Molecular and Cellular Basis of Hemoglobin Switching

doi:10.1017/CBO9780511596582.009

5 - Molecular and Cellular Basis of Hemoglobin Switching

from SECTION ONE - THE MOLECULAR, CELLULAR, AND GENETIC BASIS OF HEMOGLOBIN DISORDERS

Published online by Cambridge University Press: 03 May 2010

Martin H. Steinberg ,

Bernard G. Forget ,

Douglas R. Higgs and

David J. Weatherall

George Stamatoyannopoulos ,

Patrick A. Navas and

Qiliang Li

Show author details

Martin H. Steinberg: Affiliation:
Boston University
Bernard G. Forget: Affiliation:
Yale University, Connecticut
Douglas R. Higgs: Affiliation:
MRC Institute of Molecular Medicine, University of Oxford
David J. Weatherall: Affiliation:
Albert Einstein College of Medicine, New York

Book contents

Get access

Summary

INTRODUCTION

Hemoglobin switching is characteristic of all animal species that use hemoglobin for oxygen transport. Most species have only one switch, from embryonic to adult globin formation. Humans and a few other mammals have two globin gene switches, from embryonic to fetal globin coinciding with the transition from embryonic (yolk sac) to definitive (fetal liver) hematopoiesis and from fetal to adult globin formation, occurring around the perinatal period (Fig. 5.1; see Chapters 1 and 2). The switch from ε- to γ-globin production begins very early in gestation, as fetal hemoglobin (HbF) is readily detected in 5-week-old human embryos, and it is completed well before the 10th week of gestation. β-globin expression starts early in human development, and small amounts of adult hemoglobin (HbA) have been detected by biosynthetic or immunochemical methods even in the smallest human fetuses studied. In these fetuses γ- and β-globins are present in the same fetal red cells. β-chain synthesis increases to approximately 10% of total hemoglobin by 30–35 weeks of gestation. At birth, HbF comprises 60%–80% of the total hemoglobin. It takes approximately 2 years to reach the level of 0.5%–1% HbF that is characteristic of adult red cells. HbF in the adult is restricted to a few erythrocytes called “F cells” (see chapter 7). Approximately 3%–7% of erythrocytes are F cells and each contains approximately 4–8 pg of HbF.

Hemoglobin switching has been the target of intensive investigation for two reasons.

Information

Type: Chapter
Information: Disorders of Hemoglobin
Genetics, Pathophysiology, and Clinical Management
, pp. 86 - 100

DOI: https://doi.org/10.1017/CBO9780511596582.009 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Huehns, ER, Dance, N, Beaven, GH, Keil, JV, Hecht, F, Motulsky, AG. Human embryonic haemoglobins. Nature. 1964;201:1095–1097.CrossRef Google Scholar PubMed

Hecht, F, Motulsky, AG, Lemire, RJ, Shepard, TE. Predominance of hemoglobin Gower 1 in early human embryonic development. Science. 1966;152:91–92.CrossRef Google Scholar PubMed

Gale, RE, Clegg, JB, Huehns, ER. Human embryonic haemoglobins Gower 1 and Gower 2. Nature. 1979;280:162–164.CrossRef Google Scholar PubMed

Papayannopoulou, T, Shepard, TH, Stamatoyannopoulos G. Studies of hemoglobin expression in erythroid cells of early human fetuses using antiγ- and anti-β-globin chain fluorescent antibodies. Prog Clin Biol Res. 1983;134:421–430.Google Scholar

Boyer, SH, Belding, TK, Margolet, L, Noyes, AN. Fetal hemoglobin restriction to a few erythrocytes (F cells) in normal human adults. Science. 1975;188:361–363.CrossRef Google Scholar

Wood, WG, Stamatoyannopoulos, G, Lim, G, Nute, PE. F-cells in the adult: normal values and levels in individuals with hereditary and acquired elevations of Hb F. Blood. 1975;46:671–682.Google Scholar PubMed

Ingram, VM. Embryonic red blood cell formation. Nature. 1972;235:338–339.CrossRef Google Scholar PubMed

Weatherall, DJ, Edwards, JA, Donohoe, WT. Haemoglobin and red cell enzyme changes in juvenile myeloid leukaemia. Br Med J. 1968;1:679–681.CrossRef Google Scholar PubMed

Weatherall, DJ, Clegg, JB, Wood, WG. A model for the persistence or reactivation of fetal haemoglobin production. Lancet. 1976;2:660–663.CrossRef Google Scholar PubMed

Alter, BP, Rappeport, JM, Huisman, TH, Schroeder, WA, Nathan, DG. Fetal erythropoiesis following bone marrow transplantation. Blood. 1976;48:843–853.Google Scholar PubMed

Alter, BP, Jackson, BT, Lipton, JM, et al. Control of the simian fetal hemoglobin switch at the progenitor cell level. J Clin Invest. 1981;67:458–466.CrossRef Google Scholar PubMed

Alter, BP, Jackson, BT, Lipton, JM, et al. Three classes of erythroid progenitors that regulate hemoglobin synthesis during ontogeny in the primate. In: Stamatoyannopoulos, G, Nienhuis, AW, eds. Hemoglobins in Development and Differentiation. New York: Alan R. Liss; 1981:331–340.Google Scholar

Papayannopoulou, T, Brice, M, Stamatoyannopoulos, G. Hemoglobin F synthesis in vitro: evidence for control at the level of primitive erythroid stem cells. Proc Natl Acad Sci USA.1977;74:2923–2927.CrossRef Google Scholar PubMed

Chapman, BS, Tobin, AJ. Distribution of developmentally regulated hemoglobins in embryonic erythroid populations. Dev Biol. 1979;69:375–387.CrossRef Google Scholar PubMed

Brotherton, TW, Chui, DH, Gauldie, J, Patterson, M.Hemoglobin ontogeny during normal mouse fetal development. Proc Natl Acad Sci USA. 1979;76:2853–2857.CrossRef Google Scholar PubMed

