The Hemoglobin Regulatory Regions

  • Betty S. PaceEmail author
  • Levi H. Makala


All animals that use hemoglobin for oxygen transport synthesize different hemoglobin types during the various stages of development. In humans, two gene clusters direct the production of hemoglobin including the α-locus which contains the embryonic ζ gene and two adult α genes on chromosome 16. A second cluster, the β-globin locus located on chromosome 11, contains the ε, Gγ, Aγ, δ, and β genes. The globin genes are arranged from 5′ to 3′ according to the order of their expression and are developmentally regulated to produce different hemoglobin species during ontogeny. Two switches in the type of hemoglobin synthesized during development occur, a process known as hemoglobin switching. Through research efforts over the last two decades, several insights have been gained into the molecular mechanisms of hemoglobin switching. However, the entire process has not been fully elucidated. Studies of naturally occurring globin gene promoter mutations and transgenic mouse investigations have contributed to our understanding of the effect of DNA mutations on globin gene expression. Furthermore, the developmental regulation of globin gene expression has shaped research efforts to establish therapeutic modalities for individuals affected with sickle cell disease and β-thalassemia. Here, we will review the progress made toward understanding molecular mechanisms that control globin gene expression and the consequences of mutations on hemoglobin switching.


Hemoglobin ε-Globin γ-Globin β-Globin α-Globin Hereditary persistence of fetal hemoglobin Hemoglobin switching Thalassemia Sickle cell disease 



