The human β-globin locus is a complex genetic system widely used for analysis of eukaryotic gene expression. The locus consists of five functional β-like globin genes, ε, Gγ, Aγ, δ, and β, arrayed on the chromosome in the order that they are expressed during ontogeny. Globin gene expression is regulated, in part, by the locus control region, which physically consists of five DNasel-hypersensitive sites located 6-22 Kb upstream of the ε-globin gene. During ontogeny two switches occur in β-globin gene expression that reflect the changing oxygen requirements of the fetus. The first switch from embryonic ε- to fetal γ-globin occurs at six weeks of gestation. The second switch from γ- to adult δ- and β-globin occurs shortly after birth. Throughout the locus, cis-acting elements exist that are dynamically bound by trans-acting proteins, including transcription factors, co-activators, repressors, and chromatin modifiers. Discovery of novel erythroid-specific transcription factors and a role for chromatin structure in gene expression have enhanced our understanding of the mechanism of globin gene switching. However, the hierarchy of events regulating gene expression during development, from extracellular signaling to transcriptional activation or repression, is complex. In this review we attempt to unify the current knowledge regarding the interplay of cis-acting elements, transcription factors, and chromatin modifiers into a comprehensive overview of globin gene switching.
StamatoyannopoulosG. The molecular basis of blood diseases. 3rd ed.Philadelphia: W.B. Saunders, 2001.
2.
GrosveldF, van AssendelftGB, GreavesDR, KolliasG. Position-independent, high-level expression of the human β-globin gene in transgenic mice. Cell51: 975985, 1987.
3.
TownesTM, LingrelJB, ChenHY, BrinsterRL, PalmiterRD. Erythroid-specific expression of human β-globin genes in transgenic mice. EMBO J4: 17151723, 1985.
4.
ChadaK, MagramJ, CostantiniF. An embryonic pattern of expression of a human fetal globin gene in transgenic mice. Nature319: 685689, 1986.
5.
KolliasG, WrightonN, HurstJ, GrosveldF. Regulated expression of human A γ-, β-, and hybrid γ β- globin genes in transgenic mice: manipulation of the developmental expression patterns. Cell46: 8994, 1986.
6.
ForresterWC, TakegawaS, PapayannopoulouT, StamatoyannopoulosG, GroudineM. Evidence for a locus activation region: the formation of developmentally stable hypersensitive sites in globin-expressing hybrids. Nucleic Acids Res15: 1015910177, 1987.
7.
EnverT, RaichN, EbensAJ, PapayannopoulouT, CostantiniF, StamatoyannopoulosG. Developmental regulation of human fetal-to-adult globin gene switching in transgenic mice. Nature344: 309313, 1990.
8.
BehringerRR, RyanTM, PalmiterRD, BrinsterRL, TownesTM. Human γ- to β-globin gene switching in transgenic mice. Genes Dev4: 380389, 1990.
RaichN, EnverT, NakamotoB, JosephsonB, PapayannopoulouT, StamatoyannopoulosG. Autonomous developmental control of human embryonic globin gene switching in transgenic mice. Science250: 11471149, 1990.
11.
TanimotoK, LiuQ, BungertJ, EngelJD. Effects of altered gene order or orientation of the locus control region on human β-globin gene expression in mice. Nature398: 344348, 1999.
12.
RamchandranR, BengraC, WhitneyB, LanclosK, TuanDA. (GATA)(7) motif located in the 5′ boundary area of the human β-globin locus control region exhibits silencer activity in erythroid cells. Am J Hematol65: 1424, 2000.
13.
RaichN, PapayannopoulouT, StamatoyannopoulosG, EnverT. Demonstration of a human ε-globin gene silencer with studies in transgenic mice. Blood79: 861864, 1992.
14.
LiQ, BlauCA, CleggCH, RohdeA, StamatoyannopoulosG. Multiple ε-promoter elements participate in the developmental control of ε-globin genes in transgenic mice. J Biol Chem273: 1736117367, 1998.
15.
LiuQ, BungertJ, EngelJD. Mutation of gene-proximal regulatory elements disrupts human ε-, γ-, and β-globin expression in yeast artificial chromosome transgenic mice. Proc Natl Acad Sci USA94: 169174, 1997.
16.
