Regulation of β-globin gene expression: Straightening out the locus

Current Opinion in Genetics and Development

Volumn 6, Issue 4, 1996, Pages 488-495

  Martin, David I K ^a   Fiering, Steven ^a   Groudine, Mark ^a  

^a UNIVERSITY OF WASHINGTON   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA GLOBIN;

DEVELOPMENTAL GENETICS; GENE CONTROL; GENE EXPRESSION REGULATION; GENE LOCATION; GENE LOCUS; GENETIC TRANSCRIPTION; GLOBIN GENE; NONHUMAN; PRIORITY JOURNAL; REVIEW;

EID: 0030219342     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(96)80072-4     Document Type: Article

References (65)

1. 1. Stamatoyannopoulos G, Nienhuis A: Hemoglobin switching. In The Molecular Basis of Blood Diseases. Edited by Stamatoyannopoulos G. Philadelphia: WB Saunders; 1994:107-156.
2. 2. Weatherall DJ: The thalassemias. In The Molecular Basis of Blood Diseases. Edited by Stamatoyannopoulos G. Philadelphia: WB Saunders; 1994:157-206.
3. 3. Forrester WC, Thompson C, Elder JT, Groudine M: A developmentally stable chromatin structure in the human β-globin gene cluster. Proc Natl Acad Sci USA 1986, 83:1359-1363.
4. 4. Tuan D, Solomon W, Li Q, London IM: The β-like-globin gene domain in human erythroid cells. Proc Natl Acad Sci USA 1985, 82:6384-6388.
5. 5. Driscoll C, Dobkin CS, Alter BP: γδβ thalassemia due to a de novo mutation deleting the 5′ β-globin locus activating region hypersensitive sites. Proc Natl Acad Sci USA 1989, 86:7470-7474.
6. 6. Forrester WC, Epner E, Driscoll MC, Enver T, Brice M, Papayannopoulou T, Groudine M: A deletion of the human β-globin locus control region causes a major alteration in chromatin structure and replication across the entire β-globin locus. Genes Dev 1990, 4:1637-1649.
7. 7. Kioussis D, Vanin E, DeLange T, Flavell RA, Grosveld FG: β-globin gene inactivation by DNA translocation in γβ-thalassemia. Nature 1983, 306:662-666.
8. 8. Aladjem MI, Groudine M, Brody LL, Dieken ES, Fournier REK, Wahl GM, Epner EM: Participation of the human β-globin locus control region in initiation of DNA replication. Science 1995, 270:815-819.
9. 9. Magram J, Chada K, Costantini F: Developmental regulation of a cloned adult β-gobin gene in transgenic mice. Nature 1985, 315:338-340.
10. 10. Townes TM, Lingrel JB, Chen HY, Brinster RL, Palmiter RD: Erythroid-specific expression of human β-globin genes in transgenic mice. EMBO J 1985, 4:1715-1723.
11. 11. Grosveld F, Assendelft GBV, Greaves D, Kollias G: Position-independent, high-level expression of the human β-globin gene in transgenic mice. Cell 1987, 51:975-985.
12. 12. Evans T, Felsenfeld G, Reitman M: Control of globin gene transcription. Annu Rev Cell Biol 1 990, 6:95-124.
13. 13. Moon AM, Ley TJ: Conservation of the primary structure, organization, and function of the human and mouse β-globin locus-activating regions. Proc Natl Acad Sci USA 1990, 87:7693-7697.
14. 14. Forrester WC, Novak U, Gelinas R, Groudine M: Molecular analysis of the human β-globin locus activation region. Proc Natl Acad Sci USA 1989, 86:5439-5443.
15. 15. Ryan TM, Behringer RR, Martin NC, Townes TM, Palmiter RD, Brinster RL: A single erythroid-specific DNase I superhypersensitive site activates high levels of human β-globin gene expression in transgenic mice. Genes Dev 1989, 3:314-323.
16. 16. Tuan DH, Solomon WB, London IM, Lee DP: An erythroid-specific, developmental-stage-independent enhancer far upstream of the human 'β-like globin' genes, Proc Natl Acad Sci USA 1989, 86:2554-2558.
17. 17. Tuan D, Abeliovich A, Lee-Oldham M, Lee D: Identification of regulatory elements of human β-like globin genes. In Developmental Control of Globin Gene Expression. Edited by Stamatoyannopoulos G, Nienhuis AW. New York: Alan R Liss Inc.; 1987:211-220.
18. 18. Fraser P, Hurst J, Collis P, Grosveld F: DNasel hypersenstive sites 1,2,3 of the human β-globin dominant control region direct position-independent expression. Nucleic Acids Res 1990, 18:3503-3508.
19. 19. Collis P, Antoniou M, Grosveld F: Definition of the minimal requirements within the human β-globin gene and the dominant control region for high level expression. EMBO J 1990, 9:233-240.
20. 20. Fraser P, Pruzina S, Antoniou M, Gosveld F: Each hypersensitive site of the human β-globin locus control region confers a different developmental pattern of expression on the globin genes. Genes Dev 1993, 7:106-113.