Douarin, N. Ontogeny of hematopoietic organs studied in avian embryo interspecific chimeras. In: Clarkson, BMarks, P, Till, J, eds. Differentiation in Normal and Neoplastic Hemopoietic Cells. New York: Cold Spring Harbor; 1978:5–31.Google Scholar

Beaupain, D, Martin, C, Dieterlen-Lievre, F. Origin and evolution of hemopoietic stem cells in the avian embryo. In: Stamatoyannopoulos, G, Nienhuis, AW, eds. Hemoglobins in Development and Differentiation. New York: Alan R. Liss; 1981:161–169.Google Scholar

Peschle, C, Migliaccio, AR, Migliaccio, G, et al. Embryonic–Fetal Hb switch in humans: studies on erythroid bursts generated by embryonic progenitors from yolk sac and liver. Proc Natl Acad Sci USA. 1984;81:2416–2420.CrossRef Google Scholar PubMed

Stamatoyannopoulos, G, Constantoulakis, P, Brice, M, Kurachi, S, Papayannopoulou, T. Coexpression of embryonic, fetal, and adult globins in erythroid cells of human embryos: relevance to the cell-lineage models of globin switching. Dev Biol. 1987;123:191–197.CrossRef Google Scholar PubMed

Stamatoyannopoulos, G, Grosveld, F. Hemoglobin switching. In: Stamatoyannopoulos, G, Majerus, P, Perlmutter, R, Varmus, H, eds. The Molecular Basis of Blood Diseases. 3rd ed. Philadelphia: W.B. Saunders Co.; 2001:135–182.Google Scholar

Papayannopoulou, T, Brice, MStamatoyannopoulos, G. Analysis of human hemoglobin switching in MEL × human fetal erythroid cell hybrids. Cell. 1986;46:469–476.CrossRef Google Scholar PubMed

Wintour, EM, Smith, MB, Bell, RJ, McDougall, JG, Cauchi, MN. The role of fetal adrenal hormones in the switch from fetal to adult globin synthesis in the sheep. J Endocrinol. 1985;104:165–170.CrossRef Google Scholar PubMed

Zitnik, G, Li, Q, Stamatoyannopoulos, G, Papayannopoulou, T. Serum factors can modulate the developmental clock of γ- to β-globin gene switching in somatic cell hybrids. Mol Cell Biol. 1993;13:4844–4851.CrossRef Google Scholar PubMed

Zitnik, G, Peterson, K, Stamatoyannopoulos, G, Papayannopoulou, T. Effects of butyrate and glucocorticoids on γ- to β-globin gene switching in somatic cell hybrids. Mol Cell Biol. 1995;15:790–795.CrossRef Google Scholar PubMed

Della Torre, L, Meroni, P. [Studies of fetal blood. I. Fetal and adult hemoglobin levels in normal pregnancy. Relation to fetal maturity]. Ann Ostet Ginecol Med Perinat. 1969;91:148–157.Google Scholar

Bard, H, Makowski, EL, Meschia, G, Battaglia, FC. The relative rates of synthesis of hemoglobins A and F in immature red cells of newborn infants. Pediatrics. 1970;45:766–772.Google Scholar

Zanjani, ED, Lim, G, McGlave, PB, et al. Adult haematopoietic cells transplanted to sheep fetuses continue to produce adult globins. Nature. 1982;295:244–246.CrossRef Google Scholar PubMed

Wood, WG, Bunch, C, Kelly, S, Gunn, Y, Breckon, G. Control of haemoglobin switching by a developmental clock?Nature. 1985;313:320–323.CrossRef Google Scholar PubMed

Holliday, R, Pugh, JE. DNA modification mechanisms and gene activity during development. Science. 1975;187:226–232.CrossRef Google Scholar PubMed

Melis, M, Demopulos, G, Najfeld, V, et al. A chromosome 11-linked determinant controls fetal globin expression and the fetal-to-adult globin switch. Proc Natl Acad Sci USA. 1987;84:8105–8109.CrossRef Google Scholar PubMed

Stanworth, SJ, Roberts, NA, Sharpe, JA, Sloane-Stanley, JA, Wood, WG. Established epigenetic modifications determine the expression of developmentally regulated globin genes in somatic cell hybrids. Mol Cell Biol. 1995;15:3969–3978.CrossRef Google Scholar PubMed

Gong, Q, Dean, A. Enhancer-dependent transcription of the ε-globin promoter requires promoter-bound GATA-1 and enhancer-bound AP-1/NF-E2. Mol Cell Biol. 1993;13: 911–917.CrossRef Google Scholar PubMed

Gong, QH, Stern, J, Dean, A. Transcriptional role of a conserved GATA-1 site in the human ε-globin gene promoter. Mol Cell Biol. 1991;11:2558–2566.CrossRef Google Scholar PubMed

Walters, M, Martin, DI. Functional erythroid promoters created by interaction of the transcription factor GATA-1 with CACCC and AP-1/NFE-2 elements. Proc Natl Acad Sci USA. 1992;89:10444–10448.CrossRef Google Scholar PubMed

Filipe, A, Li, Q, Deveaux, S, et al. Regulation of embryonic/fetal globin genes by nuclear hormone receptors: a novel perspective on hemoglobin switching. EMBO J. 1999;18:687–697.CrossRef Google Scholar PubMed

Yu, CY, Motamed, K, Chen, J, Bailey, AD, Shen, CK. The CACC box upstream of human embryonic ε globin gene binds Sp1 and is a functional promoter element in vitro and in vivo. J Biol Chem. 1991;266:8907–8915.Google Scholar PubMed

Marin, M, Karis, A, Visser, P, Grosveld, F, Philipsen, S. Transcription factor Sp1 is essential for early embryonic development but dispensable for cell growth and differentiation. Cell. 1997;89:619–628.CrossRef Google Scholar PubMed

