International Journal of Hematology

, Volume 76, Issue 5, pp 420–426 | Cite as

The Control of Expression of the α-Globin Gene Cluster

  • Hua-bing Zhang 
  • De-Pei Liu 
  • Chih-Chuan Liang 
Progress in hematology


The α-globin gene cluster is located at the very tip of the short arm of chromosome 16. It produces the α-like globins, which is combined with the β-like globins to form hemoglobin, and its mutants cause α-thalassemia, which is one of the most common genetic diseases. Its expression shows a tissue and developmental stage specificity that is balanced with that of the β-globin gene cluster. In this article, we summarize the research on the control of expression of the α-globin gene cluster, mainly with respect to the α—major regulatory element (α-MRE): HS-40, the tissue-specific and developmental control of its expression, and its chromosomal environment. In summary, the α-globin gene cluster is expressed in an open chromosomal environment; HS-40, the 5-flanking sequence, the transcribed region, and the 3-flanking sequence interact to fully regulate its expression.Int J Hematol. 2002;76:420-426.

Key words

α-Globin gene cluster Control of expression HS-40 Developmental control Chromosomal environment 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Higgs DR, Vickers MA, Wilkie AO, Pretorius IM, Jarman AP, Weatherall DJ. A review of the molecular genetics of the human α-globin gene cluster.Blood. 1989; 73: 1081–1104.PubMedGoogle Scholar
  2. 2.
    Higgs DR, Sharpe JA, Wood WG. Understanding α-globin gene expression: a step towards effective gene therapy.Semin Hematol. 1998; 35: 93–104.PubMedGoogle Scholar
  3. 3.
    Higgs DR,Wood WG, Jarman AP, et al. A major positive regulatory region located far upstream of the human α-globin gene locus.Genes Dev. 1990; 4: 1588–1601.CrossRefPubMedGoogle Scholar
  4. 4.
    Jarman AP, Wood WG, Sharpe JA, Gourdon G, Ayyub H, Higgs DR. Characterization of the major regulatory element upstream of the human α-globin gene cluster.Mol Cell Biol. 1991; 11: 4679–4689.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Strauss EC, Andrews NC, Higgs DR, Orkin SH. In vivo footprinting of the human α-globin locus upstream regulatory element by guanine and adenine ligation-mediated polymerase chain reaction.Mol Cell Biol. 1992; 12: 2135–2142.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Zhang Q, Reddy PMS, Yu CH, et al. Transcriptional activation of human ζ2-globin promoter by the a-globin regulatory element (HS-40): functional role of specific nuclear factor-DNA complexes.Mol Cell Biol. 1993; 13: 2298–2308.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Blank V, Andrews NC. The maf transcription factors: regulators of differentiation.Trends Biochem Sci. 1997; 22: 437–441.CrossRefPubMedGoogle Scholar
  8. 8.
    Kobayashi A, Ito E, Toki T, et al. Molecular cloning and functional characterization of a new Capʼnn’ collar family transcription factor Nrf3.J Biol Chem. 1999; 274: 6443–6452.CrossRefPubMedGoogle Scholar
  9. 9.
    Motohashi H, Shavit JA, Igarashi K, Yamamoto M, Engel JD. The world according to maf.Nucleic Acids Res. 1997; 25: 2953–2960.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Huang BL, Fan-Chiang IR, Wen SC, et al. Derepression of human embryonic ζ-globin promoter by a locus-control region sequence.Proc Natl Acad Sci U S A. 1998; 95: 14669–14674.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Pondel MD, Proudfoot NJ, Whitelaw C, Whitelaw E. The developmental regulation of the human ζ-globin gene in transgenic mice employing β-galactosidase as a reporter gene.Nucleic Acids Res. 1992; 20: 5655–5660.CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Ren S, Luo XN, Atweh GF. The major regulatory element upstream of the alpha-globin gene has classical and inducible enhancer activity.Blood. 1993; 81: 1058–1066.PubMedGoogle Scholar
  13. 13.