CCAAT displacement protein


CREB-binding protein


Direct repeat erythroid-definitive

Hb F

Fetal hemoglobin


Hereditary persistence of fetal hemoglobin


Hypersensitive site


Locus control region


Stage selector element


Stage selector protein


Signal transducers and activators of transcription


Sickle cell anemia


Sickle cell disease


Single nucleotide polymorphism


  1. Antonarakis SE, Orkin SH, Cheng TC, Scott AF, Sexton JP, Trusko SP, Charache S, Kazazian HH Jr (1984) Beta-Thalassemia in American Blacks: novel mutations in the “TATA” box and an acceptor splice site. Proc Natl Acad Sci USA 81:1154–1158PubMedCrossRefGoogle Scholar
  2. Antoniou M, deBoer E, Habets G, Grosveld F (1988) The human beta-globin gene contains multiple regulatory regions: identification of one promoter and two downstream enhancers. EMBO J 7:377–384Google Scholar
  3. Antoniou M, Grosveld F (1990) Beta-globin dominant control region interacts differently with distal and proximal promoter elements. Genes Dev 4:1007–1013PubMedCrossRefGoogle Scholar
  4. Antoniou M, de Boer E, Spanopoulou E, Imam A, Grosveld F (1995) TBP binding and the rate of transcription initiation from the human beta-globin gene. Nucleic Acids Res 23:3473–3480PubMedCrossRefGoogle Scholar
  5. Asano H, Li XS, Stamatoyannopoulos G (1999) FKLF, a novel Kruppel-like factor that activates human embryonic and fetal β-like globin genes. Mol Cell Biol 19:3571–3579PubMedGoogle Scholar
  6. Asano H, Li XS, Stamatoyannopoulos G (2000) FKLF-2: a novel Kruppel like transcriptional factor that activates globin and other erythroid lineage genes. Blood 95:3578–3584PubMedGoogle Scholar
  7. Atweh GF, Sutton M, Nassif I, Boosalis V, Dover GJ, Wallenstein S, Wright E, Mc-Mahon L, Stamatoyannopoulos G, Faller DV, Perrine SP (1999) Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood 93:1790–1797PubMedGoogle Scholar
  8. Aufiero B, Neufeld EJ, Orkin SH (1994) Sequence-specific DNA binding of individual cut repeats of the human CCAAT displacement/cut homeodomain protein. Proc Natl Acad Sci USA 91:7757–7761PubMedCrossRefGoogle Scholar
  9. Barberis A, Superti-Furga G, Busslinger M (1987) Mutually exclusive interaction of the CCAAT-binding factor and of a displacement protein with overlapping sequences of a histone gene promoter. Cell 50:347–359PubMedCrossRefGoogle Scholar
  10. Bacolla A, Ulrich MJ, Larson JE, Ley TJ, Wells RD (1995) An intramolecular triplex in the human gamma-globin 5′-flanking region is altered by point mutations associated with hereditary persistence of fetal hemoglobin. J Biol Chem 270:24556–24563PubMedCrossRefGoogle Scholar
  11. Behringer RR, Hammer RE, Brinster RL, Palmiter RD, Townes TM (1987) Two 3′ sequences direct adult erythroid-specific expression of human beta-globin genes in transgenic mice. Proc Natl Acad Sci USA 8:7056–7060CrossRefGoogle Scholar
  12. Bond DR (2005) Three decades of innovation in the management of sickle cell disease: the road to understanding the sickle cell disease clinical phenotype. Blood Rev 19:99–110CrossRefGoogle Scholar
  13. Bookchin RM, Nagel RL, Balaza T (1975) Role of hybrid tetramer formation in gelation of haemoglobin S. Nature 256:667–668PubMedCrossRefGoogle Scholar
  14. Bookchin RM, Balazs T, Nagel RL, Tellez I (1977) Polymerisation of haemoglobin SA hybrid tetramers. Nature 269:526–527PubMedCrossRefGoogle Scholar
  15. Borg J, Papadopoulos P, Georfitsi M, Gutierrez L, Grech G, Franis P, Phylactides M, Verkerk AJ, van der Spek PJ, Scerri CA, Cassar W, Galdies R, van Licken W, Ozqur Z, Gillemans N, Hou J, Bugeja M, Grosveld FG, von Lindern M, Felice AE, Patronis GP, Philipsen S (2010) Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet 42:801–805PubMedCrossRefGoogle Scholar
  16. Browne P, Shalev O, Hebbel RP (1998) The molecular pathobiology of cell membrane iron: the sickle red cell as a model. Free Radic Biol Med 24:1040–1048PubMedCrossRefGoogle Scholar
  17. Bulger M, van Doorninck JH, Saitoh N, Telling A, Farrell C, Bender MA, Felsenfeld G, Axel R, Groudine M (1999) Conservation of sequence and structure flanking the mouse and human beta-globin loci: the beta-globin genes are embedded within an array of odorant receptor genes. Proc Natl Acad Sci USA 96:5129–5134PubMedCrossRefGoogle Scholar
  18. Cai SP, Eng B, Francombe WH, Olivieri NF, Kendall AG, Waye JS, Chui DH (1992) Two novel beta-thalassemia mutations in the 5′ and 3′ noncoding regions of the beta-globin gene. Blood 79:1342–1346PubMedGoogle Scholar
