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Mol Cell Biol. 2005 February; 25(4): 1215–1227.
PMCID: PMC548021

GATA1 Function, a Paradigm for Transcription Factors in Hematopoiesis

TRANSCRIPTIONAL CONTROL OF HEMATOPOIESIS

The development of mature blood cells of distinct lineages, from the hematopoietic stem cells (HSCs), involves a progressive restriction of differentiation potential and the establishment of lineage-specific gene expression profiles (Fig. (Fig.1).1). The establishment of these expression profiles relies on lineage-specific transcription factors to modulate the expression of their target genes. Therefore, hematopoiesis is an excellent model system to investigate how particular transcription factors influence the establishment of lineage-specific expression profiles and how their activity is regulated. In this review we focus on the present knowledge of the biological functions of the hematopoietic transcription factor GATA1. Many aspects of its function have been revealed since its first description in 1988. Yet many new questions have surfaced, and many old questions remain to be answered. Thus, GATA1 has been in the floodlight of modern biology as a paradigm for hematopoietic transcription factors in general and GATA factors in particular.

FIG. 1.
The hematopoietic tree. Schematic representation of the main lineage commitment steps in hematopoiesis. The hematopoietic stem cell (HSC) is the basis of the hematopoietic hierarchy and gives rise to multilineage progenitors (MLP), which can differentiate ...

THE GATA FAMILY OF TRANSCRIPTION FACTORS

The GATA family consists of six transcription factors, GATA1 to GATA6. These transcription factors are categorized as a family due to the fact that they all bind to the DNA consensus sequence (A/T)GATA(A/G) by two characteristic C4 (Cys-X2-Cys-X17-Cys-X2-Cys) zinc-finger motifs specific to the GATA family (50, 60, 65, 126, 129). The DNA-binding regions are highly homologous between the GATA family members (Fig. (Fig.2).2). Outside these regions, the conservation between GATA factors is low (81, 129). Furthermore, the overall homologies for individual members are higher between species than between different members of the same species (129, 136).

FIG. 2.
The hematopoietic GATA transcription factors. A schematic representation of the mouse hematopoietic GATA proteins is shown. The highly conserved region comprising the zinc-finger domains is indicated in black; the regions between the zinc-chelating cysteines ...

The GATA family is divided into two subfamilies on the basis of the expression profiles of the individual transcription factors. GATA1, GATA2, and GATA3 belong to the hematopoietic subfamily, since they are expressed mainly in the hematopoietic system (Fig. (Fig.2)2) (121). The nonhematopoietic subfamily is composed of GATA4, GATA5, and GATA6, which are expressed in several tissues, including intestine, lung, and heart (70).

GATA1: A BIRD IN THE HAND

GATA1, also known as NF-E1, NF-1, Ery-1 and GF-1, is the founding member of the GATA family of transcription factors. It was first identified as a protein with binding specificity to the β-globin 3′ enhancer (117) and cloned from a mouse erythroleukemia cell line cDNA expression library (105) and from chicken red cells (21). The human homologue was cloned soon after, and its localization was assigned to the X chromosome at position Xp21-11 (137). The mouse GATA1 gene is also located on the X chromosome (137).

GATA1 is expressed in primitive and definitive erythroid cells (27, 55), megakaryocytes (61, 92), eosinophils (138), and mast cells (61) and in the Sertoli cells of the testis (46, 131). Several gene-targeting studies were performed to elucidate the importance of GATA1 function in these cells.