RaichN, CleggCH, GroftiJ, RomeoPH, StamatoyannopoulosG. GATAI and YY1 are developmental repressors of the human ε-globin gene. EMBO J14: 801809, 1995.
17.
KellumR, SchedlP. A position-effect assay for boundaries of higher order chromosomal domains. Cell64: 941950, 1991.
18.
PikaartMJ, Recillas-TargaF, FelsenfeldG. Loss of transcriptional activity of a transgene is accompanied by DNA methylation and histone deacetylation and is prevented by insulators. Genes Dev12: 28522862, 1998.
19.
BellAC, FelsenfeldG. Stopped at the border: boundaries and insulators. Curr Opin Genet Dev9: 191198, 1999.
20.
TanimotoK, LiuQ, BungertJ, EngelJD. The polyoma virus enhancer cannot substitute for DNase I core hypersensitive sites 2-4 in the human β-globin LCR. Nucleic Acids Res27: 31303137, 1999.
21.
BoulikasT. Nature of DNA sequences at the attachment regions of genes to the nuclear matrix. J Cell Biochem52: 1422, 1993.
22.
ChungJH, WhiteleyM, FelsenfeldG. A 5′ element of the chicken β-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila. Cell74: 505514, 1993.
23.
JarmanAP, HiggsDR. Nuclear scaffold attachment sites in the human globin gene complexes. EMBO J7: 33373344, 1988.
24.
BenderMA, ReikA, CloseJ, TellingA, EpnerE, FieringS, HardisonR, GroudineM. Description and targeted deletion of 5′ hypersensitive site 5 and 6 of the mouse β-globin locus control region. Blood92: 43944403, 1998.
25.
LiQ, StamatoyannopoulosJA. Position independence and proper developmental control of γ-globiri gene expression require both a 5′ locus control region and a downstream sequence element. Mol Cell Biol14: 60876096, 1994.
26.
GribnauJ, DiderichK, PruzinaS, CalzolariR, FraserP. Intergenic transcription and developmental remodeling of chromatin subdomains in the human β-globin locus. Mol Cell5: 377386, 2000.
27.
BulgerM, von DoorninckJH, SaitohN, TellingA, FarrellC, BenderMA, FelsenfeldG, AxelR, GroudineM. Conservation of sequence and structure flanking the mouse and human β-globin loci: the β-globin genes are embedded within an array of odorant receptor genes. Proc Natl Acad Sci USA96: 51295134, 1999.
28.
TownesTM, BehringerRR. Human globin locus activation region (LAR): role in temporal control. Trends Genet6: 219223, 1990.
29.
CaterinaJJ, CiavattaDJ, DonzeD, BehringerRR, TownesTM. Multiple elements in human β-globin locus control region 5′ HS 2 are involved in enhancer activity and position-independent, transgene expression. Nucleic Acids Res22: 10061011, 1994.
30.
KongS, BohlD, LiC, TuanD. Transcription of the HS2 enhancer toward a cis-linked gene is independent of the orientation, position, and distance of the enhancer relative to the gene. Mol Cell Biol17: 39553965, 1997.
31.
ElnitskiL, MillerW, HardisonR. Conserved E boxes function as part of the enhancer in hypersensitive site 2 of the β-globin locus control region. Role of basic helix- loop-helix proteins. J Biol Chem272: 369378, 1997.
32.
BungertJ, TanimotoK, PatelS, LiuQ, FearM, EngelJD. Hypersensitive site 2 specifies a unique function within the human β-globin locus control region to stimulate globin gene transcription. Mol Cell Biol19: 30623072, 1999.
33.
EllisJ, Tan-UnKC. Harper A, Michalovich D, Yannoutsos N, Philipsen S, Grosveld F. A dominant chromatin-opening activity in 5′ hypersensitive site 3 of the human β-globin locus control region. EMBO J15: 562568, 1996.
34.
MilotE, StrouboulisJ, TrimbornT, WijgerdeM, de BoerE, LangeveldA, Tan-UnK, VergeerW, YannoutsosN, GrosveldF, FraserP. Heterochromatin effects on the frequency and duration of LCR-mediated gene transcription. Cell87: 105114, 1996.
35.
WijgerdeM, GribnauJ, TrimbornT, NuezB, PhilipsenS, GrosveldF, FraserP. The role of EKLF in human β-globin gene competition. Genes Dev10: 28942902, 1996.