Asano, H, Li, XS, Stamatoyannopoulos, G. FKLF, a novel Kruppel-like factor that activates human embryonic and fetal β-like globin genes. Mol Cell Biol. 1999;19:3571–3579.CrossRef Google Scholar PubMed

Asano, H, Li, XS, Stamatoyannopoulos, G. FKLF-2: a novel Kruppel-like transcriptional factor that activates globin and other erythroid lineage genes. Blood. 2000;95:3578–3584.Google Scholar PubMed

Tanimoto, K, Liu, Q, Grosveld, F, Bungert, J, Engel, JD. Context-dependent EKLF responsiveness defines the developmental specificity of the human ε-globin gene in erythroid cells of YAC transgenic mice. Genes Dev. 2000;14:2778–2794.CrossRef Google Scholar PubMed

Tanabe, O, Katsuoka, F, Campbell, AD, et al. An embryonic/fetal β-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer. EMBO J. 2002;21:3434–3442.CrossRef Google Scholar PubMed

Tanabe, O, McPhee, D, Kobayashi, S, et al. Embryonic and fetal β-globin gene repression by the orphan nuclear receptors, TR2 and TR4. EMBO J. 2007;26:2295–2306.CrossRef Google Scholar PubMed

Raich, N, Clegg, CH, Grofti, J, Romeo, PH, Stamatoyannopoulos, G. GATA1 and YY1 are developmental repressors of the human ε-globin gene. EMBO J. 1995;14:801–809.Google Scholar PubMed

Li, J, Noguchi, CT, Miller, W, Hardison, R, Schechter, AN. Multiple regulatory elements in the 5′-flanking sequence of the human ε-globin gene. J Biol Chem. 1998;273:10202–10209.CrossRef Google Scholar PubMed

Trepicchio, WL, Dyer, MA, Baron, MH. Developmental regulation of the human embryonic β-like globin gene is mediated by synergistic interactions among multiple tissue- and stage-specific elements. Mol Cell Biol. 1993;13:7457–7468.CrossRef Google Scholar PubMed

Yi, Z, Cohen-Barak, O, Hagiwara, N, et al. Sox6 directly silences ε globin expression in definitive erythropoiesis. PLoS Genet. 2006;2:e14.CrossRef Google Scholar PubMed

Cohen-Barak, O, Erickson, DT, Badowski, MS, et al. Stem cell transplantation demonstrates that Sox6 represses εy globin expression in definitive erythropoiesis of adult mice. Exp Hematol. 2007;35:358–367.CrossRef Google Scholar

Gumucio, DL, Heilstedt-Williamson, H, Gray, TA, et al. Phylogenetic footprinting reveals a nuclear protein which binds to silencer sequences in the human γ and ε globin genes. Mol Cell Biol. 1992;12:4919–4929CrossRef Google Scholar PubMed

Jane, SM, Ney, PA, Vanin, EF, Gumucio, DL, Nienhuis, AW. Identification of a stage selector element in the human γ-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.Google Scholar PubMed

Jane, SM, Gumucio, DL, Ney, PA, Cunningham, JM, Nienhuis, AW. Methylation-enhanced binding of Sp1 to the stage selector element of the human γ-globin gene promoter may regulate development specificity of expression. Mol Cell Biol. 1993;13:3272–3281.CrossRef Google Scholar

Jane, SM, Nienhuis, AW, Cunningham, JM. 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. 1995;14:97–105.Google Scholar

Zhou, WL, Clouston, X, Wang, L, Cerruti, J, Cunningham, JM, Jane, SM. Isolation and characteriztion of human NF-E4, the tissue restricted component of the stage selector protein complex. Blood. 1999;94(Suppl 1):614a.Google Scholar

Gumucio, DL, Rood, KL, Gray, TA, Riordan, MF, Sartor, CI, Collins, FS. Nuclear proteins that bind the human γ-globin gene promoter: alterations in binding produced by point mutations associated with hereditary persistence of fetal hemoglobin. Mol Cell Biol. 1988;8:5310–5322.CrossRef Google Scholar PubMed

Mantovani, R, Malgaretti, N, Nicolis, S, Ronchi, A, Giglioni, B, Ottolenghi, S. The effects of HPFH mutations in the human γ-globin promoter on binding of ubiquitous and erythroid specific nuclear factors. Nucl Acids Res. 1988;16:7783–7797.CrossRef Google Scholar PubMed

Mantovani, R, Superti-Furga, G, Gilman, J, Ottolenghi, S. The deletion of the distal CCAAT box region of the A γ-globin gene in black HPFH abolishes the binding of the erythroid specific protein NFE3 and of the CCAAT displacement protein. Nucl Acids Res. 1989;17:6681–6691.CrossRef Google Scholar PubMed

Fucharoen, S, Shimizu, K, Fukumaki, Y. A novel C-T transition within the distal CCAAT motif of the G γ-globin gene in the Japanese HPFH: implication of factor binding in elevated fetal globin expression. Nucl Acids Res. 1990;18:5245–5253.CrossRef Google Scholar

McDonagh, K, Nienhuis, AW. Induction of the human γ-globin gene promoter in K562 cells by sodium butyrate: Reversal of repression by CCAAT displacement protein. Blood. 1991;78:255a.Google Scholar

Berry, M, Grosveld, F, Dillon, N. A single point mutation is the cause of the Greek form of hereditary persistence of fetal haemoglobin. Nature. 1992;358:499–502.CrossRef Google Scholar PubMed

Skalnik, DG, Strauss, EC, Orkin, SH. CCAAT displacement protein as a repressor of the myelomonocytic-specific gp91-phox gene promoter. J Biol Chem. 1991;266:16736–16744.Google Scholar PubMed