  19. Carlson J, Nash GB, Gabutti V, al-Yaman F, Wahlgren M (1994) Natural protection against severe Plasmodium falciparum malaria due to impaired rosette formation. Blood 84:3909PubMedGoogle Scholar
  20. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, DR B (1995) Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N Eng J Med 332:1317–1322CrossRefGoogle Scholar
  21. Chen Z, Luo HY, Steinberg MH, Chui DH (2009) BCL11A represses HBG transcription in K562 cells. Blood Cells Mol Dis 42:144–149PubMedCrossRefGoogle Scholar
  22. Cheng TC, Orkin SH, Antonarakis SE, Potter MJ, Sexton JP, Markham AF, Giardina PJ, Li A, Kazazian HH Jr (1984) Beta-thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. Proc Natl Acad Sci USA 81:2821–2825PubMedCrossRefGoogle Scholar
  23. Clegg JB, Weatherall DJ, Milner PF (1971) Haemoglobin constant spring – a chain termination mutant? Nature 234:337–340PubMedCrossRefGoogle Scholar
  24. Clegg JB, Weatherall DJ, Contopoou-Griva I, Caroutsos K, Poungouras P, Tsevrenis H (1974) Haemoglobin Icaria, a new chain-termination mutant with causes alpha thalassaemia. Nature 251:245–247PubMedCrossRefGoogle Scholar
  25. Crossley M, Whitelaw E, Perkins A, Williams G, Fujiwara Y, Orkin SH (1996) Isolation and characterization of the cDNA encoding BKLF/TEF-2, a major CACCC-box-binding protein in erythroid cells and selected other cells. Mol Cell Biol 16:1695–1705PubMedGoogle Scholar
  26. Cunningham MJ (2010) Update on thalassemia: clinical care and complications. Hematol Oncol Clin N Am 24:215–227CrossRefGoogle Scholar
  27. deBoer E, Antoniou M, Mignotte V, Wall L, Grosveld F (1988) The human beta-globin promoter: nuclear protein factors and erythroid specific induction of transcription. EMBO J 7:4203–4212PubMedGoogle Scholar
  28. Embury SH, Dozy AM, Miller J, Davis JR Jr, Kleman KM, Preisler H, Vichinsky E, Lande WN, Lubin BH, Kan YW, Mentzer WC (1982) Concurrent sickle-cell anemia and alpha-thalassemia: effect on severity of anemia. N Engl J Med 306:270–274PubMedCrossRefGoogle Scholar
  29. Ellis J, Tan-Un KC, Harper A, Michalovich D, Yannoutsos N, Philipsen S, Grosveld F (1996) A dominant chromatin-opening activity in 5′ hypersensitive site 3 of the human beta-globin locus control region. EMBO J 15:562–568PubMedGoogle Scholar
  30. Enver T, Zhang J-W, Papayannopoulou T, Stammatoyannopoulos G (1988) DNA methylation: a secondary event in globin gene switching? Genes Dev 2:698–706PubMedCrossRefGoogle Scholar
  31. Enver T, Raich N, Ebens AJ, Papayannopoulou T, Costantini F, Stamatoyannopoulos G (1990) Developmental regulation of human fetal to-adult globin gene switching in transgenic mice. Nature 344:309–313PubMedCrossRefGoogle Scholar
  32. Ferry A, Baliga S, Monterio C, Chen Y, Pace BS (1997) γ-Globin gene silencing in primary erythroid cultures: an inhibitory role for interleukin-6. J Biol Chem 272:20030–20037PubMedCrossRefGoogle Scholar
  33. Flint J, Harding RM, Boyce AJ, Clegg JB (1998) The population genetics of the haemoglobinopathies. Bailieres Clin Haematol 11:1–51CrossRefGoogle Scholar
  34. Foley H, Ofori-Acquah S, Baliga BS, Pace BS (2002) STAT3 mediates globin repression by interleukin-6 in K562 cells. J Biol Chem 77:16211–16219CrossRefGoogle Scholar
  35. Forrester WC, Takegawa S, Papayannopoulou T, Stamatoyannopoulos G, Groudine M (1987) Evidence for a locus activation region: the formation of developmentally stable hypersensitive sites in globin expressing hybrids. Nucleic Acids Res 15:10159–10177PubMedCrossRefGoogle Scholar
  36. Forrester WC, Epner E, Driscoll MC, Enver T, Brice M, Papayannopoulou T, Groudine M (1990) A deletion of the human beta-globin locus activation region causes a major alteration in chromatin structure and replication across the entire beta-globin locus. Genes Dev 4:1637–1649PubMedCrossRefGoogle Scholar
  37. Fraser P, Grosveld F (1998) Locus control regions, chromatin activation and transcription. Curr Opin Cell Biol 10:361–365PubMedCrossRefGoogle Scholar
  38. Fucharoen S, Shimizu K, Fukumaki Y (1990) A novel C-T transition within the distal CCAAT motif of the G gamma-globin gene in the Japanese HPFH: implication of factor binding in elevated fetal globin expression. Nucleic Acids Res 18:5245–5253PubMedCrossRefGoogle Scholar