These studies have shown that GATA1 is essential for normal erythropoiesis. GATA1-deficient embryonic stem cells are able to contribute to all different tissues in chimeric mice, with the exception of the mature red blood cells (87). More detailed analysis of erythropoiesis in these chimeric mice revealed that GATA1 null erythroid cells fail to mature beyond the proerythroblast stage (86). In vitro differentiation of GATA1-deficient embryonic stem cells confirmed this arrest of both primitive and definitive erythropoiesis at the proerythroblast stage (120) and showed that the arrested precursors die by apoptosis (122). Not surprisingly, GATA1 null mouse embryos die from severe anemia between embryonic day 10.5 (E10.5) and E11.5 (27). GATA1 knockdown embryos (GATA1.05), which express only approximately 5% of the wild-type GATA1 levels, also show an arrest of the primitive erythropoiesis and die between E11.5 and E12.5 (100). Other GATA1 knockdown mice (GATA1 low) (63), which express about 20% of the wild-type GATA1 levels, show a somewhat milder phenotype. Despite the fact that the majority of GATA1-low mice die between E13.5 and E14.5 due to ineffective primitive and definitive erythroid differentiation, some are born alive (2% instead of the expected 25%) and a small number survive to adulthood. These mice are anemic at birth, but they recover from the anemia and show a normal life span. From the analysis of these different mouse models a direct relationship between the expression levels of GATA1 and the severity of the phenotype is evident.

The analysis of a megakaryocyte-specific knockdown of GATA1 has revealed a critical role for this factor in megakaryocytic development (97). Absence of GATA1 in megakaryocytes leads to an increased proliferation and deficient maturation of megakaryocytic progenitors as well as reduced number of circulating platelets. The platelets produced are not fully functional and show an abnormal morphology (113).

GATA1 also plays an essential role in eosinophil development. The first evidence of the role of GATA1 in eosinophil development came from the observation that forced GATA1 expression in Myb-Ets-transformed chicken myeloblasts induced a reprogramming of these myeloblasts into cells resembling either transformed eosinophils or thromboblasts (52). Furthermore, the deletion of a double GATA site present in the GATA1 promoter causes the selective loss of the eosinophilic lineage (132).

Mast cells are somewhat different from the majority of the hematopoietic cells. They originate in the HSC in the bone marrow, but the precursor cells migrate, through the blood, to connective or mucosal tissues, where they proliferate and differentiate into mature mast cells. GATA1 is abundant in the more mature mast cells, but it is almost undetectable in the bone marrow progenitors, suggesting a possible role in the terminal differentiation of mast cells (38). Also, it was noticed that with GATA1.05 heterozygous female mice, expressing 5% of the wild-type GATA1 levels in approximately 50% of the cells owing to the process of X inactivation, some mast cells show defective maturation (38). Final proof of the importance of GATA1 in mast cell maturation arose from the analysis of GATA1-low mice (67). Since some reach adulthood, a more detailed analysis of the mast cell phenotype could be performed. Indeed, connective tissues from GATA1-low mice contain large numbers of mast cell precursors but normal numbers of mature mast cells, with abnormal morphology. Many of these precursors die by apoptosis, which explains the normal numbers of mature cells. The defect observed is GATA1 specific, since forced expression of GATA1 rescues the maturation potential of these cells.

Outside the hematopoietic system, GATA1 is expressed in the Sertoli cells of the testis at critical stages of spermatogenesis (46, 131). However, Sertoli cell-specific deletion of GATA1 does not result in an apparent phenotype (56).

Despite all the knowledge about the consequences of GATA1 absence in different hematopoietic lineages we are far from knowing the specific functions performed by this transcription factor in those cells. On the basis of the observation that GATA1 null erythroid cells undergo apoptosis, it as been suggested that GATA1 is directly involved in cell survival. Several lines of evidence support this theory: GATA1 activates transcription of the erythropoietin receptor (EpoR) (10), and Epo signaling is known to be important for the survival of erythroid progenitors (53). Furthermore, one of the known target genes of GATA1 is Bcl-XL, a gene encoding an antiapoptotic protein (32).

Another possible GATA1 function is the regulation of G1/S cell cycle progression. Cell cycle control is of the utmost importance in hematopoietic differentiation, since progenitors must be able to proliferate to proceed through hematopoietic development, but for terminal differentiation to occur cells must exit the cell cycle (127). A variety of GATA1 target genes have been identified that are involved in cell cycle regulation or have known functions in proliferation and differentiation processes (93).