Ronchi, AE, Bottardi, S, Mazzucchelli, C, Ottolenghi, S, Santoro, C. Differential binding of the NFE3 and CP1/NFY transcription factors to the human γ- and ε-globin CCAAT boxes. J Biol Chem. 1995;270:21934–21941.CrossRef Google Scholar PubMed

Ronchi, A, Berry, M, Raguz, S, et al. Role of the duplicated CCAAT box region in γ-globin gene regulation and hereditary persistence of fetal haemoglobin. EMBO J. 1996;15:143–149.Google Scholar PubMed

Li, Q, Fang, X, Olave, I, et al. Transcriptional potential of the γ-globin gene is dependent on the CACCC box in a developmental stage-specific manner. Nucl Acids Res. 2006;34:3909–3916.CrossRef Google Scholar

McDonagh, KT, Lin, HJ, Lowrey, CH, Bodine, DM, Nienhuis, AW. The upstream region of the human γ-globin gene promoter. Identification and functional analysis of nuclear protein binding sites. J Biol Chem. 1991;266:11965–11974.Google Scholar PubMed

Magis, W, Martin, DI. HMG-I binds to GATA motifs: implications for an HPFH syndrome. Biochem Biophys Res Commun. 1995;214:927–933.CrossRef Google Scholar PubMed

Ulrich, MJ, Gray, WJ, Ley, TJ. An intramolecular DNA triplex is disrupted by point mutations associated with hereditary persistence of fetal hemoglobin. J Biol Chem. 1992;267:18649–18658.Google Scholar PubMed

Bacolla, A, Ulrich, MJ, Larson, JE, Ley, TJ, Wells, RD. An intramolecular triplex in the human γ-globin 5′-flanking region is altered by point mutations associated with hereditary persistence of fetal hemoglobin. J Biol Chem. 1995;270: 24556–24563.CrossRef Google Scholar PubMed

Ponce, E, Lloyd, JA, Pierani, A, Roeder RG, Lingrel JB. Transcription factor OTF-1 interacts with two distinct DNA elements in the A γ-globin gene promoter. Biochemistry. 1991;30:2961–2967.CrossRef Google Scholar PubMed

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.CrossRef Google Scholar PubMed

Pace, BS, Li, Q, Stamatoyannopoulos G. In vivo search for butyrate responsive sequences using transgenic mice carrying A γ gene promoter mutants. Blood. 1996;88:1079–1083.Google Scholar PubMed

Luo, HY, Mang, D, Patrinos, GP, et al. A mutation in a GATA-1 binding site 5' to the Gγ-globin gene (nt -567, T>G) may be associated with increased levels of fetal hemoglobin. Blood. 2004;104:500.G) may be associated with increased levels of fetal hemoglobin' href=https://scholar.google.com/scholar_lookup?title=A+mutation+in+a+GATA-1+binding+site+5'+to+the+G%CE%B3-globin+gene+(nt+-567%2C+T%3EG)+may+be+associated+with+increased+levels+of+fetal+hemoglobin&author=Luo+HY&author=Mang+D&author=Patrinos+GP&publication+year=2004&journal=Blood&volume=104>Google Scholar

Peterson, KR, Costa, FC, Harju-Baker, S. Silencing of γ-globin gene expression during adult definitive erythropoiesis is mediated by a GATA-1 repressor complex. Blood. 2007;110:271.Google Scholar

Ahringer, J. NuRD and SIN3 histone deacetylase complexes in development. Trends Genet. 2000;16:351–356.CrossRef Google Scholar PubMed

Bowen, NJ, Fujita, N, Kajita, M, Wade, PA. Mi-2/NuRD: multiple complexes for many purposes. Biochim Biophys Acta. 2004;1677:52–57.CrossRef Google Scholar PubMed

Guezennec, X, Vermeulen, M, Brinkman, AB, et al. MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Mol Cell Biol. 2006;26:843–851.CrossRef Google Scholar PubMed

Bodine, DM, Ley, TJ. An enhancer element lies 3′ to the human A γ globin gene. EMBO J. 1987;6:2997–3004.Google Scholar

Purucker, M, Bodine, D, Lin, H, McDonagh, K, Nienhuis, AW. Structure and function of the enhancer 3′ to the human A γ globin gene. Nucl Acids Res. 1990;18:7407–7415.CrossRef Google Scholar

Dickinson, , Joh, T, Kohwi, Y, Kohwi-Shigematsu, T. A tissue-specific MAR/SAR DNA-binding protein with unusual binding site recognition. Cell. 1992;70:631–645.CrossRef Google Scholar PubMed

Liu, Q, Tanimoto, K, Bungert, J, Engel, JD. The A γ-globin 3′ element provides no unique function(s) for human β-globin locus gene regulation. Proc Natl Acad Sci USA. 1998;95:9944–9949.CrossRef Google Scholar PubMed

Li, Q, Stamatoyannopoulos, JA. Position independence and proper developmental control of γ-globin gene expression require both a 5′ locus control region and a downstream sequence element. Mol Cell Biol. 1994;14:6087–6096.CrossRef Google Scholar

Stamatoyannopoulos, JA, Clegg, CH, Li, Q. Sheltering of γ-globin expression from position effects requires both an upstream locus control region and a regulatory element 3' to the A g-globin gene. Mol Cell Biol. 1997;17:240–247.CrossRef Google Scholar

Duan, ZJ, Fang, X, Rohde, A, Han, H, Stamatoyannopoulos, G, Li, Q. Developmental specificity of recruitment of TBP to the TATA box of the human γ-globin gene. Proc Natl Acad Sci USA. 2002;99:5509–5514.CrossRef Google Scholar PubMed

Fang, X, Han, H, Stamatoyannopoulos, G, Li, Q. Developmentally specific role of the CCAAT box in regulation of human γ-globin gene expression. J Biol Chem. 2004;279:5444–5449.CrossRef Google Scholar PubMed