  39. Gardiner MR, Daggett DF, Zon LI, Perkins AC (2005) Zebrafish KLF4 is essential for anterior mesendoderm/pre-polster differentiation and hatching. Dev Dyn 234:992–996PubMedCrossRefGoogle Scholar
  40. Gardiner MR, Gongora MM, Grimmone SM, Perkins AC (2007) A global role for zebrafish klf4 in embryonic erythropoiesis. Mech Dev 124:762–774PubMedCrossRefGoogle Scholar
  41. Gong QH, Stern J, Dean A (1991) Transcriptional role of a conserved GATA-1 site in the human epsilon-globin gene promoter. Mol Cell Biol 11:2558–2566PubMedGoogle Scholar
  42. Gonzalez-Redondo JM, Stoming TA, Kutlar A, Kutlar F, Lanclos KD, Howard EF, Fei YJ, Aksoy M, Altay C, Gurgey A et al (1989) A C–T substitution at nt–101 in a conserved DNA sequence of the promotor region of the beta-globin gene is associated with “silent” beta-thalassemia. Blood 73:1705–1711PubMedGoogle Scholar
  43. Gonzalez-Redondo JM, Stoming TA, Lanclos KD, Gu YC, Kutlar A, Kutlar F, Nakatsuji T, Deng B, Han IS, McKie VC et al (1988) Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. Blood 72:1007–1014PubMedGoogle Scholar
  44. Goodwin AJ, McInerney JM, Glander MA, Pomerantz O, Lowrey CH (2001) In vivo formation of a human beta-globin locus control region core element requires binding sites for multiple factors including GATA-1, NF-E2, erythroid Kruppel-like factor, and Sp1. J Biol Chem 276:26883–26892PubMedCrossRefGoogle Scholar
  45. Grosveld F, van Assendelft GB, Greaves DR, Kollias G (1987) Position independent, high-level expression of the human β-globin gene in transgenic mice. Cell 51:975–985PubMedCrossRefGoogle Scholar
  46. Gumucio DL, Rood KL, Gray TA, Riordan MF, Sartor CI, Collins FS (1988) Nuclear proteins that bind the human gamma-globin gene promoter: alterations in binding produced by point mutations associated with hereditary persistence of fetal hemoglobin. Mol Cell Biol 8:5310–5322PubMedGoogle Scholar
  47. Hankins JS, Ware RE, Rogers ZR et al (2005) Long-term hydroxyurea therapy for infants with sickle cell anemia – the HUSOFT extension study. Blood 106:2269–2275PubMedCrossRefGoogle Scholar
  48. Hardison RC, Chui DH, Giardine B, Riemer C, Patrinos GP, Anagnou N, Miller W, Wajcman H (2002) HbVar: a relational database of human hemoglobin variants and thalassemia mutations at the globin gene server. Hum Mutat 19:225–233PubMedCrossRefGoogle Scholar
  49. Harju-Baker S, Costa FC, Fedosyuk H, Neades R, Peterson KR (2008) Silencing of Aγ-globin gene expression during adult definitive erythropoiesis mediated by GATA-1-FOG-1-Mi2 complex binding at the −566 GATA site. Mol Cell Biol 28:3101–3113PubMedCrossRefGoogle Scholar
  50. Higgs DR, Wood WG, Jarman AP, Sharpe J, Lida J, Pretorius IM, Ayyub H (1990) A major positive regulatory region located far upstream of the human alpha-globin gene locus. Genes Dev 4:1588–1601PubMedCrossRefGoogle Scholar
  51. Higgs DR, Vickers MA, Wilkie AO, Pretorius IM, Jarman AP, Weatherall DJ (1989) A review of the molecular genetics of the human alpha-globin gene cluster. Blood 73:1081–1104PubMedGoogle Scholar
  52. Higgs DR, Goodbourn SE, Lamb J, Clegg JB, Weatherall DJ, Proudfoot NJ (1983) Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature 306:398–400PubMedCrossRefGoogle Scholar
  53. Higgs DR, Gibbons RJ (2010) The molecular basis of α-thalassemia: a model for understanding human molecular genetics. Hematol Oncol Clin N Am 24:1033–1054CrossRefGoogle Scholar
  54. Huisman TH (1997) Combinations of beta chain abnormal hemoglobins with each other or with beta-thalassemia determinants with known mutations: influence on phenotype. Clin Chem 43:1850–1856PubMedGoogle Scholar
  55. Ingram VM (1957) Gene mutations in human haemoglobins: the chemical difference between normal and sickle cell haemoglobin. Nature 180:326PubMedCrossRefGoogle Scholar
  56. Jackson DA, McDowell JC, Dean A (2003) Beta-globin locus control region HS2 and HS3 interact structurally and functionally. Nucleic Acids Res 31:1180–1190PubMedCrossRefGoogle Scholar
  57. Jane SM, Gumucio DL, Ney PA, Cunningham JM, Nienhuis AW (1993) Methylation-enhanced binding of Sp1 to the stage selector element of the human gamma-globin gene promoter may regulate development specificity of expression. Mol Cell Biol 13:3272–3281PubMedGoogle Scholar
  58. Jane SM, Nienhuis AW, Cunningham JM (1995) Hemoglobin switching in man and chicken is mediated by a heteromeric complex between the ubiquitous transcription factor CP2 and a developmentally specific protein. EMBO J 14:97–105PubMedGoogle Scholar