GATA1 has also been implicated in the reprogramming of hematopoietic precursors. Forced expression of GATA1 was shown to reprogram myeloblasts and CD34+ bone marrow cells to develop into eosinophils (41, 52). Furthermore, forced expression of GATA1 reprograms granulocyte-monocyte progenitors (GMPs) to give rise to erythroid, eosinophilic, and basophile-like cells (40). By clone tracking the authors demonstrated that the GATA1 effect occurs at the cell commitment level and is not due to effects on clone selection. Another recent report (47) shows that ectopic GATA1 expression guides hematopoietic precursors to commitment to the erythrocyte-megakaryocytic lineage. It is not clear from these reports whether lineage reprogramming is a GATA1-specific characteristic or whether it is a general effect of the ectopic expression of lineage-specific transcription factors.

FUNCTIONAL DOMAINS OF GATA1

At least three functional domains have been identified within the GATA1 protein (Fig. (Fig.2):2): an N-terminal activation domain, the N-terminal zinc finger (N-finger), and the C-terminal zinc finger (C-finger). The C-finger is essential for GATA1 function, since it is responsible for the recognition of the GATA consensus sequence and consequent binding to DNA (Fig. (Fig.3)3) (60, 130). The importance of the N-finger to GATA1 function has been more difficult to define. Although early studies, in nonerythroid cells, indicated that the N-finger was not essential for GATA1-mediated transcriptional activation (60), it was later shown that this zinc finger plays a crucial role in GATA1's ability to induce terminal erythroid differentiation (123). The N-finger contributes to the stabilization and specificity of DNA binding (28, 60, 104, 126). The N-finger mediates the formation of complexes with cofactors. These interactions can involve only the N-finger, as is the case with FOG-1 (23), or occur in collaboration with the C-finger, for example, with Sp1 and EKLF (31, 66) and GATA1 itself (58). Early studies, using reporter assays in nonerythroid cells, showed that the most N-terminal 80 amino acids of the GATA1 protein are essential for its transcriptional activation activity (60). Surprisingly, in another study (123) this transactivation domain appeared to be dispensable for GATA1-mediated terminal erythroid differentiation.

FIG. 3.
Three-dimensional (3D) representation of the C-terminal finger of chicken GATA1 bound to DNA. The figure was prepared using the file 2GAT.pdb (101) and Swiss-pdb viewer software (http://www.expasy.org/spdbv/) (33). The 3D structure of the 66-aa peptide ...

To examine the function of each of the three GATA1 domains in a more robust way, Shimizu and colleagues (95) made use of transgenic rescue of GATA1.05 knockdown mice. By analysis of the offspring resulting from the crossing between GATA1.05 mice and transgenic mice expressing different GATA1 mutants, the requirements for the different functional domains were unraveled. In agreement with the previous reports, the C-finger was found to be indispensable for GATA1 function in both primitive and definitive erythropoiesis, but the N-finger was found to be necessary only for definitive erythropoiesis. Like the N-finger, the transactivation domain appeared to have different functions in primitive and definitive erythropoiesis. When expressed at levels higher than that of the endogenous GATA1, the transactivation domain mutant can sustain both primitive and definitive erythropoiesis, but when expressed at lower levels, definitive erythropoiesis is impaired. From these data it can be concluded that all three GATA1 domains are required for definitive erythropoiesis. For primitive erythropoiesis, GATA1 lacking either the N-terminal transactivation domain or the N-finger suffices. This demonstrates that the primitive and definitive erythroid lineages have distinct requirements for GATA1.

REGULATION OF GATA1 ACTIVITY

GATA1 activity in vivo is tightly regulated. Increasing GATA1 activity can lead to phenotypes as strong as embryonic lethality (see, e.g., reference 125). The activity of proteins can be regulated by a wide variety of mechanisms. The mechanisms thought to be involved in the regulation of GATA1 activity is discussed in this section.

Transcriptional regulation.