36.
StrouboulisJ, DillonN, GrosveldF. Developmental regulation of a complete 70-kb human β-globin locus in transgenic mice. Genes Dev6: 18571864, 1992.
37.
DillonN, TrimbornT, StrouboulisJ, FraserP, GrosveldF. The effect of distance on long-range chromatin interactions. Mol Cell1: 131139, 1997.
38.
BulgerM, GroudineM. Looping versus linking: toward a model for long-distance gene activation. Genes Dev13: 24652477, 1999.
39.
PetersonKR, CleggCH, HuxleyC, JosephsonBM, HaugenHS, FurukawaT, StamatoyannopoulosG. Transgenic mice containing a 248-kb yeast artificial chromosome carrying the human β-globin locus display proper developmental control of human globin genes. Proc Natl Acad Sci USA90: 75937597, 1993.
40.
BresnickEH, TzeL. Synergism between hypersensitive sites confers long-range gene activation by the β-globin locus control region. Proc Natl Acad Sci USA94: 45664571, 1997.
41.
GribnauJ, de BoerE, TrimbornT, WijgerdeM, MilotE, GrosveldF, FraserP. Chromatin interaction mechanism of transcriptional control in vivo. EMBO J17: 60206027, 1998.
42.
HardisonR, SlightomJL, GumucioDL, GoodmanM, StojanovicN, MillerW. Locus control regions of mammalian β-globin gene clusters: combining phylogenetic analyses and experimental results to gain functional insights. Gene205: 7394, 1997.
43.
JiX, LiuD, XuD, LiL, WangJ, LiangC. Both locus control region and proximal regulatory elements direct the developmental regulation of β-globin gene cluster. J Cell Biochem76: 376385, 2000.
44.
GrosveldF. Activation by locus control regions?Curr Opin Genet Dev9: 152157, 1999.
45.
PetersonKR, CleggCH, NavasPA, NortonEJ, KimbroughTG, StamatoyannopoulosG. Effect of deletion of 5′HS3 or 5′HS2 of the human β-globin locus control region on the developmental regulation of globin gene expression in β-globin locus yeast artificial chromosome transgenic mice. Proc Natl Acad Sci USA93: 66056609, 1996.
46.
BungertJ, DaveU, LimKC, LieuwKH, ShavitJA, LiuQ, EngelJD. Synergistic regulation of human β-globin gene switching by locus control region elements HS3 and HS4. Genes Dev9: 30833096, 1995.
47.
TuanD, KongS, HuK. Transcription of the hypersensitive site HS2 enhancer in erythroid cells. Proc Natl Acad Sci USA89: 1121911223, 1992.
48.
BlackwoodEM, KadonagaJT. Going the distance: a current view of enhancer action. Science281: 6163, 1998.
49.
EngelJD, TanimotoK. Looping, linking, and chromatin activity: new insights into β-globin locus regulation. Cell100: 499502, 2000.
50.
TylerJK, KadonagaJT. The “dark side” of chromatin remodeling: repressive effects on transcription. Cell99: 443446, 1999.
ForresterWC, EpnerE, DriscollMC, EnverT, BriceM, PapayannopoulouT, GroudineM. 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 Dev4: 16371649, 1990.
53.
EpnerE, ReikA, CimboraD, TellingA, BenderMA, FieringS, EnverT, MartinDI, KennedyM, KellerG, GroudineM. The β-globin LCR is not necessary for an open chromatin structure or developmentally regulated transcription of the native mouse β-globin locus. Mol Cell2: 447455, 1998.
54.
ReikA, TellingA, ZitnikG, CimboraD, EpnerE, GroudineM. 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 Biol18: 59926000, 1998.
55.
HiggsDR. Do LCRs open chromatin domains?Cell95: 299302, 1998.
56.
IlerN, GoodwinAJ, McInern'eyJ, NemethMJ, PomerantzO, LayonME, LowreyCH. Targeted remodeling of human β-globin promoter chromatin structure produces increased expression and decreased silencing. Blood Cells Mol Dis25: 4760, 1999.
57.
TalbotD, PhilipsenS, FraserP, GrosveldF. Detailed analysis of the site 3 region of the human β-globin dominant control region. EMBO J9: 21692177, 1990.
58.