  59. Kalra IS, Alam MM, Choudhary PK, Pace BS (2011) Krüppel-like factor 4 activates HBG gene expression in primary erythroid cells. Br J Hematol 154:248–259CrossRefGoogle Scholar
  60. Kazazian HH Jr, Orkin SH, Antonarakis SE, Sexton JP, Boehm CD, Goff SC, Waber PG (1984) Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J 3:593–596PubMedGoogle Scholar
  61. Kollias G, Wrighton N, Hurst J, Grosveld F (1986) Regulated expression of human Aγ-, β-, and hybrid β γ-globin genes in transgenic mice: manipulation of the developmental expression patterns. Cell 46:89–94PubMedCrossRefGoogle Scholar
  62. Kollias G, Hurst J, deBoer E, Grosveld F (1987) The human beta-globin gene contains a downstream developmental specific enhancer. Nucleic Acids Res 15:5739–5747PubMedCrossRefGoogle Scholar
  63. Lauer J, Shen CK, Maniatis T (1980) The chromosomal arrangement of human alpha-like globin genes: sequence homology and alpha-globin gene deletions. Cell 20:119–130PubMedCrossRefGoogle Scholar
  64. Levings PP, Bungert J (2002) The human beta-globin locus control region. Eur J Biochem 269:1589–1599PubMedCrossRefGoogle Scholar
  65. Lewis BA, Orkin SH (1995) A functional initiator element in the human beta-globin promoter. J Biol Chem 270:28139–28144PubMedCrossRefGoogle Scholar
  66. Li S, Moy L, Pittman N, Shue G, Aufiero B, Neufeld EJ, LeLeiko NS, Walsh MJ (1999) Transcriptional repression of the cystic fibrosis transmembrane conductance regulator gene, mediated by CCAAT displacement protein/cut homolog, is associated with histone deacetylation. J Biol Chem 274:7803–7815PubMedCrossRefGoogle Scholar
  67. Li S, Aufiero B, Schiltz RL, Walsh MJ (2000) Regulation of the homeodomain CCAAT displacement/cut protein function by histone acetyltransferases p300/CREB-binding protein (CBP)-associated factor and CBP. Proc Natl Acad Sci USA 97:7166–7171PubMedCrossRefGoogle Scholar
  68. Liu Q, Bungert J, Engel JD (1997) Mutation of gene-proximal regulatory elements disrupts human epsilon-, gamma-, and beta-globin expression in yeast artificial chromosome transgenic mice. Proc Natl Acad Sci USA 94:169–174PubMedCrossRefGoogle Scholar
  69. Liu LR, Du ZW, Zhao HL, Liu XL, Huang XD, Shen J, Ju LM, Fang FD, Zhang JW (2005) T to C substitution at −175 or −173 of the gamma-globin promoter affects GATA-1 and OCT-1 binding in vitro differently but can independently reproduce the hereditary persistence of fetal hemoglobin phenotype in transgenic mice. J Biol Chem 280:7452–7459PubMedCrossRefGoogle Scholar
  70. Magram J, Niederreither K, Costantini F (1989) Beta-globin enhancers target expression of a heterologous gene to erythroid tissues of transgenic mice. Mol Cell Biol 9:4581–4584PubMedGoogle Scholar
  71. Maier-Redelsperger M, de Noguchi CT, Montalembert M, Rodgers GP, Schechter AN, Gourbil A, Blanchard D, Jais JP, Ducrocq R, Peltier JY (1994) Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian prospective study on sickle cell disease. Blood 84:3182–3188PubMedGoogle Scholar
  72. Mantovani R, Malgaretti N, Nicolis S, Ronchi A, Giglioni B, Ottolenghi S (1988) The effects of HPFH mutations in the human gamma-globin promoter on binding of ubiquitous and erythroid specific nuclear factors. Nucleic Acids Res 16:7783–7797PubMedCrossRefGoogle Scholar
  73. Mantovani R (1998) A survey of 178 NF-Y binding CCAAT boxes. Nucleic Acids Res 26:1135–1143PubMedCrossRefGoogle Scholar
  74. Mantovani R (1999) The molecular biology of the CCAAT-binding factor NF-Y. Gene 239:15–27PubMedCrossRefGoogle Scholar
  75. Marini MG, Procu L, Asunis I, Loi MG, Ristaldi MS, Procu S, Ikuta T, Cao A, Moi P (2010) Regulation of the human HBA genes by KLF4 in erythroid cell lines. Br J Haematol 149:748–758PubMedCrossRefGoogle Scholar
  76. Martin DI, Orkin SH (1990) Transcriptional activation and DNA binding by the erythroid factor GF-1/NF-E1/Eryf 1. Genes Dev 4:1886–1898PubMedCrossRefGoogle Scholar
  77. Mavilio F, Giampaolo A, Care A, Migliaccio G, Calandrini M, Russo G, Pagliardi GL, Mastroberardino G, Marinucci M, Peschle C (1983) Molecular mechanisms of human hemoglobin switching: selective undermethylation and expression of globin genes in embryonic, fetal, and adult erythroblasts. Proc Natl Acad Sci USA 80:6907–6911PubMedCrossRefGoogle Scholar
  78. Miller IJ, Bieker JJ (1993) A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Kruppel family of nuclear proteins. Mol Cell Biol 13:2776–2786PubMedGoogle Scholar