The GATA1 transcription unit is composed of two alternative untranslated first exons, IT and IE (46), and five translated exons, II to VI (106). Exon IT is primarily used in Sertoli cells of the testis, while exon IE is used in hematopoietic cells (Fig. (Fig.4)4) (46). The proteins expressed in hematopoietic and Sertoli cells are identical, since exon II harbors the translation start site. The two zinc-finger motifs are encoded separately in exons IV and V.

FIG. 4.
The mouse GATA1 locus. The exon-intron structure of the mouse GATA1 gene is displayed, and the positions of known regulatory elements (bars) and hematopoietic DNase I HS sites (red arrows) (36, 63) are shown. Translated sequences are in dark purple. IT, ...

The testis promoter and exon IT are located 8 kb upstream of exon IE. Disruption of the erythroid promoter leads to an arrest in primitive erythropoiesis without affecting the expression from the testis promoter (100). Both testis- and erythroid-specific promoters contain GATA sites that are required for the proper functioning of the promoter (46, 80, 114), suggesting a possible feedback loop (106). Both GATA1 promoters lack an obvious TATA box (37, 106).

DNase I hypersensitivity analysis of the GATA1 locus in erythroid cells identified three main hypersensitive (HS) regions. HS1 is located between 3.9- and 2.6kb upstream of IE, HS2 corresponds to the region surrounding the IE promoter, and HS3 is localized in intron 1 (Fig. (Fig.4)4) (62, 110).

Transcription of the GATA1 gene in different hematopoietic lineages has different regulatory sequence requirements. HS1, coinciding with the GATA1 hematopoietic enhancer, can drive reporter gene transcription exclusively in primitive erythrocytes whereas together with intron 1 this element can drive expression of a reporter gene in both primitive and definitive erythroid cells (79). Furthermore, GATA1 transcription in erythroid and megakaryocytic cells has different sequence requirements within HS1 (97, 114). Expression in both lineages is dependent on the presence of an intact GATA site, but megakaryocytic expression requires the 3′ end of HS1, which is dispensable for erythroid expression. Surprisingly, deletion of HS1 does not affect the expression of GATA1 in eosinophils, suggesting that the intron 1 enhancer/HS3 is essential for this function (36).

Translational regulation.

GATA1 possesses an alternative translation initiation site located at methionine 84 (8). Translation from this site gives rise to a 40-kDa protein, GATA1s, which lacks 83 amino acids at the N-terminal region, i.e., the N-terminal transactivation domain (Fig. (Fig.2).2). GATA1s can be detected in MEL and K562 cells as well as in mouse tissues, but its expression level is much lower than that of full-length GATA1. The GATA1s protein shows normal DNA binding activity but a reduced transactivation potential, which is in agreement with the reported role of the N terminus as a transactivation domain (60).

Although GATA1 mutants lacking the N-terminal transactivation domain can rescue the GATA1.05 knockdown phenotype when expressed at high levels (95), it can be concluded that GATA1s is not fully functional and therefore is unable to drive terminal erythroid and megakaryocytic differentiation when expressed at normal levels.

Posttranslational regulation. (i) Acetylation.

GATA1 can be acetylated both in vitro and in vivo by the ubiquitously expressed acetyltransferases P300 (6) and CREB-binding protein (CBP) (43). Mouse GATA1 is acetylated at two conserved lysine-rich motifs (amino acids 245 to 252 and 308 to 316) localized just C terminal from each of the zinc fingers (Fig. (Fig.22 and and3).3). These motifs are conserved among members of the GATA family and between different species.

The functional importance of GATA1 acetylation is not clear. The interaction between GATA1 and P300/CBP and, consequently, acetylation of the transcription factor appears to stimulate its transcriptional activity (5, 6). Boyes et al. reported that in chicken GATA1, acetylation increased DNA-binding activity (6), but Hung et al. did not see this effect with mouse GATA1 (43). Acetylation of GATA1 appears to be required for the in vitro differentiation of the GATA1 null cell line G1E (43). Furthermore, an acetylation mutant of GATA1 was severely impaired in its ability to rescue the phenotype of the GATA1 mutation vlad tepes in the zebra fish, which was attributed to the reduced ability of the acetylation mutant to self-associate (76).