Li, Q, Han, H, Ye, X, Stafford, M, Barkess, G, Stamatoyannopoulos, G. Transcriptional potentials of the β-like globin genes at different developmental stages in transgenic mice and hemoglobin switching. Blood Cells Mol Dis. 2004;33:318–325.CrossRef Google Scholar PubMed

Antoniou, M, Boer, E, Habets, G, Grosveld, F. The human β-globin gene contains multiple regulatory regions: identification of one promoter and two downstream enhancers. EMBO J. 1988;7:377–384.Google Scholar PubMed

deBoer, E, Antoniou, M, Mignotte, V, Wall, L, Grosveld, F. The human β-globin promoter; nuclear protein factors and erythroid specific induction of transcription. EMBO J. 1988;7:4203–4212.Google Scholar

Wall, L, Destroismaisons, N, Delvoye, N, Guy, LG. CAAT/enhancer-binding proteins are involved in β-globin gene expression and are differentially expressed in murine erythroleukemia and K562 cells. J Biol Chem. 1996;271:16477–16484.CrossRef Google Scholar PubMed

Hartzog, GA, Myers, RM. Discrimination among potential activators of the β-globin CACCC element by correlation of binding and transcriptional properties. Mol Cell Biol. 1993;13:44–56.CrossRef Google Scholar PubMed

Miller, IJ, Bieker, JJ. 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. 1993;13:2776–2786.CrossRef Google Scholar PubMed

Feng, WC, Southwood, CM, Bieker, JJ. Analyses of β-thalassemia mutant DNA interactions with erythroid Kruppel-like factor (EKLF), an erythroid cell-specific transcription factor. J Biol Chem. 1994;269:1493–1500.Google Scholar

Donze, D, Townes, TM, Bieker, JJ. Role of erythroid Kruppel-like factor in human γ- to β-globin gene switching. J Biol Chem. 1995;270:1955–1959.CrossRef Google Scholar PubMed

Behringer, RR, Hammer, RE, Brinster, RL, Palmiter, RD, Townes, TM. Two 3′ sequences direct adult erythroid-specific expression of human β-globin genes in transgenic mice. Proc Natl Acad Sci USA. 1987;84:7056–7060.CrossRef Google Scholar PubMed

Kollias, G, Hurst, J, Boer, E, Grosveld, F. The human β-globin gene contains a downstream developmental specific enhancer. Nucl Acids Res. 1987;15:5739–5747.CrossRef Google Scholar PubMed

Trudel, M, Costantini, F. A 3′ enhancer contributes to the stage-specific expression of the human β-globin gene. Genes Dev. 1987;1:954–961.CrossRef Google Scholar PubMed

Liu, Q, Bungert, J, Engel, JD. Mutation of gene-proximal regulatory elements disrupts human ε-, γ-, and β-globin expression in yeast artificial chromosome transgenic mice. Proc Natl Acad Sci USA. 1997;94:169–174.CrossRef Google Scholar PubMed

Rubin, JE, Pasceri, P, Wu, X, Leboulch, P, Ellis, J. Locus control region activity by 5'HS3 requires a functional interaction with β-globin gene regulatory elements: expression of novel β/γ-globin hybrid transgenes. Blood. 2000;95:3242–3249.Google Scholar PubMed

Bharadwaj, RR, Trainor, CD, Pasceri, P, Ellis, J. LCR-regulated transgene expression levels depend on the Oct-1 site in the AT-rich region of β-globin intron-2. Blood. 2003;101:1603–1610.CrossRef Google Scholar PubMed

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.CrossRef Google Scholar PubMed

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.CrossRef Google Scholar PubMed

Grosveld, F, Assendelft, GB, Greaves, DR, Kollias, G. Position-independent, high-level expression of the human β-globin gene in transgenic mice. Cell. 1987;51:975–985.CrossRef Google Scholar PubMed

Fraser, P, Grosveld, F. Locus control regions, chromatin activation and transcription. Curr Opin Cell Biol. 1998;10:361–365.CrossRef Google Scholar

Milot, E, Strouboulis, J, Trimborn, T, et al. Heterochromatin effects on the frequency and duration of LCR-mediated gene transcription. Cell. 1996;87:105–114.CrossRef Google Scholar PubMed

Epner, E, Reik, A, Cimbora, D, et al. The β-globin LCR is not necessary for an open chromatin structure or developmentally regulated transcription of the native mouse β-globin locus. Mol Cell. 1998;2:447–455.CrossRef Google Scholar PubMed

Reik, A, Telling, A, Zitnik, G, Cimbora, D, Epner, E, Groudine, M. The locus control region is necessary for gene expression in the human β-globin locus but not the maintenance of an open chromatin structure in erythroid cells. Mol Cell Biol. 1998;18:5992–6000.CrossRef Google Scholar

Bender, MA, Bulger, M, Close, J, Groudine, M. β-globin gene switching and DNase I sensitivity of the endogenous β-globin locus in mice do not require the locus control region. Mol Cell. 2000;5:387–393.CrossRef Google Scholar

Ploeg, LH, Konings, A, Oort, M, Roos, D, Bernini, L, Flavell, RA. γ-β-Thalassaemia studies showing that deletion of the γ- and δ-genes influences β-globin gene expression in man. Nature. 1980;283:637–642.CrossRef Google Scholar PubMed

Vanin, EF, Henthorn, PS, Kioussis, D, Grosveld, F, Smithies, O. Unexpected relationships between four large deletions in the human β-globin gene cluster. Cell. 1983;35:701–709.CrossRef Google Scholar PubMed

Curtin, P, Pirastu, M, Kan, YW, Gobert-Jones, JA, Stephens, AD, Lehmann, H. A distant gene deletion affects β-globin gene function in an atypical γ δ β-thalassemia. J Clin Invest. 1985;76:1554–1558.CrossRef Google Scholar