NeyPA, SorrentinoBP, McDonaghKT, NienhuisAW. Tandem AP-1-binding sites within the human β-globin dominant control region function as an inducible enhancer in erythroid cells. Genes Dev4: 9931006, 1990.
59.
JaneSM, CunninghamJM. Molecular mechanisms of hemoglobin switching. Int J Biochem Cell Biol28: 11971209, 1996.
60.
KobayashiA, ItoE, TokiT, KogameK, TakahashiS, IgarashiK, HayashiN, YamamotoM. Molecular cloning and functional characterization of a new cap' n' collar family transcription factor Nrf3. J Biol Chem274: 64436452, 1999.
61.
KatsuokaF, MotohashiH, OnoderaK, SuwabeN, EngelJD, YamamotoM. One enhancer mediates MafK transcriptional activation in both hematopoietic and cardiac muscle cells. EMBO J19: 29802991, 2000.
62.
KataokaK, IgarashiK, ItohK, FujiwaraKT, NodaM, YamamotoM, NishizawaM. Small Maf proteins heterodimerize with Fos and may act as competitive repressors of the NF-E2 transcription factor. Mol Cell Biol15: 21802190, 1995.
63.
ForsbergEC, DownsKM, BresnickEH. Direct interaction of NF-E2 with hypersensitive site 2 of the β- globin locus control region in living cells. Blood96: 334339, 2000.
64.
GongQH, McDowellJC, DeanA. Essential role of NF-E2 in remodeling of chromatin structure and transcriptional activation of the ε-globin gene in vivo by 5′ hypersensitive site 2 of the β-globin locus control region. Mol Cell Biol16: 60556064, 1996.
65.
ShivdasaniRA, OrkinSH. Erythropoiesis and globin gene expression in mice lacking the transcription factor NF-E2. Proc Natl Acad Sci USA92: 86908694, 1995.
66.
ChanJY, HanXL, KanYW. Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast. Proc Natl Acad Sci USA90: 1137111375, 1993.
67.
MoiP, ChanK, AsunisI, CaoA, KanYW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the β-globin locus control region. Proc Natl Acad Sci USA91: 99269930, 1994.
68.
KotkowKJ, OrkinSH. Dependence of globin gene expression in mouse erythroleukemia cells on the NF-E2 heterodimer. Mol Cell Biol15: 46404647, 1995.
69.
MartinF, van DeursenJM, ShivdasaniRA, JacksonCW, TroutmanAG, NeyPA. Erythroid maturation and globin gene expression in mice with combined deficiency of NF-E2 and nrf-2. Blood91: 34593466, 1998.
70.
CasteelD, SuhasiniM, GudiT, NaimaR, PilzRB. Regulation of the erythroid transcription factor NF-E2 by cyclic adenosine monophosphate-dependent protein kinase. Blood91: 31933201, 1998.
71.
GaringoAD, SuhasiniM, AndrewsNC, PilzRB. cAMP-dependent protein kinase is necessary for increased NF-E2.DNA complex formation during erythroleukemia cell differentiation. J Biol Chem270: 91699177, 1995.
72.
VersawWK, BlankV, AndrewsNM, BresnickEH. Mitogen-activated protein kinases enhance long-range activation by the β-globin locus control region. Proc Natl Acad Sci USA95: 87568760, 1998.
73.
AmroliaPJ, RamamurthyL, SalujaD, TaneseN, JaneSM, CunninghamJM. The activation domain of the enhancer binding protein p45NF-E2 interacts with TAFII130 and mediates long-range activation of the α- and β-globin gene loci in an erythroid cell line. Proc Natl Acad Sci USA94: 1005110056, 1997.
74.
ChenCJ, DengZ, KimAY, BlobelGA, LiebermanPM. Stimulation of CREB binding protein nucleosomal histone acetyltransferase activity by a class of transcriptional activators. Mol Cell Biol21: 476487, 2001.
75.
MerikaM, OrkinSH. DNA-binding specificity of GATA family transcription factors. Mol Cell Biol13: 39994010, 1993.
76.
KoLJ, EngelJD. DNA-binding specificities of the GATA transcription factor family. Mol Cell Biol13: 40114022, 1993.
77.
LiJ, NoguchiCT, MillerW, HardisonR, SchechterAN. Multiple regulatory elements in the 5′-flanking sequence of the human ε-globin gene. J Biol Chem273: 1020210209, 1998.