(ii) Phosphorylation.

GATA1 can be phosphorylated at seven serine residues (16). Six of these residues (S26, S49, S72, S142, S178, and S187), situated at the N terminus of the protein, are phosphorylated in uninduced MEL cells. The seventh serine (S310), which is located near the DNA-binding domain (Fig. (Fig.3),3), only becomes phosphorylated upon dimethyl sulfoxide induction of the MEL cells. This suggests a possible role of phosphorylation in both DNA binding and transcriptional activity of the protein. Surprisingly, substitution of the serines for alanines did not have any consequence in GATA1 DNA binding or transcriptional activity (16). Another somewhat contradictory report shows that the phosphorylation of GATA1, in induced K562 cells, increases DNA binding (84). The same report confirms that such an increase in DNA binding does not occur in induced MEL cells and suggests that GATA1 is already phosphorylated in uninduced MEL cells whereas in K562 cells GATA1 becomes phosphorylated upon induction, which leads to an increased DNA binding activity of the protein. Recently, it has been demonstrated that mitogen-activated protein kinase signaling has a role in the control of GATA1 phosphorylation and that GATA1 is phosphorylated in response to cytokine-induced signaling in factor-dependent hemopoietic progenitor cells (103). This study identified extracellular signal-regulated kinase as an in vivo GATA1 kinase.

(iii) SUMOylation.

The small ubiquitin-related modifier (SUMO) is a ubiquitin-like peptide that can be ligated to a lysine residue of the target protein. A number of transcription factors can be modified by SUMOylation (111). This reversible modification is thought to be associated with transcriptional repression (94). The consensus site for SUMOylation (I/L/V)KXE is present at K137 of mouse GATA1 (Fig. (Fig.2).2). This motif can be modified by SUMOylation through the action of the SUMO ligase PIASy (13). The functional significance of this modification remains unknown.

Protein degradation.

Another possible regulatory mechanism for protein activity in general is degradation. One hypothesis is that levels of GATA1 activity must be high at early stages of erythroid differentiation but must be downregulated for terminal erythroid differentiation to occur (125). This implies that protein degradation is a potentially important regulatory mechanism for GATA1 function.

GATA1 degradation via caspase-mediated cleavage has been reported previously (18). This study shows that activation of caspases, via death receptors, leads to an arrest in terminal erythroid differentiation. The authors attributed the differentiation arrest to a decrease in GATA1 protein levels due to caspase-mediated cleavage, since expression of a caspase-resistant GATA1 mutant, but not that of wild-type GATA1, restored erythroid differentiation.

From the observation that the Fas death receptor is expressed throughout erythroid differentiation but its ligand, FasL, is only expressed in the more mature erythroblasts a model emerges in which mature erythroblasts participate in a negative-feedback loop to attenuate differentiation of earlier erythroid progenitors.

Intriguingly, we have shown that overexpression of GATA1 in erythroid cells, both in vitro (127) and in vivo (125), inhibits erythroid differentiation. On the basis of these observations a slightly different model can be envisaged: GATA1 degradation by caspases leads to a reduction of GATA1 levels at late stages of erythroid differentiation, thereby allowing terminal differentiation (Fig. (Fig.5).5). We have found that in the presence of high levels of GATA1, erythroid cells fail to differentiate but, surprisingly, that if wild-type erythroid cells are present, the overexpressing cells can differentiate normally (125). Further analysis showed that differentiating erythroid cells can signal to GATA1-overexpressing erythroid cells, which are normally blocked in differentiation, to terminally differentiate (35). This might involve activation of death receptors present in differentiating cells by ligands produced by terminally differentiating erythroid cells, promoting caspase-mediated cleavage of GATA1. Such a homotypic signaling mechanism could ensure that the production of mature erythrocytes is in keeping with demand, because the abundance of terminally differentiating cells would show an inverse correlation with the expansion of erythroid progenitors.

