 10.1056/NEJM197307122890202. [DOI] [PubMed] [Google Scholar]
  24. Konkel D. A., Maizel J. V., Jr, Leder P. The evolution and sequence comparison of two recently diverged mouse chromosomal beta--globin genes. Cell. 1979 Nov;18(3):865–873. doi: 10.1016/0092-8674(79)90138-7. [DOI] [PubMed] [Google Scholar]
  25. Lau Y. F., Kan Y. W. Versatile cosmid vectors for the isolation, expression, and rescue of gene sequences: studies with the human alpha-globin gene cluster. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5225–5229. doi: 10.1073/pnas.80.17.5225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Leder A., Weir L., Leder P. Characterization, expression, and evolution of the mouse embryonic zeta-globin gene. Mol Cell Biol. 1985 May;5(5):1025–1033. doi: 10.1128/mcb.5.5.1025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ley T. J., Maloney K. A., Gordon J. I., Schwartz A. L. Globin gene expression in erythroid human fetal liver cells. J Clin Invest. 1989 Mar;83(3):1032–1038. doi: 10.1172/JCI113944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Liebhaber S. A. Alpha thalassemia. Hemoglobin. 1989;13(7-8):685–731. doi: 10.3109/03630268908998845. [DOI] [PubMed] [Google Scholar]
  29. Liebhaber S. A., Cash F. E., Ballas S. K. Human alpha-globin gene expression. The dominant role of the alpha 2-locus in mRNA and protein synthesis. J Biol Chem. 1986 Nov 15;261(32):15327–15333. [PubMed] [Google Scholar]
  30. Liebhaber S. A., Goossens M., Kan Y. W. Homology and concerted evolution at the alpha 1 and alpha 2 loci of human alpha-globin. Nature. 1981 Mar 5;290(5801):26–29. doi: 10.1038/290026a0. [DOI] [PubMed] [Google Scholar]
  31. Liebhaber S. A., Rappaport E. F., Cash F. E., Ballas S. K., Schwartz E., Surrey S. Hemoglobin I mutation encoded at both alpha-globin loci on the same chromosome: concerted evolution in the human genome. Science. 1984 Dec 21;226(4681):1449–1451. doi: 10.1126/science.6505702. [DOI] [PubMed] [Google Scholar]
  32. Magram J., Niederreither K., Costantini F. Beta-globin enhancers target expression of a heterologous gene to erythroid tissues of transgenic mice. Mol Cell Biol. 1989 Oct;9(10):4581–4584. doi: 10.1128/mcb.9.10.4581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nicholls R. D., Jonasson J. A., McGee J. O., Patil S., Ionasescu V. V., Weatherall D. J., Higgs D. R. High resolution gene mapping of the human alpha globin locus. J Med Genet. 1987 Jan;24(1):39–46. doi: 10.1136/jmg.24.1.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Peschle C., Mavilio F., Carè A., Migliaccio G., Migliaccio A. R., Salvo G., Samoggia P., Petti S., Guerriero R., Marinucci M. Haemoglobin switching in human embryos: asynchrony of zeta----alpha and epsilon----gamma-globin switches in primitive and definite erythropoietic lineage. Nature. 1985 Jan 17;313(5999):235–238. doi: 10.1038/313235a0. [DOI] [PubMed] [Google Scholar]
  35. Phillips J. A., 3rd, Snyder P. G., Kazazian H. H., Jr Ratios of alpha-to beta-globin mRNA and regulation of globin synthesis in reticulocytes. Nature. 1977 Sep 29;269(5627):442–445. doi: 10.1038/269442a0. [DOI] [PubMed] [Google Scholar]
  36. Raich N., Enver T., Nakamoto B., Josephson B., Papayannopoulou T., Stamatoyannopoulos G. Autonomous developmental control of human embryonic globin gene switching in transgenic mice. Science. 1990 Nov 23;250(4984):1147–1149. doi: 10.1126/science.2251502. [DOI] [PubMed] [Google Scholar]
  37. Ryan T. M., Behringer R. R., Martin N. C., Townes T. M., Palmiter R. D., Brinster R. L. A single erythroid-specific DNase I super-hypersensitive site activates high levels of human beta-globin gene expression in transgenic mice. Genes Dev. 1989 Mar;3(3):314–323. doi: 10.1101/gad.3.3.314. [DOI] [PubMed] [Google Scholar]
  38. Ryan T. M., Behringer R. R., Townes T. M., Palmiter R. D., Brinster R. L. High-level erythroid expression of human alpha-globin genes in transgenic mice. Proc Natl Acad Sci U S A. 1989 Jan;86(1):37–41. doi: 10.1073/pnas.86.1.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ryan T. M., Townes T. M., Reilly M. P., Asakura T., Palmiter R. D., Brinster R. L., Behringer R. R. Human sickle hemoglobin in transgenic mice. Science. 1990 Feb 2;247(4942):566–568. doi: 10.1126/science.2154033. [DOI] [PubMed] [Google Scholar]
  40. Talbot D., Collis P., Antoniou M., Vidal M., Grosveld F., Greaves D. R. A dominant control region from the human beta-globin locus conferring integration site-independent gene expression. Nature. 1989 Mar 23;338(6213):352–355. doi: 10.1038/338352a0. [DOI] [PubMed] [Google Scholar]
  41. Tuan D., Solomon W., Li Q., London I. M. The "beta-like-globin" gene domain in human erythroid cells. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6384–6388. doi: 10.1073/pnas.82.19.6384. [DOI] [PMC free article] [PubMed] [Google Scholar]

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