78.
CrossleyM, MerikaM, OrkinSH. Self-association of the erythroid transcription factor GATA-1 mediated by its zinc finger domains. Mol Cell Biol15: 24482456, 1995.
79.
DorfmanDM, WilsonDB, BrunsGA, OrkinSH. Human transcription factor GATA-2. Evidence for regulation of preproendothelin-1 gene expression in endothelial cells. J Biol Chem267: 12791285, 1992.
80.
JimenezG, GriffithsSD, FordAM, GreavesMF, EnverT. Activation of the β-globin locus control region precedes commitment to the erythroid lineage. Proc Natl Acad Sci USA89: 1061810622, 1992.
81.
TsaiFY, KellerG, KuoFC, WeissM, ChenJ, RosenblattM, AltFW, OrkinSH. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature371: 221226, 1994.
82.
PersonsDA, AllayJA, AllayER, AshmunRA, OrlicD, JaneSM, CunninghamJM, NienhuisAW. Enforced expression of the GATA-2 transcription factor blocks normal hematopoiesis. Blood93: 488499, 1999.
83.
TsangAP, VisvaderJE, TurnerCA, FujiwaraY, YuC, WeissMJ, CrossleyM, OrkinSH. FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell90: 109119, 1997.
84.
TsangAP, FujiwaraY, HornDB, OrkinSH. Failure of megakaryopoiesis and arrested erythropoiesis in mice lacking the GATA-1 transcriptional cofactor FOG. Genes Dev12: 11761188, 1998.
85.
MillerIJ, BiekerJJ. A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Krüppel family of nuclear proteins. Mol Cell Biol13: 27762786, 1993.
86.
FengWC, SouthwoodCM, BiekerJJ. Analyses of β-thalassemia mutant DNA interactions with erythroid Krüppel-like factor (EKLF), an erythroid cell-specific transcription factor. J Biol Chem269: 14931500, 1994.
87.
PerkinsAC, SharpeAH, OrkinSH. Lethal β-thalassaemia in mice lacking the erythroid CACCC- transcription factor EKLF. Nature375: 318322, 1995.
88.
NuezB, MichalovichD, BygraveA, PloemacherR, GrosveldF. Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene. Nature375: 316318, 1995.
89.
PerkinsAC, GaenslerKM, OrkinSH. Silencing of human fetal globin expression is impaired in the absence of the adult β-globin gene activator protein EKLF. Proc Natl Acad Sci USA93: 1226712271, 1996.
90.
LeeJS, LeeCH, ChungJH. The β-globin promoter is important for recruitment of erythroid Krüppel-like factor to the locus control region in erythroid cells. Proc Natl Acad Sci U S A96: 1005110055, 1999.
91.
DonzeD, TownesTM, BiekerJJ. Role of erythroid Krüppel-like factor in human γ- to β-globin gene switching. J Biol Chem270: 19551959, 1995.
92.
ChenX, BiekerJJ. Unanticipated repression function linked to erythroid Krüppel-like factor. Mol Cell Biol21: 31183125, 2001.
93.
OuyangL, ChenX, BiekerJJ. Regulation of erythroid Krüppel-like factor (EKLF) transcriptional activity by phosphorylation of a protein kinase casein kinase II site within its interaction domain. J Biol Chem273: 2301923025, 1998.
94.
WillertK, BrinkM, WodarzA, VarmusH, NusseR. Casein kinase 2 associates with and phosphorylates disheveled. EMBO J16: 30893096, 1997.
95.
MerikaM, OrkinSH. Functional synergy and physical interactions of the erythroid transcription factor GATA-1 with the Krüppel family proteins Sp1 and EKLF. Mol Cell Biol15: 24372447, 1995.
96.
AsanoH, LiXS, StamatoyannopoulosG. FKLF, a novel Krüppel-like factor that activates human embryonic and fetal β-like globin genes. Mol Cell Biol19: 35713579, 1999.
97.
AsanoH, LiXS, StamatoyannopoulosG. FKLF-2: a novel Krüppel-like transcriptional factor that activates globin and other erythroid lineage genes. Blood95: 35783584, 2000.
98.
TanimotoK, LiuQ, GrosveldF, BungertJ, EngelJD. Context-dependent EKLF responsiveness defines the developmental specificity of the human ε-globin gene in erythroid cells of YAC transgenic mice. Genes Dev14: 27782794, 2000.