21. 21. Fiering S, Epner E, Robinson K, Zhuang Y, Telling A, Hu M, Martin DIK, Enver T, Ley T, Groudine M: Targeted deletion of 5′HS2 of the murine β-globin locus reveals that it is not essential for proper regulation of the β-globin locus. Genes Dev 1995, 9:2203-2213. The targeted deletion of 5′HS2 from the mouse β-globin LCR has no significant effect on the developmental regulation, and only a slight effect on the overall expression, of genes in the locus. The authors discuss these results in the context of the model in which the multiple factor binding sites in the LCR alter the topology of the locus and suggest that deletion of any one 5′HS may not delete sufficient numbers of such sites to alter the topology.
22. 22. Hug B, Wesselschmidt RL, Fiering S, Bender MA, Groudine M, Ley TJ: Analysis of mice containing a targeted deletion of the β-globin locus control region 5′HS-3. Mol Cell Biol 1996, 16:2906-2912. The targeted deletion of 5′HS3 from the murine β-globin locus produces results very similar to those described in [21•] and are interpreted as showing that 5′HS3 is not required for globin switching but is responsible for ∼30% of the activity of the β-globin gene in adult erythrocytes.
23. 23. Gaensler KML, Burmeister M, Brownstein BH, Taillon-Miller P, Myers RM: Physical mapping of yeast artificial chromosomes containing sequences from the human β-globin gene region. Genomics 1991, 10:976-984.
24. 24. Bungert J, Dave U, Lim K-C, Lieuw KH, Shavit JA, Liu Q, Engel JD: Synergistic regulation of human β-globin gene switching by locus control region elements HS3 and HS4. Genes Dev 1995, 9:3083-3096. This transgenic study describes the consequences of deleting the core regions of 5′HS3 and 5′HS4 from the human β-globin gene locus YAC. Deletion of either of these HS cores results in the failure to express any of the globin genes at any developmental stage. The authors interpret these results as indicating that the LCR functions as a cooperative unit.
25. 25. Peterson KR, Clegg CH, Navas PA, Norton EJ, Kimbrough TG, Stamatoyannopoulos G: Effect of deletion of 5′HS3 or 5′HS2 of the human β-globin LCR on the developmental regulation of globin gene expression in β-YAC transgenic mice. Proc Natl Acad Sci USA 1996, 93:6605-6609. The authors make larger deletions of 5′HS3 or 5′HS2 than those described in [23] and find that expression occurs at all developmental stages. Deletion of 5′HS2 reduces expression at all developmental stages and deletion of 5′HS3 reduces expression of the ε-globin gene preferentially.
26. 26. Orkin SH: Regulation of globin gene expression in erythroid cells. Eur J Biochem 1995, 231:271-281.
27. 27. Engel JD: Developmental regulation of human β-globin gene transcription: a switch of loyalties. Trends Genet 1993, 9:304-309.
28. 28. Behringer RR, Hammer RE, Brinster RL, Townes TM: Human γ to β-globin switching in transgenic mice. Genes Dev 1990, 4:380-389.
29. 29. Enver T, Raich N, Ebens AJ, Papayannopoulou T, Costantini F, Stamatoyannopoulos G: Developmental regulation of human fetal-to-adult globin gene switching in transgenic mice. Nature 1990, 344:309-313.
30. 30. Starck J, Sarkar R, Romana M, Bhargava A, Scarpa AL, Tanaka M, Chamberlain JW, Weissman SM, Forget BG: Developmental regulation of human γ-and β-globin genes in the absence of the locus control region. Blood 1994, 84:1656-1665.
31. 31. Peterson KR, Stamatoyannopoulos G: Role of gene order in developmental control of human γ-and β-globin synthesis. Mol Cell Biol 1993, 13:4836-4843.
32. 32. Hanscombe O, Whyatt D, Fraser P, Yannoutsos N, Greaves D, Dillon N, Grosveld F: Importance of globin gene order for correct developmental expression. Genes Dev 1991, 5:1387-1394.
33. 33. Huisman THJ, Harris H, Gravely M: The chemical heterogeneity of the fetal hemoglobin in normal new-born infants and in adults. Mol Cell Biochem 1977, 17:45-55.
34. 34. Groudine M, Weintraub H: Propagation of globin DNAasel-hypersensitive sites in absence of factors required for induction: a possible mechanism for determination. Cell 1982, 30:131-139.
35. 35. Stanworth SJ, Roberts NA, Sharpe JA, Sloane-Stanley JA, Wood WG: Established epigenetic modifications determine the expression of developmentally regulated gfobin genes in somatic cell hybrids. Mol Cell Biol 1995, 15:3969-3978. Globin gene switching is studied using somatic cell hybrids between transgenic mouse erythroblasts and murine erythroleukemia (MEL) cells; MEL cells maintain an adult program of globin expression. The study found that expression in the hybrids reflected the developmental stage of the erythroblasts and was not sensitive to the adult-stage MEL environment. Regardless of the developmental stage of the erythroblasts, switching to β-globin expression occurred in 10-40 weeks, suggesting that it was not driven by a developmental clock. Use of irradiated erythroblasts as donors also leads the authors to conclude that transcription factors expressed by the erythroblasts are not necessary for maintenance of the program of expression. The authors interpret their results as suggesting that the locus is established in a stable conformation that is maintained through multiple rounds of replication and is not sensitive to changes in the transcription factor environment.
