Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-8448b6f56d-sxzjt Total loading time: 0 Render date: 2024-04-25T03:53:53.479Z Has data issue: false hasContentIssue false

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
By
George Stamatoyannopoulos ,
Patrick A. Navas  and
Qiliang Li
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
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.

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

References

Huehns, ER, Dance, N, Beaven, GH, Keil, JV, Hecht, F, Motulsky, AG. Human embryonic haemoglobins. Nature. 1964;201:1095–1097.CrossRefGoogle ScholarPubMed
Hecht, F, Motulsky, AG, Lemire, RJ, Shepard, TE. Predominance of hemoglobin Gower 1 in early human embryonic development. Science. 1966;152:91–92.CrossRefGoogle ScholarPubMed
Gale, RE, Clegg, JB, Huehns, ER. Human embryonic haemoglobins Gower 1 and Gower 2. Nature. 1979;280:162–164.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle 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 ScholarPubMed
Ingram, VM. Embryonic red blood cell formation. Nature. 1972;235:338–339.CrossRefGoogle ScholarPubMed
Weatherall, DJ, Edwards, JA, Donohoe, WT. Haemoglobin and red cell enzyme changes in juvenile myeloid leukaemia. Br Med J. 1968;1:679–681.CrossRefGoogle ScholarPubMed
Weatherall, DJ, Clegg, JB, Wood, WG. A model for the persistence or reactivation of fetal haemoglobin production. Lancet. 1976;2:660–663.CrossRefGoogle ScholarPubMed
Alter, BP, Rappeport, JM, Huisman, TH, Schroeder, WA, Nathan, DG. Fetal erythropoiesis following bone marrow transplantation. Blood. 1976;48:843–853.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Chapman, BS, Tobin, AJ. Distribution of developmentally regulated hemoglobins in embryonic erythroid populations. Dev Biol. 1979;69:375–387.CrossRefGoogle ScholarPubMed
Brotherton, TW, Chui, DH, Gauldie, J, Patterson, M.Hemoglobin ontogeny during normal mouse fetal development. Proc Natl Acad Sci USA. 1979;76:2853–2857.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Wood, WG, Bunch, C, Kelly, S, Gunn, Y, Breckon, G. Control of haemoglobin switching by a developmental clock?Nature. 1985;313:320–323.CrossRefGoogle ScholarPubMed
Holliday, R, Pugh, JE. DNA modification mechanisms and gene activity during development. Science. 1975;187:226–232.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Yi, Z, Cohen-Barak, O, Hagiwara, N, et al. Sox6 directly silences ε globin expression in definitive erythropoiesis. PLoS Genet. 2006;2:e14.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle 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;12:4919–4929CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle 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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle 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.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle 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 ScholarPubMed
Magis, W, Martin, DI. HMG-I binds to GATA motifs: implications for an HPFH syndrome. Biochem Biophys Res Commun. 1995;214:927–933.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Bowen, NJ, Fujita, N, Kajita, M, Wade, PA. Mi-2/NuRD: multiple complexes for many purposes. Biochim Biophys Acta. 2004;1677:52–57.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle 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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Fraser, P, Grosveld, F. Locus control regions, chromatin activation and transcription. Curr Opin Cell Biol. 1998;10:361–365.CrossRefGoogle 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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle 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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle 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.CrossRefGoogle Scholar
Higgs, DR. Do LCRs open chromatin domains?Cell. 1998;95:299–302.CrossRefGoogle ScholarPubMed
Grosveld, F. Activation by locus control regions?Curr Opin Genet Dev. 1999;9:152–157.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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 ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle 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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Dillon, N, Grosveld, F. Human γ-globin genes silenced independently of other genes in the β-globin locus. Nature. 1991;350:252–254.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Hanscombe, O, Whyatt, D, Fraser, P, et al. Importance of globin gene order for correct developmental expression. Genes Dev. 1991;5:1387–1394.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Wijgerde, M, Grosveld, F, Fraser, P. Transcription complex stability and chromatin dynamics in vivo. Nature. 1995;377:209–213.CrossRefGoogle ScholarPubMed
Dekker, J, Rippe, K, Dekker, M, Kleckner, N. Capturing chromosome conformation. Science. 2002;295:1306–1311.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Carter, D, Chakalova, L, Osborne, CS, Dai, YF, Fraser, P. Long-range chromatin regulatory interactions in vivo. Nat Genet. 2002;32:623–626.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle 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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Sheridan, BL, Weatherall, DJ, Clegg, JB, et al. The patterns of fetal haemoglobin production in leukaemia. Br J Haematol. 1976;32:487–506.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle 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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle 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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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 ScholarPubMed
Platt, OS, Falcone, JF. Membrane protein interactions in sickle red blood cells: evidence of abnormal protein 3 function. Blood. 1995;86:1992–1998.Google ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Constantoulakis, P, Papayannopoulou, T, Stamatoyannopoulos, G. α-Amino-N-butyric acid stimulates fetal hemoglobin in the adult. Blood. 1988;72:1961–1967.Google ScholarPubMed
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 ScholarPubMed
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 ScholarPubMed
Collins, AF, Dover, GJ, Luban, NL. Increased fetal hemoglobin production in patients receiving valproic acid for epilepsy. Blood. 1994;84:1690–1691.Google ScholarPubMed
Little, JA, Dempsey, NJ, Tuchman, MGinder, GD. Metabolic persistence of fetal hemoglobin. Blood. 1995;85:1712–1718.Google ScholarPubMed
Peters, A, Rohloff, D, Kohlmann, T, et al. Fetal hemoglobin in starvation ketosis of young women. Blood. 1998;91:691–694.Google ScholarPubMed
Cao, H, Stamatoyannopoulos, G, Jung, M. Induction of human γ globin gene expression by histone deacetylase inhibitors. Blood. 2004;103:701–709.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Mizzen, CA, Yang, XJ, Kokubo, T, et al. The TAF(II)250 subunit of TFIID has histone acetyltransferase activity. Cell. 1996;87:1261–1270.CrossRefGoogle ScholarPubMed
Ogryzko, VV, Schiltz, RL, Russanova, V, Howard, BH, Nakatani, Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 1996;87:953–959.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Chen, Z, Luo, HY, Steinberg, MH, Chui, DH. BCL11A represses HBG transcription in K562 cells. Blood Cells Mol Dis. 2009;42:144–149.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×