    Gourdon G, Sharpe JA, Wells D, Wood WG, Higgs DR. Analysis of a 70 kbs segment of DNA containing the human ζ and α-globin genes linked to their regulatory element (HS-40) in transgenic mice.Nucleic Acids Res. 1994; 22: 4139–4147.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Wang Z, Liebhaber SA. A 3-flanking NF-kappaB site mediates developmental silencing of the human zeta-globin gene.EMBO J. 1999; 18: 2218–2228.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Sharpe JA, Summerhill RJ, Vyas P, Gourdon G, Higgs DR, Wood WG. Role of upstream DNase I hypersensitive sites in the regulation of human alpha-globin gene expression.Blood. 1993; 82: 1666–1671.PubMedGoogle Scholar
  16. 16.
    Sharpe JA, Wells DJ, Whitelaw E, Vyas P, Higgs DR, Wood WG. Analysis of the human α-globin gene cluster in transgenic mice.Proc Natl Acad Sci U S A. 1993; 90: 11262–11266.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Sharpe JA, Chan-Thomas PS, Lida J, Ayyub H, Wood WG, Higgs DR. Analysis of the human alpha-globin upstream regulatory element (HS-40) in transgenic mice.EMBO J. 1992; 11: 4565–4572.PubMedCentralCrossRefGoogle Scholar
  18. 18.
    Grosveld F, Assendelft GB, Greares DR, et al. Position-independent, high-level expression of the human β-globin gene in transgenic mice.Cell. 1987; 51: 975–985.CrossRefPubMedGoogle Scholar
  19. 19.
    Hanscombe O, Whyatt D, Fraser P, et al. Importance of globin gene order for correct developmental expression.Genes Dev. 1991; 5: 1387–1394.CrossRefPubMedGoogle Scholar
  20. 20.
    Feng DX, Liu DP, Huang Y, et al. The expression of human alphalike globin genes in transgenic mice mediated by bacterial artificial chromosome.Proc Natl Acad Sci U S A. 2001; 98: 15073–15077.CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Wilgerde M, Grosveld F, Fraser P, et al. Transcription complex stability and chromatin dynamics in vivo.Nature. 1995; 377: 209–213.CrossRefGoogle Scholar
  22. 22.
    Bulger M, Groudine M. Looping versus linking: toward a model for long-distance gene activation.Genes Dev. 1999; 13: 2465–2477.CrossRefPubMedGoogle Scholar
  23. 23.
    Esperet C, Sabatier S, Deville MA, et al. Non-erythroid genes inserted on either side of human HS-40 impair the activation of its natural alpha-globin gene targets without being themselves preferentially activated.J Biol Chem. 2000; 275: 25831–25839.CrossRefPubMedGoogle Scholar
  24. 24.
    Leder A, Daugherty C, Whitney B, Leder P. Mouse zeta- and alpha-globin genes: embryonic survival, alpha-thalassemia, and genetic background effects.Blood. 1997; 90: 1275–1282.PubMedGoogle Scholar
  25. 25.
    Trimborn T, Gribnau J, Grosveld F, Fraser P. Mechanisms of developmental control of transcription in the murine alpha- and beta-globin loci.Genes Dev. 1999; 13: 112–124.CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Esperet C, Starck J, Godet J, Morle F. Coactivation of human alpha1- and alpha2-globin genes in single induced MEL cells containing one human alpha-globin locus.Biochim Biophys Acta. 1997; 1352: 27–32.CrossRefPubMedGoogle Scholar
  27. 27.
    Sabath DE, Koehler KM, Yang WQ, Phan V, Wilson J. DNA-protein interactions in the proximal zeta-globin promoter: identification of novel CCACCC- and CCAAT-binding proteins.Blood Cells Mol Dis. 1998; 24: 183–198.CrossRefPubMedGoogle Scholar
  28. 28.
    Treisman R, Green MR, Maniatis T. cis and trans activation of globin gene transcription in transient assays.Proc Natl Acad Sci U S A. 1983; 80: 7428–7432.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Ren S, Li J, Atweh GF. CACCC and GATA-1 sequences make the constitutively expressed alpha-globin gene erythroid-responsive in mouse erythroleukemia cells.Nucleic Acids Res. 1996; 24: 342–347.CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Shewchuk BM, Hardison RC. CpG islands from the alpha-globin gene cluster increase gene expression in an integration-dependent manner.Mol Cell Biol. 1997; 17: 5856–5866.CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Iudinkova ES, Lagar’kova MA, Razin SV. Molecular cloning and characteristics of the 5-terminal end of alpha-globin genes of chickens including potential regulator element of domain level.Dokl Akad Nauk. 1997; 356: 407–408.PubMedGoogle Scholar