  79. Modiano D, Bancone G, Ciminelli BM, Pompei F, Blot I, Simpore J, Modiano G (2007) Haemoglobin S and haemoglobin C: ‘quick but costly’ versus ‘slow but gratis’ genetic adaptations to plasmodium falciparum malaria. Hum Mol Genet 17:789–799PubMedCrossRefGoogle Scholar
  80. Myers RM, Cowie A, Stuve L, Hartzog G, Gaensler K (1989) Genetic and biochemical analysis of the mouse beta-major globin promoter. Prog Clin Biol Res 316A:117–127PubMedGoogle Scholar
  81. Nagel RL, Bookchin RM, Johnson J, Labie D, Wajcman H, Isaac-Sodeye WA, Honig GR, Schiliro G, Crookston JH, Matsutomo K (1979) Structural bases of the inhibitory effects of Hb F and A2 on the polymerization of Hb S. Proc Natl Acad Sci USA 76:670–672PubMedCrossRefGoogle Scholar
  82. Nagel RL, Fabry ME, Pagnier J, Zohoun I, Wajcman H, Baudin V, Labie D (1985) Hematologically and genetically distinct forms of sickle cell anemia in Africa. N Engl J Med 312:880PubMedCrossRefGoogle Scholar
  83. Nagel RL, Fabry ME (1985) The many pathophysiologies of sickle cell anemia. Am J Hematol 20:195PubMedCrossRefGoogle Scholar
  84. Nerlov C (2004) C/EBPalpha mutations in acute myeloid leukaemias. Nat Rev Cancer 4:394–400PubMedCrossRefGoogle Scholar
  85. Neufeld EJ, Skalnik DG, Lievens PM, Orkin SH (1992) Human CCAAT displacement protein is homologous to the Drosophila homeoprotein, cut. Nat Genet 1:50–55PubMedCrossRefGoogle Scholar
  86. Ney PA, Sorrentino BP, Lowrey CH, Nienhuis AW (1990) Inducibility of the HS II enhancer depends on binding of an erythroid specific nuclear protein. Nucleic Acids Res 18:6011–6017PubMedCrossRefGoogle Scholar
  87. Nishio H, Walsh MJ (2004) CCAAT displacement protein/cut homolog recruits G9a histone lysine methyltransferase to repress transcription. Proc Natl Acad Sci USA 101:11257–11262PubMedCrossRefGoogle Scholar
  88. Orkin SH, Antonarkis SE, Kaxazian JJJR (1984) Base substitution at position −88 in a beta-thalassemic globin gene. Further evidence for the role of distal promoter element ACACCC. J Biol Chem 259:8679–8681PubMedGoogle Scholar
  89. Orkin SH, Cheng TC, Antonarakis SE, Kazazian HH Jr (1985) Thalassemia due to a mutation in the cleavage-polyadenylation signal of the human beta-globin gene. EMBO J 4:453–456PubMedGoogle Scholar
  90. Orkin SH, Kazazian HH Jr, Antonarakis SE, Ostrer H, Goff SC, Sexton JP (1982) Abnormal RNA processing due to the exon mutation of beta E-globin gene. Nature 300:768–769PubMedCrossRefGoogle Scholar
  91. Orkin SH, Sexton JP, Cheng TC, Goff SC, Giardina PJ, Lee JI, Kazazian HH Jr.(1983) ATA box transcription mutation in beta-thalassemia. Nucleic Acids Res. 11:4727–34PubMedGoogle Scholar
  92. Osada S, Yamamoto H, Nishihara T, Imagawa M (1996) DNA binding specificity of the CCAAT/enhancer-binding protein transcription factor family. J Biol Chem 271:3891–3896PubMedCrossRefGoogle Scholar
  93. Pagnier J, Mears JG, Dunda-Belkhodia O, Schaefer-Rego KE, Beldjord C, Nagel RL, Labie D (1984) Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa. Proc Natl Acad Sci USA 81:1771–1773PubMedCrossRefGoogle Scholar
  94. Pauling L, Itano HA, Singer SJ and Wells IC (1949) Sickle cell anemia a molecular disease. Science 110:543–8PubMedCrossRefGoogle Scholar
  95. Perrine SP, Ginder GD, Faller DV, Dover GH, Ikuta T, Witkowska HE, Cai SP, Vichinsky EP, Olivieri NF (1993) A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med 328:81–86PubMedCrossRefGoogle Scholar
  96. Perrine SP, Wargin WA, Boosalis MS, Wallis WJ, Case S, Keefer JR, Faller DV, Welch WC, Berenson RJ (2011) Evaluation of safety and pharmacokinetics of sodium 2,2 dimethylbutyrate, a novel short chain fatty acid derivative, in a phase 1, double-blind, placebo-controlled, single-dose, and repeat-dose studies in healthy volunteers. J Clin Pharmacol 51:1186–1194PubMedCrossRefGoogle Scholar
  97. Peters B, Merezhinskaya N, Diffley JF, Noguchi CT (1993) Protein-DNA interactions in the epsilon-globin gene silencer. J Biol Chem 268:3430–3437PubMedGoogle Scholar
  98. Pirastu M, Saglio G, Chang JC, Cao A, Kan YW (1984) Initiation codon mutation as a cause of alpha thalassemia. J Biol Chem 259:12315–12317PubMedGoogle Scholar
  99. Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR (1991) Pain in sickle cell disease. Rates and risk factors. N Engl J Med 325:11–16PubMedCrossRefGoogle Scholar
  100. Raich N, Papayannopoulou T, Stamatoyonnopoulos G, Enver T (1992) Demonstration of a human epsilon-globin gene silencer with studies in transgenic mice. Blood 79:861–864PubMedGoogle Scholar