36. 36. Pirrotta V: Chromatin complexes regulating gene expression in Drosophila. Curr Opin Genet Dev 1995, 5:466-472.
37. 37. Wijgerde M, Grosveld F, Fraser P: Transcription complex stability and chromatin dynamics in vivo. Nature 1995, 377:209-213. Fluorescent in situ hybridization analysis was used to study primary human globin transcripts in transgenic mouse erythroblasts; the transgenic construct was a 70kb cosmid consisting of the gene cluster with the LCR. In many erythroblasts, primary transcripts from two genes within the same locus were visible. This is compatible with the view that a single globin locus can transcribe multiple genes simultaneously. The authors interpret their finding in the context of a model in which the LCR acts as a holocomplex that interacts directly with promoters to regulate transcription. The finding of multiple transcribed genes within a locus is explained by a rapid flip-flop of the LCR between promoters, so that simultaneous transcription is only apparent. The result is also compatible, however, with a model in which the role of the LCR is to establish and maintain an active locus, with genes in the locus having independent probabilities of being expressed, so that in some loci more than one gene (and possibly more than two) will be transcribed at once. No construct lacking the LCR (like that in [29]) was tested.
38. 38. Forrester WC, Takegawa S, Papayannopoulou T, Stamatoyannopoulos G, Groudine M: Evidence for a locus activation region: the formation of developmentally stable hypersensitive sites in globin-expressing hybrids. Nucleic Acids Res 1987, 15:10159-10177.
39. 39. Groudine M, Kohwi-Shigetmatsu T, Gelinas R, Stamatoyannopoulos G, Papayannopoulou T: Human fetal to adult hemoglobin switching: changes in chromatin structure of the β-globin gene locus. Proc Natl Acad Sci USA 1983, 80:7551-7555.
40. 40. Moon AM, Ley TJ: Functional properties of the β-globin locus control region in K562 erythroleukemia cells. Blood 1991, 77:2272-2284.
41. 41. Moreau P, Hen R, Wasylyk B, Everett R, Gaub MP, Chambon P: The SV40 72 base pair repeat has a striking effect on gene expression both in SV40 and in other chimeric recombinants. Nucliec Acids Res 1981, 9:6047-6068.
42. 42. Walters MC, Fiering S, Eidemiller J, Magis W, Groudine M, Martin DIK: Enhancers increase the probability but not the level of gene expression. Proc Natl Acad Sci USA 1995, 92:7125-7129.
43. 43. Weintraub H: Formation of stable transcriptional complexes as assayed by analysis of individual templates. Proc Natl Acad Sci USA 1988, 85:5819-5823.
44. 44. Walters MC, Magis W, Fiering S, Eidemiller J, Scalzo D, Groudine M, Martin DIK: Transcriptional enhancers act in cis to suppress position-effect variegation. Genes Dev 1996, 10:185-195. This is a study of the human β-globin LCR element 5′HS2, using a system that separately analyzes effects on the level of expression and effects on epigenetic stability. 5′HS2 was chosen because it had been characterized extensively as a classical enhancer. The site-specific recombinase flp was used to delete 5′HS2 from a reporter construct integrated stably in an erythroleukemia cell line. Deletion of 5′HS2 had only a small effect (less than two-fold) on expression level but increased markedly the rate at which expression was silenced. In the same study, induction of a metal-responsive enhancer prevented silencing but had no effect on the level of reporter gene expression. The results are interpreted as demonstrating that enhancers do not directly regulate transcription rate but instead create domains within which promoter activity is permitted.
45. 45. Stamatoyannopoulos G, Josephson B, Zhang JW, Li Q: Developmental regulation of human γ-globin genes in transgenic mice. Mol Cell Biol 1993, 13:7636-7644.