  32. 32.
    Razin SV, Ioudinkova ES, Scherrer. Extensive methylation of a part of the CpG island located 3.0-4.5 kbp upstream to the chicken alpha-globin gene cluster may contribute to silencing the globin genes in non-erythroid cells.J Mol Biol. 2000; 299: 845–852.CrossRefPubMedGoogle Scholar
  33. 33.
    Albitar M, Katsumata M, Liebhaber SA. Human α-globin genes demonstrate autonomous developmental regulation in transgenic mice.Mol Cell Biol. 1991; 11: 3786–3794.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Sabath DE, Spangler EA, Rubin EM, Stamatoyannopoulos G. Analysis of the human ζ-globin gene promoter in transgenic mice.Blood. 1993; 82: 2899–2905.PubMedGoogle Scholar
  35. 35.
    Spangler EA, Andrews KA, Rubin EM. Developmental regulation of the human zeta- globin gene in transgenic mice.Nucleic Acids Res. 1990; 18: 7093–7097.CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Pondel MD, Sharpe JA, Clark S, Pearson L, Wood WG, Proudfoot NJ. Proximal promoter elements of the human zeta-globin gene confer embryonic-specific expression on a linked reporter gene in transgenic mice.Nucleic Acids Res. 1996; 24: 4158–4164.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Sabath DE, Koehler KM, Yang WQ, Patton K, Stamatoyannopoulos G. Identification of a major positive regulatory element located 5 to the human ζ-globin gene.Blood. 1995; 85: 2587–2597.PubMedGoogle Scholar
  38. 38.
    Sabath DE, Koehler KM, Yang WQ. Structure and function of the zeta-globin upstream regulatory element.Nucleic Acids Res. 1996; 24: 4978–4986.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Liebhaber SA, Wang Z, Cash FE, Monks B, Russell JE. Developmental silencing of the embryonic ζ-globin gene: concerted action of the promoter and the 3-flanking region combined with stage-specific silencing by the transcribed segment.Mol Cell Biol. 1996; 16: 2637–2646.CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Chkheidze AN, Lyakhov DL, Makeyev AV, Morales J, Kong J, Liebhaber SA. Assembly of the alpha-globin mRNA stability complex reflects binary interaction between the pyrimidine-rich 3 untranslated region determinant and poly(C) binding protein alphaCP.Mol Cell Biol. 1999; 19: 4572–4581.CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Liebhaber SA, Russell JE. Expression and developmental control of the human alpha-globin gene cluster.Ann N Y Acad Sci. 1998; 850: 54–63.CrossRefPubMedGoogle Scholar
  42. 42.
    Russell JE, Morales J, Liebhaber SA. The role of mRNA stability in the control of globin gene expression.Prog Nucleic Acid Res Mol Biol. 1997; 57: 249–287.CrossRefPubMedGoogle Scholar
  43. 43.
    Russell JE, Morales J, Makeyev AV, Liebhaber SA. Sequence divergence in the 3 -untranslated regions of human ζ- and α-globin mRNAs mediates a difference in their stabilities and contributes to efficient α- to ζ-gene developmental switching.Mol Cell Biol. 1998; 18: 2173–2183.CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Wen SC, Roder K, Hu KY, et al. Loading of DNA-binding factors to an erythroid enhancer.Mol Cell Biol. 2000; 20: 1993–2003.CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Zhang Q, Rombel I, Reddy GN, Gang JB, Shen CKJ. Functional roles of in vivo footprinted DNA motifs within an α-globin enhancer: erythroid lineage and developmental stage specificities.J Biol Chem. 1995; 270: 8501–8505.CrossRefPubMedGoogle Scholar
  46. 46.
    Flint J,Thomas K,Micklem G, et al. The relationship between chromosome structure and function at a human telomeric region.Nat Genet. 1997; 15: 252–257.CrossRefPubMedGoogle Scholar
  47. 47.
    Horsley SW, Daniels RJ, Anguita E, et al. Monosomy for the most telomeric, gene-rich region of the short arm of human chromosome 16 causes minimal phenotypic effects.Eur J Hum Genet. 2001; 9: 217–225.CrossRefPubMedGoogle Scholar
  48. 48.
    Daniels RJ, Peden JF, Lloyd C, et al. Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16.Hum Mol Genet. 2001; 10: 339–352.CrossRefPubMedGoogle Scholar
  49. 49.