  101. Raich N, Clegg CH, Grofti J, Romeo PH, Stamatoyannopoulos G (1995) GATA1 and YY1 are developmental repressors of the human epsilon-globin gene. EMBO J 14:801–809PubMedGoogle Scholar
  102. Ristaldi MS, Drabek D, Gribnau J, Poddie D, Yannoutsous N, Cao A, Grosveld F, Imam AM (2001) The role of the −50 region of the human gamma-globin gene in switching. EMBO J 20:5242–5249PubMedCrossRefGoogle Scholar
  103. Ronchi A, Nicolis S, Santoro C, Ottolenghi S (1989) Increased Sp1 binding mediates erythroid-specific overexpression of a mutated (HPFH) gamma-globulin promoter. Nucleic Acids Res 17:10231–10241PubMedCrossRefGoogle Scholar
  104. Rodriguez P, Bonte E, Krijgsveld J, Kolodziej KE, Guyot B, Heck AJ, Vyas P, de Boer E, Grosveld F, Strouboulis J (2005) GATA-1 forms distinct activating and repressive complexes in erythroid cells. EMBO J 24:2354–2366PubMedCrossRefGoogle Scholar
  105. Sampietro M, Thein SL, Contreras M, Pazmany L (1992) Variation of Hb F and F-cell number with the G-gamma Xmn I (C-T) polymorphism in normal individuals. Blood 79:832–833PubMedGoogle Scholar
  106. Schroeder WA, Huisman TH, Shelton JB, Kleihauer EF, Dozy AM, Roberson B (1968a) Evidence for multiple structural genes for the gamma chain of human fetal hemoglobin. Proc Natl Acad Sci USA 60:537–544PubMedCrossRefGoogle Scholar
  107. Sankaran VG, Menne TF, Xu J, Akie TE, Letter G, Van Handel B, Mikkola HK, Hirschhorn JN, Cantor AB, Orkin SH (2008) Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 322:1839–1842PubMedCrossRefGoogle Scholar
  108. Sankaran VG, Xu J, Ragoczy T, Ippolito GC, Walkley CR, Maika SD, Fujiwara Y, Ito M, Groudin M, Bender MA, Tucker PW, Orkin SH (2009) Developmental and species-divergent globin switching are driven by BCL11A. Nature 460:1093–1097PubMedCrossRefGoogle Scholar
  109. Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, Gavazova S, Chen YH, Hoffman R, DeSimone J (2003) Effects of 5-aza-2′-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood 102:3865–3870PubMedCrossRefGoogle Scholar
  110. Skalnik DG, Strauss EC, Orkin SH (1991) CCAAT displacement protein as a repressor of the myelomonocytic-specific gp91-phox gene promoter. J Biol Chem 266:16736–16744PubMedGoogle Scholar
  111. Smith-Whitley K, Pace BS (2007) Sickle cell disease: a phenotypic patchwork. In: Pace BS (ed) Renaissance of sickle cell disease research in the genome era. Imperial College Press, London, pp 45–63Google Scholar
  112. Spritz RA, Jagadeeswaran P, Choudary PV, Biro PA, Elder JT, deRiel JK, Manley JL, Gdfter ML, Forget BG, Weissman SM (1981) Base substitution in an intervening sequence of a beta  +  −thalassemic human globin gene. Proc Natl Acad Sci USA 78:2455–2459PubMedCrossRefGoogle Scholar
  113. Stamatoyannopoulos G, Josephson B, Zhang JW, Li Q (1993) Developmental regulation of human gamma-globin genes in transgenic mice. Mol Cell Biol 13:7636–7644PubMedGoogle Scholar
  114. Stamatoyannopoulos G, Grosveld F (2001) Hemoglobin switching. In: Stamatoyannopoulos G, Majerus PW, Perlmutter RM, Varmus H (eds) The molecular basis of blood disease, vol 3. Saunders, PhiladelphiaGoogle Scholar
  115. Steinberg MH, Rosenstock W, Coleman MB, Adams JG, Platica O, Cedeno M, Rieder RF, Wilson JT, Milner P, West S (1984) Effects of thalassemia and microcytosis on the hematologic and vasoocclusive severity of sickle cell anemia. Blood 63:1353–1360PubMedGoogle Scholar
  116. Steinberg MH, Embury SH (1986) Alpha-thalassemia in blacks: genetic and clinical aspects and interactions with the sickle hemoglobin gene. Blood 68:985–990PubMedGoogle Scholar
  117. Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ (1997) Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter study of hydroxyurea. Blood 89:1078–1088PubMedGoogle Scholar
  118. Stoming TA, Stoming GS, Lanclos KD, Fei YJ, Altay C, Kutlar F, Huisman TH (1989) An A gamma type of nondeletional hereditary persistence of fetal hemoglobin with a T  →  C mutation at position −175 to the cap site of the A gamma globin gene. Blood 73:329–333PubMedGoogle Scholar
  119. Strouboulis J, Dillon N, Grosveld F (1992) Developmental regulation of a complete 70-kb human β-globin locus in transgenic mice. Genes Dev 6:1857–1864PubMedCrossRefGoogle Scholar
  120. Stuve LL, Myers RM (1990) A directly repeated sequence in the beta-globin promoter regulates transcription in murine erythroleukemia cells. Mol Cell Biol 10:972–981PubMedGoogle Scholar