Driscoll, MC, Dobkin, CS, Alter, BP. γ δ β-thalassemia due to a de novo mutation deleting the 5′ β-globin gene activation-region hypersensitive sites. Proc Natl Acad Sci USA. 1989; 86:7470–7474.CrossRef Google Scholar PubMed

Forrester, WC, Epner, E, Driscoll, MC, et al. A deletion of the human β-globin locus activation region causes a major alteration in chromatin structure and replication across the entire β-globin locus. Genes Dev. 1990;4:1637–1649.CrossRef Google Scholar

Bender, MA, Byron, R, Ragoczy, T, Telling, A, Bulger, M, Groudine, M. Flanking HS-62.5 and 3′ HS1, and regions upstream of the LCR, are not required for β-globin transcription. Blood. 2006;108:1395–1401.CrossRef Google Scholar

Higgs, DR. Do LCRs open chromatin domains?Cell. 1998;95:299–302.CrossRef Google Scholar PubMed

Grosveld, F. Activation by locus control regions?Curr Opin Genet Dev. 1999;9:152–157.CrossRef Google Scholar PubMed

Fraser, P, Pruzina, S, Antoniou, M, Grosveld, 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.CrossRef Google Scholar PubMed

Navas, PA, Peterson, KR, Li, Q, et al. Developmental specificity of the interaction between the locus control region and embryonic or fetal globin genes in transgenic mice with an HS3 core deletion. Mol Cell Biol. 1998;18:4188–4196.CrossRef Google Scholar PubMed

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;250:1147–1149.CrossRef Google Scholar PubMed

Shih, DM, Wall, RJ, Shapiro, SG. Developmentally regulated and erythroid-specific expression of the human embryonic β-globin gene in transgenic mice. Nucl Acids Res. 1990;18:5465–5472.CrossRef Google Scholar PubMed

Wada-Kiyama, Y, Peters, B, Noguchi, CT. The ε-globin gene silencer. Characterization by in vitro transcription. J Biol Chem. 1992;267:11532–11538.Google Scholar PubMed

Li, Q, Blau, CA, Clegg, CH, Rohde, A, Stamatoyannopoulos, GMultiple ε-promoter elements participate in the developmental control of ε-globin genes in transgenic mice. J Biol Chem. 1998;273:17361–17367.CrossRef Google Scholar PubMed

Cao, SX, Gutman, PD, Dave, HP, Schechter, AN. Negative control of the human ε-globin gene. Prog Clin Biol Res. 1989;316A:279–289.Google Scholar PubMed

Peters, B, Merezhinskaya, N, Diffley, JF, Noguchi, CT. Protein-DNA interactions in the ε-globin gene silencer. J Biol Chem. 1993;268:3430–3437.Google Scholar PubMed

Raich, N, Papayannopoulou, T, Stamatoyannopoulos, G, Enver, T. Demonstration of a human ε-globin gene silencer with studies in transgenic mice. Blood. 1992;79:861–864.Google Scholar PubMed

Li, Q, Clegg, C, Peterson, K, Shaw, S, Raich, N, Stamatoyannopoulos, G. Binary transgenic mouse model for studying the trans control of globin gene switching: evidence that GATA-1 is an in vivo repressor of human ε gene expression. Proc Natl Acad Sci USA. 1997;94:2444–2448.CrossRef Google Scholar

Navas, PA, Li, Q, Peterson, KR, Stamatoyannopoulos, G. Investigations of a human embryonic globin gene silencing element using YAC transgenic mice. Exp Biol Med (Maywood). 2006;231:328–334.CrossRef Google Scholar PubMed

Behringer, RR, Ryan, TM, Palmiter, RD, Brinster, RL, Townes, TM. Human γ- to β-globin gene switching in transgenic mice. Genes Dev. 1990;4:380–389.CrossRef Google Scholar PubMed

Enver, TRaich, 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.CrossRef Google Scholar PubMed

Dillon, N, Grosveld, F. Human γ-globin genes silenced independently of other genes in the β-globin locus. Nature. 1991;350:252–254.CrossRef Google Scholar PubMed

Peterson, KR, Li, QL, Clegg, CH, et al. Use of yeast artificial chromosomes (YACs) in studies of mammalian development: production of β-globin locus YAC mice carrying human globin developmental mutants. Proc Natl Acad Sci USA. 1995;92:5655–5659.CrossRef Google Scholar PubMed

Dillon, N, Trimborn, T, Strouboulis, J, Fraser, P, Grosveld, F. The effect of distance on long-range chromatin interactions. Mol Cell. 1997;1:131–139.CrossRef Google Scholar PubMed

Harju, S, Navas, PA, Stamatoyannopoulos, G, Peterson, KR. Genome architecture of the human β-globin locus affects developmental regulation of gene expression. Mol Cell Biol. 2005;25:8765–8778.CrossRef Google Scholar PubMed

Yu, M, Han, H, Xiang, P, Li, Q, Stamatoyannopoulos, G. Autonomous silencing as well as competition controls γ-globin gene expression during development. Mol Cell Biol. 2006;26:4775–4781.CrossRef Google Scholar PubMed

Hanscombe, O, Whyatt, D, Fraser, P, et al. Importance of globin gene order for correct developmental expression. Genes Dev. 1991;5:1387–1394.CrossRef Google Scholar PubMed

Peterson, KR, Stamatoyannopoulos, G. Role of gene order in developmental control of human γ- and β-globin gene expression. Mol Cell Biol. 1993;13:4836–4843.CrossRef Google Scholar PubMed

Wijgerde, M, Grosveld, F, Fraser, P. Transcription complex stability and chromatin dynamics in vivo. Nature. 1995;377:209–213.CrossRef Google Scholar PubMed

Dekker, J, Rippe, K, Dekker, M, Kleckner, N. Capturing chromosome conformation. Science. 2002;295:1306–1311.CrossRef Google Scholar PubMed