    Vyas P, Vickers MA, Simmons DL, Ayyub H, Craddock CF, Higgs DR. Cis-acting sequences regulating expression of the human a-globin cluster lie within constitutively open chromatin.Cell. 1992; 69: 781–793.CrossRefPubMedGoogle Scholar
  50. 50.
    Craddock CF, Vyas P, Sharpe JA, Ayyub H, Wood WG, Higgs DR. Contrasting effects of α and β globin regulatory elements on chromatin structure may be related to their different chromosomal environments.EMBO J. 1995; 14: 1718–1726.PubMedCentralCrossRefGoogle Scholar
  51. 51.
    Smith ZE, Higgs DR. The pattern of replication at a human telomeric region (16p13.3): its relationship to chromosome structure and gene expression.Hum Mol Genet. 1999; 8: 1373–1386.CrossRefPubMedGoogle Scholar
  52. 52.
    Jarman AP, Higgs DR. Nuclear scaffold attachment sites in the human globin gene complexes.EMBO J. 1988; 7: 3337–3344.PubMedCentralCrossRefGoogle Scholar
  53. 53.
    Brown KE, Amoils S, Horn JM, et al. Expression of alpha- and beta-globin genes occurs within different nuclear domains in haemopoietic cells.Nat Cell Biol. 2001; 3: 602–606.CrossRefPubMedGoogle Scholar
  54. 54.
    Flint J, Tufarelli C, Peden J, et al. Comparative genome analysis delimits a chromosomal domain and identifies key regulatory elements in the alpha-globin cluster.Hum Mol Genet. 2001; 10: 371–382.CrossRefPubMedGoogle Scholar
  55. 55.
    Anguita E, Johnson CA,Wood WG,Turner BM, Higgs DR. Identification of a conserved erythroid specific domain of histone acetylation across the alpha-globin gene cluster.Proc Natl Acad Sci U S A. 2001; 98: 12114–12119.CrossRefPubMedCentralPubMedGoogle Scholar
  56. 56.
    Tufarelli C, Frischauf AM, Hardison R, Flint J, Higgs DR. Characterization of a widely expressed gene (LUC7-LIKE; LUC7L) defining the centromeric boundary of the human alpha-globin domain.Genomics. 2001; 71: 307–314.CrossRefPubMedGoogle Scholar
  57. 57.
    Nicholls RD, Fischel-Ghodsian N, Higgs DR. Recombination at the human alpha-globin gene cluster: sequence features and topological constraints.Cell. 1987; 49: 369–378.CrossRefPubMedGoogle Scholar
  58. 58.
    Barbour VM, Tufarelli C, Sharpe JA, et al. Alpha-thalassemia resulting from a negative chromosomal position effect.Blood. 2000; 96: 800–807.PubMedGoogle Scholar
  59. 59.
    Vyas P, Vickers MA, Picketts DJ, Higgs DR. Conservation of position and sequence of a novel, widely expressed gene containing the major human alpha-globin regulatory element.Genomics. 1995; 29: 679–689.CrossRefPubMedGoogle Scholar
  60. 60.
    Bernet A, Sabatier S, Picketts DJ, et al. Targeted inactivation of the major positive regulatory element (HS-40) of the human alpha-globin gene locus.Blood. 1995; 86: 1202–1211.PubMedGoogle Scholar
  61. 61.
    Vickers MA,Vyas P, Harris PC, Simmons DL, Higgs DR. Structure of the human 3-methyladenine DNA glycosylase gene and localization close to the 16p telomere.Proc Natl Acad Sci U S A. 1993; 90: 3437–3441.CrossRefPubMedCentralPubMedGoogle Scholar
  62. 62.
    Dillon N, Sabbattini P. Functional gene expression domains: defining the functional unit of eukaryotic gene regulation.Bioessays. 2000; 22: 657–665.CrossRefPubMedGoogle Scholar
  63. 63.
    Goldman MA,Holmquist GP, Gray MC, Caston LA, Nag A. Replication timing of genes and middle repetitive sequences.Science. 1984; 224: 686–692.CrossRefPubMedGoogle Scholar
  64. 64.
    Gibbons RJ, Higgs DR. Molecular-clinical spectrum of the ATR-X syndrome.Am J Med Genet. 2000; 97: 204–212.CrossRefPubMedGoogle Scholar
  65. 65.
    Gibbons RJ, McDowell TL, Raman S, et al. Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation.Nat Genet. 2000; 24: 368–371.CrossRefPubMedGoogle Scholar
  66. 66.
    Pennisi E. Behind the scenes of gene expression.Science. 2001; 293: 1064–1067.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2002

Authors and Affiliations

  • Hua-bing Zhang 
    • 1
  • De-Pei Liu 
    • 1
  • Chih-Chuan Liang 
    • 1
  1. 1.National Laboratory of Medical Molecular BiologyInstitute of Basic Medical Sciences,Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing, P. R.China

Personalised recommendations