99.
FilipeA, LiQ, DeveauxS, GodinI, RomeoPH, StamatoyannopoulosG, MignotteV. Regulation of embryonic/fetal globin genes by nuclear hormone receptors: a novel perspective on hemoglobin switching. EMBO J18: 687697, 1999.
100.
JaneSM, NienhuisAW, CunninghamJM. Hemoglobin switching in man and chicken is mediated by a heteromeric complex between the ubiquitous transcription factor CP2 and a developmentally specific protein. EMBO J14: 97105, 1995.
101.
HolmesML, HaleyJD, CerrutiL, ZhouW, ZogosH, SmithDE, CunninghamJM, JaneSM. Identification of Id2 as a globin regulatory protein by representational difference analysis of K562 cells induced To express γ-globin with a fungal compound. Mol Cell Biol19: 41824190, 1999.
102.
LamLT, BresnickEH. A novel DNA-binding protein, HS2NF5, interacts with a functionally important sequence of the human β-globin locus control region. J Biol Chem271: 3242132429, 1996.
103.
LamLT, BresnickEH. Identity of the β-globin locus control region binding protein HS2NF5 as the mammalian homolog of the notch-regulated transcription factor suppresser of hairless. J Biol Chem273: 2422324231, 1998.
104.
FurukawaT, MaruyamaS, KawaichiM, HonjoT. The Drosophila homolog of the immunoglobulin recombination signal- binding protein regulates peripheral nervous system development. Cell69: 11911197, 1992.
105.
SchweisguthF, PosakonyJW. Suppresser of hairless, the Drosophila homolog of the mouse recombination signal-binding protein gene, controls sensory organ cell fates. Cell69: 11991212, 1992.
106.
CheungP, AllisCD, Sassone-CorsiP. Signaling to chromatin through histone modifications. Cell103: 263271, 2000.
107.
PazinMJ, KadonagaJT. What's up and down with histone deacetylation and transcription?Cell89: 325328, 1997.
108.
SchubelerD, LorinczMC, CimboraDM, TellingA, FengYQ, BouhassiraEE, GroudineM. Genomic targeting of methylated DNA: influence of methylation on transcription, replication, chromatin structure, and histone acetylation. Mol Cell Biol20: 91039112, 2000.
109.
Martin-BlancoE. p38 MAPK signaling cascades: ancient roles and new functions. Bioessays22: 637645, 2000.
110.
OnoK, HanJ. The p38 signal transduction pathway: activation and function. Cell Signal12: 113, 2000.
111.
TamuraK, SudoT, SenftlebenU, DadakAM, JohnsonR, KarinM. Requirement for p38α in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell102: 221231, 2000.
112.
CrossleyM, OrkinSH. Phosphorylation of the erythroid transcription factor GATA-1. J Biol Chem269: 1658916596, 1994.
ArmstrongJA, EmersonBM. NF-E2 disrupts chromatin structure at human β-globin locus control region hypersensitive site 2 in vitro. Mol Cell Biol16: 56345644, 1996.
115.
BirdAP, WolffeAP. Methylation-induced repression—belts, braces, and chromatin. Cell99: 451454, 1999.
116.
NgHH, BirdA. DNA methylation and chromatin modification. Curr Opin Genet Dev9: 158163, 1999.
117.
HardisonR. Hemoglobins from bacteria to man: evolution of different patterns of gene expression. J Exp Biol201: 10991117, 1998.
118.
MuchardtC, YanivM. ATP-dependent chromatin remodeling: SWI/SNF and Co. are on the job. J Mol Biol293: 187198, 1999.
119.
ArmstrongJA, BiekerJJ, EmersonBM. A SWI/SNF-related chromatin remodeling complex, E-RC1, is required for tissue-specific transcriptional regulation by EKLF in vitro. Cell95: 93104, 1998.
120.
O'neillD, YangJ, Erdjument-BromageH, BornschlegelK, TempstP, BankA. Tissue-specific and developmental stage-specific DNA binding by a mammalian SWI/SNF complex associated with human fetal-to-adult globin gene switching. Proc Natl Acad Sci USA96: 349354, 1999.
121.
MolnarA, GeorgopoulosK. The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol14: 82928303, 1994.