Tolhuis, B, Palstra, RJ, Splinter, E, Grosveld, F, Laat, W. Looping and interaction between hypersensitive sites in the active β-globin locus. Mol Cell. 2002;10:1453–1465.CrossRef Google Scholar PubMed

Palstra, RJ, Tolhuis, B, Splinter, E, Nijmeijer, R, Grosveld, F, Laat, W. The β-globin nuclear compartment in development and erythroid differentiation. Nat Genet. 2003;35:190–194.CrossRef Google Scholar PubMed

Carter, D, Chakalova, L, Osborne, CS, Dai, YF, Fraser, P. Long-range chromatin regulatory interactions in vivo. Nat Genet. 2002;32:623–626.CrossRef Google Scholar PubMed

Drissen, R, Palstra, RJ, Gillemans, N, et al. The active spatial organization of the β-globin locus requires the transcription factor EKLF. Genes Dev. 2004;18:2485–2490.CrossRef Google Scholar PubMed

Vakoc, CR, Letting, DL, Gheldof, N, et al. Proximity among distant regulatory elements at the β-globin locus requires GATA-1 and FOG-1. Mol Cell. 2005;17:453–462.CrossRef Google Scholar PubMed

Kooren, J, Palstra, RJ, Klous, P, et al. B-globin active chromatin Hub formation in differentiating erythroid cells and in p45 NF-E2 knock-out mice. J Biol Chem. 2007;282:16544–16552.CrossRef Google Scholar

Papayannopoulou, TH, Brice, M, Stamatoyannopoulos, G. Stimulation of fetal hemoglobin synthesis in bone marrow cultures from adult individuals. Proc Natl Acad Sci USA. 1976;73:2033–2037.CrossRef Google Scholar PubMed

Stamatoyannopoulos, G, Veith, R, Galanello, R, Papayannopoulou, T. Hb F production in stressed erythropoiesis: observations and kinetic models. Ann NY Acad Sci. 1985;445:188–197.CrossRef Google Scholar PubMed

Papayannopoulou, T, Vichinsky, E, Stamatoyannopoulos, G. Fetal Hb production during acute erythroid expansion. I. Observations in patients with transient erythroblastopenia and post-phlebotomy. Br J Haematol. 1980;44:535–546.CrossRef Google Scholar PubMed

Sheridan, BL, Weatherall, DJ, Clegg, JB, et al. The patterns of fetal haemoglobin production in leukaemia. Br J Haematol. 1976;32:487–506.CrossRef Google Scholar PubMed

DeSimone, J, Biel, SI, Heller, P. Stimulation of fetal hemoglobin synthesis in baboons by hemolysis and hypoxia. Proc Natl Acad Sci USA. 1978;75:2937–2940.CrossRef Google Scholar PubMed

Nute, PE, Papayannopoulou, T, Chen, P, Stamatoyannopoulos, G. Acceleration of F-cell production in response to experimentally induced anemia in adult baboons (Papio cynocephalus). Am J Hematol. 1980;8:157–168.CrossRef Google Scholar

Al-Khatti, A, Veith, RW, Papayannopoulou, T, Fritsch, EF, Goldwasser, E, Stamatoyannopoulos, G. Stimulation of fetal hemoglobin synthesis by erythropoietin in baboons. N Engl J Med. 1987;317:415–420.CrossRef Google Scholar PubMed

Umemura, T, Al-Khatti, A, Papayannopoulou, T, Stamatoyannopoulos, G. Fetal hemoglobin synthesis in vivo: direct evidence for control at the level of erythroid progenitors. Proc Natl Acad Sci USA. 1988;85:9278–9282.CrossRef Google Scholar PubMed

Beaven, GH, Ellis, MJ, White, JC. Studies on human foetal haemoglobin. II. Foetal haemoglobin levels in healthy children and adults and in certain haematological disorders. Br J Haematol. 1960;6:201–222.CrossRef Google Scholar PubMed

Stamatoyannopoulos, G, Papayannopoulou, T. Fetal hemoglobin and the erythroid stem cell differentiation process. In: Stamatoyannopoulos, G, Nienhuis, AW, eds. Cellular and Molecular Regulation of Hemoglobin Switching. New York: Grune & Stratton; 1979:323–349.Google Scholar

DeSimone, J, Heller, P, Hall, L, Zwiers, D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci USA. 1982;79:4428–4431.CrossRef Google Scholar PubMed

Ley, TJ, DeSimone, J, Anagnou, NP, et al. 5-azacytidine selectively increases γ-globin synthesis in a patient with b+thalassemia. N Engl J Med. 1982;307:1469–1475.CrossRef Google Scholar

Torrealba de Ron, AT, Papayannopoulou, T, Knapp, MS, Fu, MF, Knitter, G, Stamatoyannopoulos, G. Perturbations in the erythroid marrow progenitor cell pools may play a role in the augmentation of HbF by 5-azacytidine. Blood. 1984;63:201–210.Google Scholar PubMed

Papayannopoulou, T, Torrealba de Ron, A, Veith, R, Knitter, G, Stamatoyannopoulos, G. Arabinosylcytosine induces fetal hemoglobin in baboons by perturbing erythroid cell differentiation kinetics. Science. 1984;224:617–619.CrossRef Google Scholar PubMed

Letvin, NL, Linch, DC, Beardsley, GP, McIntyre, KW, Nathan, DG. Augmentation of fetal-hemoglobin production in anemic monkeys by hydroxyurea. N Engl J Med. 1984;310:869–873.CrossRef Google Scholar PubMed

Veith, R, Papayannopoulou, T, Kurachi, S, Stamatoyannopoulos, G. Treatment of baboon with vinblastine: insights into the mechanisms of pharmacologic stimulation of Hb F in the adult. Blood. 1985;66:456–459.Google Scholar PubMed