46. 46. Robertson G, Garrick D, Wenlian W, Kearns M, Martin DIK, Whitelaw E: Position-dependent variegation of globin transgene expression in mice. Proc Natl Acad Sci USA 1995, 92:5371-5375. This study used a LacZ transgene driven by a globin promoter and enhancer, permitting staining for β-galactosidase and examination of individual erythrocytes. The globin transgenes used in previous transgenic studies were assayed by RNase protection of blood lysates, which provides an average level of expression for the entire population of cells. This study found that, in every transgenic line, expression of β-galactosidase was heterocellular and that within a transgenic line individual mice had the same percentage of expressing cells; differences in total β-gal expression between lines made with the same transgene were caused almost entirely by differences in the percentage of expressing erythrocytes. The authors compare this phenomenon to position effect variegation.
47. 47. Enver T, Li Q, Gale K, Hu M, May G, Karlinsey J, Jimenez G, Papayannopoulou T, Costantini F: Analysis of the developmental and transcriptional potentiation functions of 5′HS2 of the murine β-globin locus control region in transgenic mice. Dev Biol 1994, 165:574-584.
48. 48. Festenstein R, Tolaini M, Corbella P, Mamalaki C, Parrington J, Fox M, Miliou A, Jones M, Kioussis D: Locus control region function and heterochromatin-induced position effect variegation. Science 1996, 271:1123-1125. Variegated expression of a human CD2 transgene in murine T cells is studied. The authors find that this variegation may be related to integration near pericentric heterochromatin and is suppressed by inclusion in the transgene of a DNasel HS from the CD2 gene. The HS does not act as an enhancer in transient assays, leading the authors to propose that the suppression of variegation is an LCR function. Enhancers, however, also suppress variegation (see [43,47]).
49. 49. Ptashne M: Gene regulation by proteins acting nearby and at a distance. Nature 1986, 322:697-701.
50. 50. Darnell J, Lodish H, Baltimore D: Molecular Cell Biology. New York: Scientific American Books; 1990.
51. 51. Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD: Molecular Biology of the Cell. New York and London: Garland Publishing Inc.; 1994.
52. 52. Muller H-P, Sogo JM, Schaffner W: An enhancer stimulates transcription in trans when attached to the promoter via a protein bridge. Cell 1989, 58:767-777.
53. 53. Jane SM, Ney PA, Vanin EF, Gumucio DL, Nienhuis AW: Identification of a stage selector element in the human gamma-globin gene promoter that fosters preferential interaction with the 5′HS2 enhancer when in competition with the β-promoter. EMBO J 1992, 11:2961-2969.
54. 54. Choi OR, Engel JD: Developmental regulation of β-globin gene switching. Cell 1988, 55:17-26.
55. 55. Bonanou-Tzedaki SA, Arnstein HRV: Macromolecular synthesis and degradation during terminal erythroid cell development. 1987, 46:121-149.
56. 56. Robertson G, Garrick D, Wilson M, Martin D, Whitelaw E: Age-dependent silencing of globin transgene expresion in the mouse. Nucleic Acids Res 1996, 24:1465-1471.
57. 57. Rees MI, Worwood M, Thompson PW, Gillbertson C, May A: Red cell dimorphism in a young man with a constitutional translocation t(11;22)(p15.5;q11.21). Br J Haematol 1994, 87:386-395.
58. 58. Weintraub H, Cheng PF, Conrad K: Expression of transfected DNA depends on DNA topology. Cell 1986, 46:115-122.
59. 59. Pruitt SC, Reeder RH: Effect of topological constraint on transcription of ribosomal DNA in Xenopus oocytes. J Mol Biol 1984, 174:121-139.
60. 60. Dunaway M, Ostrander E: Local domains of supercoiling activate a eukaryotic promoter in vivo. Nature 1993, 361:746-748.
61. 61. Ciejek EM, Tsai MJ, O'Malley B: Actively transcribed genes are associated with the nuclear matrix. Nature 1983, 306:607-609.
62. 62. Robinson SI, Small D, Idzerda R, McKnight GS, Vogelstein B: The association of transcriptionally active genes with the nuclear matrix of the chicken oviduct. Nucleic Acids Res 1983, 11:5113-5130.
63. 63. Gerdes MG, Carter KC, Moen PT, Lawrence JB: Dynamic changes in the higher-level chromatin organization of specific sequences revealed by in situ hybridization to nuclear halos. J Cell Biol 1994, 126:289-304.
64. 64. Stadler J, Groudine M, Dodgson JB, Engel JD, Weintraub H: Hb switching in chickens. Cell 1980, 19:973-980.
65. 65. Groudine M, Peretz M, Weintraub H: The structure and expression of globin chromatin during haematopoesis in the chicken embryo. In Organization and Expression of Globin Genes. Edited by Stamatoyannopoulos G, Nienhuis AW. New York: Alan R Liss Inc.; 1987:211-220.