122.
WangJH, NichogiannopoulouA, WuL, SunL, SharpeAH, BigbyM, GeorgopoulosK. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity5: 537549, 1996.
123.
GeorgopoulosK, BigbyM, WangJH, MolnarA, WuP, WinandyS, SharpeA. The Ikaros gene is required for the development of all lymphoid lineages. Cell79: 143156, 1994.
124.
ZhangW, BiekerJJ. Acetylation and modulation of erythroid Krüppel-like factor (EKLF) activity by interaction with histone acetyl-transferases. Proc Natl Acad Sci USA95: 98559860, 1998.
125.
BlobelGA, NakajimaT, EcknerR, MontminyM, OrkinSH. CREB-binding protein cooperates with transcription factor GATA-1 and is required for erythroid differentiation. Proc Natl Acad Sci USA95: 20612066, 1998.
126.
BoyesJ, NakataniY, OrgyzkoV. Regulation of activity of the transcription factorGATA-1 by acetylation. Nature396: 594598, 1998.
127.
VisvaderJE, CrossleyM, HillJ, OrkinSH, AdamsJM. The C-terminal zinc finger of GATA-1 or GATA-2 is sufficient to induce megakaryocytic differentiation of an early myeloid cell line. Mol Cell Biol15: 634641, 1995.
128.
HungHL, KimAY, HongW, RakowskiC, BlobelGA. Stimulation of nf-e2 dna binding by creb-binding protein (cbp)-mediated acetylation. J Biol Chem276: 1071510721, 2001.
129.
ZhaoK, WangW, RandoOJ, XueY, SwiderekK, KuoA, CrabtreeGR. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell95: 625636, 1998.
130.
ZhumaT, TyrrellR, SekkaliB, SkavdisG, SavelievA, TolainiM, RoderickK, NortonT, SmerdonS, SedgwickS, FestensteinR, KioussisD. Human HMG box transcription factor HBP1: a role in hCD2 LCR function. EMBO J18: 63966406, 1999.
131.
LavenderP, VandelL, BannisterAJ, KouzaridesT. The HMG-box transcription factor HBP1 is targeted by the pocket proteins and E1A. Oncogene14: 27212728, 1997.
132.
BrehmA, MiskaEA, McCanceDJ, ReidJL, BannisterAJ, KouzaridesT. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature391: 597601, 1998.
133.
Kowenz-LeutzE, LeutzA. A C/EBP β isoform recruits the SWI/SNF complex to activate myeloid genes. Mol Cell4: 735743, 1999.
134.
VerbeekW, GombartAF, ChumakovAM, MullerC, FriedmanAD, KoefflerHP. C/EBPe directly interacts with the DNA binding domain of c-myb and cooperatively activates transcription of myeloid promoters. Blood93: 33273337, 1999.
135.
MinkS, HaenigB, KlempnauerKH. Interaction and functional collaboration of p300 and C/EBPβ. Mol Cell Biol17: 66096617, 1997.
136.
RyanTM, BehringerRR, MartinNC, TownesTM, PalmiterRD, BrinsterRL. A single erythroid-specific DNase I super-hypersensitive site activates high levels of human β-globin gene expression in transgenic mice. Genes Dev3: 314323, 1989.
137.
FraserP, HurstJ, CollisP, GrosveldF. DNasel hypersensitive sites 1, 2 and 3 of the human β-globin dominant control region direct position-independent expression. Nucleic Acids Res18: 35033508, 1990.
138.
NavasPA, JosephsonB, FurukawaT, StamatoyannopoulosG, LiQ. The position of integration affects expression of the A γ-globin-encoding gene linked to HS3 in transgenic mice. Gene160: 165171, 1995.
139.
CaterinaJJ, RyanTM, PawlikKM, PalmiterRD, BrinsterRL, BehringerRR, TownesTM. Human β-globin locus control region: analysis of the 5′ DNase I hypersensitive site HS 2 in transgenic mice. Proc Natl Acad Sci USA88: 16261630, 1991.
140.
LiuD, ChangJC, MoiP, LiuW, KanYW, CurtinPT. Dissection of the enhancer activity of β-globin 5′ DNase I- hypersensitive site 2 in transgenic mice. Proc Natl Acad Sci USA89: 38993903, 1992.