Fibach, E, Burke, LP, Schechter, AN, Noguchi, CT, Rodgers, GP. Hydroxyurea increases fetal hemoglobin in cultured erythroid cells derived from normal individuals and patients with sickle cell anemia or β-thalassemia. Blood. 1993;81:1630–1635.Google Scholar PubMed

Platt, OS, Falcone, JF. Membrane protein interactions in sickle red blood cells: evidence of abnormal protein 3 function. Blood. 1995;86:1992–1998.Google Scholar PubMed

Steinberg, MH, Lu, ZH, Barton, FB, Terrin, ML, Charache, S, Dover, GJ. Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter study of hydroxyurea. Blood. 1997;89:1078–1088.Google Scholar PubMed

Perrine, SP, Greene, MF, Faller, DV. Delay in the fetal globin switch in infants of diabetic mothers. N Engl J Med. 1985;312:334–338.CrossRef Google Scholar PubMed

Perrine, SP, Miller, BA, Greene, MF, et al. Butryic acid analogues augment γ globin gene expression in neonatal erythroid progenitors. Biochem Biophys Res Commun. 1987;148:694–700.CrossRef Google Scholar PubMed

Constantoulakis, P, Papayannopoulou, T, Stamatoyannopoulos, G. α-Amino-N-butyric acid stimulates fetal hemoglobin in the adult. Blood. 1988;72:1961–1967.Google Scholar PubMed

Perrine, SP, Miller, BA, Faller, DV, et al. Sodium butyrate enhances fetal globin gene expression in erythroid progenitors of patients with Hb SS and b thalassemia. Blood. 1989;74:454–459.Google Scholar

Stamatoyannopoulos, G, Nienhuis, AW. Hemoglobin switching. In: Stamatoyannopoulos, G, Nienhuis, AW, Majerus, P, Varmus, H, eds. Molecular Basis of Blood Diseases. 2nd ed. Philadelphia: W.B. Saunders Co.; 1994:107–154.Google Scholar

Liakopoulou, E, Blau, CA, Li, Q, et al. Stimulation of fetal hemoglobin production by short chain fatty acids. Blood. 1995;86:3227–3235.Google Scholar PubMed

Dover, GJ, Brusilow, S, Charache, S. Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate. Blood. 1994;84:339–343.Google Scholar PubMed

Collins, AF, Dover, GJ, Luban, NL. Increased fetal hemoglobin production in patients receiving valproic acid for epilepsy. Blood. 1994;84:1690–1691.Google Scholar PubMed

Little, JA, Dempsey, NJ, Tuchman, MGinder, GD. Metabolic persistence of fetal hemoglobin. Blood. 1995;85:1712–1718.Google Scholar PubMed

Peters, A, Rohloff, D, Kohlmann, T, et al. Fetal hemoglobin in starvation ketosis of young women. Blood. 1998;91:691–694.Google Scholar PubMed

Cao, H, Stamatoyannopoulos, G, Jung, M. Induction of human γ globin gene expression by histone deacetylase inhibitors. Blood. 2004;103:701–709.CrossRef Google Scholar PubMed

Pace, BS, White, GL, Dover, GJ, Boosalis, MS, Faller, DV, Perrine, SP. Short-chain fatty acid derivatives induce fetal globin expression and erythropoiesis in vivo. Blood. 2002;100:4640–4648.CrossRef Google Scholar PubMed

Kuo, MH, Brownell, JE, Sobel, RE, et al. Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines. Nature. 1996;383:269–272.CrossRef Google Scholar PubMed

Mizzen, CA, Yang, XJ, Kokubo, T, et al. The TAF(II)250 subunit of TFIID has histone acetyltransferase activity. Cell. 1996;87:1261–1270.CrossRef Google Scholar PubMed

Ogryzko, VV, Schiltz, RL, Russanova, V, Howard, BH, Nakatani, Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 1996;87:953–959.CrossRef Google Scholar PubMed

Vettese-Dadey, M, Grant, PA, Hebbes, TR, Crane- Robinson, C, Allis, CD, Workman, JL. Acetylation of histone H4 plays a primary role in enhancing transcription factor binding to nucleosomal DNA in vitro. EMBO J. 1996;15:2508–2518.Google Scholar

Pace, B, Li, Q, Peterson, K, Stamatoyannopoulos, G. α-Amino butyric acid cannot reactivate the silenced γ gene of the β locus YAC transgenic mouse. Blood. 1994;84:4344–4353.Google Scholar PubMed

Uda, M, Galanello, R, Sanna, S, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia. Proc Natl Acad Sci USA. 2008;105:1620–1625.CrossRef Google Scholar PubMed

Lettre, G, Sankaran, VG, Bezerra, MA, et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and β-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci USA. 2008;105:11869–11874.CrossRef Google Scholar PubMed

Sankaran, VG, Menne, TF, Xu, J, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008;322:1839–1842.CrossRef Google Scholar PubMed

Senawong, T, Peterson, VJ, Leid, M. BCL11A-dependent recruitment of SIRT1 to a promoter template in mammalian cells results in histone deacetylation and transcriptional repression. Arch Biochem Biophys. 2005;434:316–325.CrossRef Google Scholar PubMed

Liu, H, Ippolito, GC, Wall, JK, et al. Functional studies of BCL11A: characterization of the conserved BCL11A-XL splice variant and its interaction with BCL6 in nuclear paraspeckles of germinal center B cells. Mol cancer. 2006;5:18–34.CrossRef Google Scholar PubMed

Chen, Z, Luo, HY, Steinberg, MH, Chui, DH. BCL11A represses HBG transcription in K562 cells. Blood Cells Mol Dis. 2009;42:144–149.CrossRef Google Scholar PubMed

Accessibility standard: Unknown

Why this information is here

This section outlines the accessibility features of this content - including support for screen readers, full keyboard navigation and high-contrast display options. This may not be relevant for you.

Accessibility Information

Accessibility compliance for the PDF of this book is currently unknown and may be updated in the future.