  121. Superti-Furga G, Barberis A, Schaffner G, Busslinger M (1988) The −117 mutation in Greek HPFH affects the binding of three nuclear factors to the CCAAT region of the gamma-globin gene. EMBO J 7:3099–3107PubMedGoogle Scholar
  122. Tanabe O, Katsuoka F, Campbell AD, Song W, Yamamoto M, Tanimoto K, Engel JD (2002) An embryonic/fetal beta-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer. EMBO J 21:3434–3442PubMedCrossRefGoogle Scholar
  123. Thein SL (1993) Beta-thalassaemia. Baillieres Clin Haematol 6:151–175PubMedCrossRefGoogle Scholar
  124. Townes TM, Behringer RR (1990) Human globin locus activation region (LAR): role in temporal control. Trends Genet 6:219–223PubMedCrossRefGoogle Scholar
  125. Trudel M, Constantini F (1987) A 3′ enhancer contributes to the stage-specific expression of the human beta-globin gene. Genes Dev 1:954–961PubMedCrossRefGoogle Scholar
  126. Tsang AP, Visvader JE, Turner CA, Fujiwara Y, Yu C, Weiss MJ, Crossley M, Orkin SH (1997) FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell 90:109–119PubMedCrossRefGoogle Scholar
  127. Tuan DY, Solomon WB, Cavallesco R, Huang G, London IM (1989) Characterization of a human globin enhancer element. Prog Clin Biol Res 316A:63–72PubMedGoogle Scholar
  128. Ulrich MJ, Gray WJ, Ley TJ (1992) An intramolecular DNA triplex is disrupted by point mutations associated with hereditary persistence of fetal hemoglobin. J Biol Chem 267:18649–18658PubMedGoogle Scholar
  129. Vakoc CR, Letting DL, Gheldof N, Sawado T, Bender MA, Groudine M, Weiss MJ, Dekker J, Blobel GA (2005) Proximity among distant regulatory elements at the beta-globin locus requires GATA-1 and FOG-1. Mol Cell 17:453–462PubMedCrossRefGoogle Scholar
  130. Walters MC, Sullivan KM (2010) Stem-cell transplantation for sickle cell disease. N Engl J Med 362:955–956PubMedCrossRefGoogle Scholar
  131. Wood WG, Bunch C, Kelly S, Gunn Y, Breckon G (1985) Control of haemoglobin switching by a developmental clock? Nature 313:320–323PubMedCrossRefGoogle Scholar
  132. Wood WG (1993) Increased HbF in adult life. Baillieres Clin Haematol 6:177–213PubMedCrossRefGoogle Scholar
  133. Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, Raba S, Thornburg CD, Roger ZR, Kalpatthi RV, Barredo JC, Brown RC, Sarnaik SA, Howard TH, Wynn LW, Kutlar A, Armstron FD, Files BA, Goldsmith JC, Waclawiw MA, Huang X, Thompson BW, BABY HUG investigators (2011) Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 377:1663–1672PubMedCrossRefGoogle Scholar
  134. Weatherall DJ, Clegg JB (1975) The alpha-chain-termination mutants and their relation to the alpha-thalassaemias. Philos Trans R Soc Lond B Biol Sci 271:411–455PubMedCrossRefGoogle Scholar
  135. Wong C, Dowling CE, Saiki RK, Higuchi RG, Erlich HA, Kazazizn JJJR (1987) Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature 330:384–386PubMedCrossRefGoogle Scholar
  136. Yannaki E, Stamatoyannopoulos G (2010) Hematopoietic stem cell mobilization strategies for gene therapy of beta thalassemia and sickle cell disease. Ann N Y Acad Sci 1202:59–63PubMedCrossRefGoogle Scholar
  137. Yu CY, Motamed K, Chen J, Bailey AD, Shen CK (1991) The CACC box upstream of human embryonic epsilon globin gene binds Sp1 and is a functional promoter element in vitro and in vivo. J Biol Chem 266:8907–8915PubMedGoogle Scholar
  138. Zhang P, Basu P, Redmond LC, Morris PE, Rupon JW, Ginder GD, Lloyd JA (2005) A functional screen for Krüppel-like factors that regulate the human gamma-globin gene through the CACCC promoter element. Blood Cells Mol Dis 35:227–235PubMedCrossRefGoogle Scholar
  139. Zhao Q, Cumming H, Cerruti L, Cunningham JM, Jane SM (2004) Site-specific acetylation of the fetal globin activator NF-E4 prevents its ubiquitination and regulates its interaction with the histone deacetylase, HDAC1. J Biol Chem 279:41477–41486PubMedCrossRefGoogle Scholar
  140. Zhou D, Liu K, Sun CW, Pawlik KM, Townes TM (2010) KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genetic 42:742–744CrossRefGoogle Scholar
  141. Zimmerman SA, Schultz WH, Davis JS, Pickens CV, Mortier NA, Howard TA (2004) Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood 103:2039–2045PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Georgia’s Health Sciences UniversityAugustaUSA

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