FIG. 5.
Model for the dynamic regulation of GATA1 and GATA2 activity during erythropoiesis. GATA2 is expressed at high levels in early erythroid progenitors. When GATA1 is activated, GATA2 is repressed and GATA1 levels increase, possibly through cross-talk between ...

PROTEIN-PROTEIN INTERACTIONS

GATA1 is now known to interact with a variety of proteins, either cofactors or transcription factors. These interactions play important roles in hematopoiesis, since they lead to transcriptional activation or repression of GATA1 target genes. The most important interactions between GATA1 and other proteins known to date are reviewed in this section.

GATA1

. It has been shown that GATA1 can self-associate in vitro (15), both in solution and when bound to DNA. Both the C-finger and the N-finger can independently associate with full-length GATA1 protein, since the interaction is mediated by N-finger-C-finger contacts (58). GATA1 dimerization may play an important role in the regulation of promoters containing multiple GATA sites, since mutation of particular residues in the finger regions reduces the GATA1 transactivation potential in reporter assays (58). Furthermore, GATA1 dimerization was shown to be important for the positive regulation of the GATA1 promoter in zebra fish (76).

Other potential functions for GATA1 dimerization may be to establish contact between promoters and enhancers and to recruit chromatin-remodeling complexes.

Friend of GATA1 (FOG, FOG-1, or ZFPM1).

FOG-1, a protein containing nine widely spaced zinc fingers, was identified in a yeast two-hybrid screening as a GATA1 cofactor (108). It binds to the N-terminal zinc finger of GATA1 mainly via its zinc finger 6 (23), although fingers 1, 5, and 9 also contribute to the binding (24). FOG-1 is coexpressed with GATA1 in the erythroid and megakaryocytic lineages and cooperates with GATA1 during erythroid and megakaryocytic differentiation (108).

The phenotype of FOG-1 null mice closely resembles the GATA1 knockout phenotype. Mutant mice of both lineages die during midgestation from severe anemia caused by a defect in primitive and definitive erythropoiesis, suggesting that FOG-1 is essential for GATA1 function. In contrast to GATA1 deficiency, however, loss of FOG-1 leads to a complete elimination of the megakaryocytic lineage, revealing a GATA1-independent role of FOG-1 in megakaryopoiesis (Fig. (Fig.1)1) (107). Definitive proof that the FOG-1/GATA1 interaction is essential for GATA1 function during erythroid differentiation was obtained by the analysis of GATA1 mutants defective in FOG-1 binding and subsequent identification of compensatory mutations in the FOG-1 (14). Erythroid precursors expressing GATA1 mutants unable to bind FOG-1 fail to differentiate, but this phenotype is rescued by the expression of the FOG-1 mutants that can bind these GATA1 mutant proteins.

Although it has no apparent DNA-binding activity, FOG-1 is known to differentially modulate GATA1 activity depending on the promoter context. It synergizes with GATA1 in the activation of certain promoters (108) while repressing GATA1-mediated activation of other promoters (24). A recent paper suggests that FOG-1 is rapidly induced by GATA1 in erythroid cells (124). This induction is independent of protein synthesis. Together with the observation that GATA-1 binds to the FOG-1 locus in vivo at a putative enhancer, these data suggest that the FOG-1 gene is activated directly by GATA1. In contrast, protein synthesis appeared to be required for the activation of β-globin transcription. Thus, a model emerges in which GATA1 first induces FOG-1, after which both factors cooperate in the activation of the β-globin locus.

RB.