141.
NavasPA, PetersonKR, LiQ, McArthurM, StamatoyannopoulosG. The 5′HS4 core element of the human β-globin locus control region is required for high-level globin gene expression in definitive but not in primitive erythropoiesis. J Mol Biol312: 1726, 2001.
142.
NavasPA, PetersonKR, LiQ, SkarpidiE, RohdeA, ShawSE, CleggCH, AsanoH, StamatoyannopoulosG. 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 Biol18: 41884196, 1998.
143.
FieringS, EpnerE, RobinsonK, ZhuangY, TellingA, HuM, MartinDI, EnverT, LeyTJ, GroudineM. Targeted deletion of 5′HS2 of the murine β-globin LCR reveals that it is not essential for proper regulation of the β-globin locus. Genes Dev9: 22032213, 1995.
144.
TrainorCD, EvansT, FelsenfeldG, BoguskiMS. Structure and evolution of a human erythroid transcription factor. Nature343: 9296, 1990.
145.
ShivdasaniRA, FujiwaraY, McDevittMA, OrkinSH. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J16: 39653973, 1997.
146.
PevnyL, SimonMC, RobertsonE, KleinWH, TsaiSF, D'agatiV, OrkinSH, CostantiniF. Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature349: 257260, 1991.
147.
PevnyL, LinCS, D'agatiV, SimonMC, OrkinSH, CostantiniF. Development of hematopoietic cells lacking transcription factor GATA-1. Development121: 163172, 1995.
148.
WhyattD, LindeboomF, KarisA, FerreiraR, MilotE, HendriksR, de BruijnM, LangeveldA, GribnauJ, GrosveldF, PhilipsenS. An intrinsic but cell-nonautonomous defect in GATA-1-overexpressing mouse erythroid cells. Nature406: 519524, 2000.
149.
BoyesJ, OmichinskiJ, ClarkD, PikaartM, FelsenfeldG. Perturbation of nucleosome structure by the erythroid transcription factor GATA-1. J Mol Biol279: 529544, 1998.
150.
TowatariM, MayGE, MaraisR, PerkinsGR, MarshallCJ, CowleyS, EnverT. Regulation of GATA-2 phosphorylation by mitogen-activated protein kinase and interleukin-3. J Biol Chem270: 41014107, 1995.
151.
ShavitJA, MotohashiH, OnoderaK, AkasakaJ, YamamotoM, EngelJD. Impaired megakaryopoiesis and behavioral defects in MafG-null mutant mice. Genes Dev12: 21642174, 1998.
152.
OnoderaK, ShavitJA, MotohashiH, YamamotoM, EngelJD. Perinatal synthetic lethality and hematopoietic defects in compound MafG::MafK mutant mice. EMBO J19: 13351345, 2000.
153.
BlankV, KimMJ, AndrewsNC. Human MafG is a functional partner for p45 NF-E2 in activating globin gene expression. Blood89: 39253935, 1997.
154.
BlankV, KnollJH, AndrewsNC. Molecular characterization and localization of the human MAFG gene. Genomics44: 147149, 1997.
155.
AndrewsNC, Erdjument-BromageH, DavidsonMB, TempstP, OrkinSH. Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein. Nature362: 722728, 1993.
156.
AndrewsNC, KotkowKJ, NeyPA, Erdjument-BromageH, TempstP, OrkinSH. The ubiquitous subunit of erythroid transcription factor NF-E2 is a small basic-leucine zipper protein related to the v-Maf oncogene. Proc Natl Acad Sci USA90: 1148811492, 1993.
GumucioDL, SheltonDA, BaileyWJ, SlightomJL, GoodmanM. Phylogenetic footprinting reveals unexpected complexity in trans factor binding upstream from the ε-globin gene. Proc Natl Acad Sci USA90: 60186022, 1993.
159.
JaneSM, NeyPA, VaninEF, GumucioDL, NienhuisAW. 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 J11: 29612969, 1992.
160.
JaneSM, GumucioDL, NeyPA, CunninghamJM, NienhuisAW. 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 Biol13: 32723281, 1993.
161.
ZhouW, CloustonDR, WangX, CerrutiL, CunninghamJM, JaneSM. Induction of human fetal globin gene expression by a novel erythroid factor, NF-E4. Mol Cell Biol20: 76627672, 2000.