The tumor suppressor protein retinoblastoma (RB) plays important roles in many stages of the differentiation process, including regulation of progenitor proliferation, terminal cell cycle exit, induction of tissue-specific gene expression, and protection from apoptosis (57). Mice deficient for RB are embryonically lethal and show neuronal and erythroid defects (Fig. (Fig.1)1) (48, 54). An intrinsic role for RB in erythropoiesis is further supported through the use of use of an in vitro erythroid differentiation culture system (11). GATA1 has been shown to bind RB. Furthermore, GATA1 overexpression in MEL cells leads to RB inactivation through hyperphosphorylation via an as-yet-unknown mechanism (127).

Krüppel-like factors.

GATA1 can physically interact and functionally synergize with Sp1 and erythroid Krüppel-like factors (EKLF or KLF1) (31, 66), two transcription factors belonging to the SP/KLF family of transcription factors (reviewed in reference 89).

Sp1 is a ubiquitously expressed transcription factor essential for early embryonic development. Sp1 null embryos die around E9.5 and show a broad range of abnormalities, but transcription of embryonic globin genes is activated (59). In contrast, EKLF is an erythroid-specific transcription factor (69). EKLF null mice are embryonic lethal due to a defect in definitive erythropoiesis (Fig. (Fig.1)1) (77, 85). These embryos succumb to fatal anemia owing to a defect in hemoglobin accumulation, explained by the EKLF requirement for β-globin expression (77, 85).

The fact that Sp1 and EKLF can recognize GC and/or CACC motifs, which are found in the close proximity to GATA motifs in several promoters, enhancers, and locus control regions (LCRs), suggests a functional cooperation between these proteins. GATA1 was shown to bind the zinc-finger domain of Sp1 and EKLF mainly via its C-finger, and reporter assays demonstrated that GATA1 transcriptional activity can be synergistically increased by these interactions (31, 66). The interaction between GATA1 and either Sp1 or EKLF is dependent on the presence of the promoter (31), suggesting discrete roles for these two factors in the regulation of erythroid-specific genes. EKLF is also a GATA1 target gene: three GATA binding sites were identified in the EKLF promoter, and one of them appears to be crucial for initiation of transcription (17). Moreover, forced expression of GATA1 can activate the EKLF promoter in nonerythroid cells, and EKLF expression is downregulated in the absence of GATA1 (125) and restored upon its reintroduction (96).

Interaction between GATA1 and Sp1 or EKLF may play a crucial role in, for example, bringing regulatory elements such as enhancers and LCRs in close proximity to promoters by promoting the formation of DNA loops. Recently, the formation of a complex containing the β-globin LCR and the promoters of the actively transcribed β-globin gene, the active chromatin hub (ACH), has been demonstrated previously (9, 102). Furthermore, the presence of the transcription factor EKLF is crucial for the formation of the ACH (19). It is conceivable that GATA1 in conjunction with EKLF also plays a role in the formation of the ACH.

Lmo2/Ldb1/Tal-1/E2A.

GATA1 is found in a complex together with Lmo2, Ldb1, Tal-1, and E2A that can activate transcription from promoters containing an E-box (CANNTG consensus sequence) and a GATA binding site separated by nine nucleotides (116). The GATA-E-box is present in the promoters of several genes (1, 12, 116), suggesting an important role for this motif. In the hematopoietic system, Tal-1 expression, driven by promoter Ia, is restricted to erythroid, megakaryocytic, and mast cell lineages (71a). The similarities between Tal-1 and GATA1 expression patterns and the presence of GATA consensus sequences in the Tal-1 promoter Ia suggested regulation of Tal-1 expression by GATA1. More detailed analysis of the promoter requirements for Tal-1 expression confirmed that GATA1 could activate its transcription (53a).

GATA1 interacts directly with Lmo2, but not with Tal-1, in erythroid cells (82, 83). These authors also showed that GATA1 and Tal-1, in the presence of Lmo2, synergistically activate transcription of reporter genes (83). From these data, a model was proposed in which GATA1 and the Tal-1-E2A complex bind DNA (109, 115). Lmo2 makes the bridge between the transcription factors, either as a single molecule or by homodimerization. The role of such a complex in hematopoiesis is not known, but, considering the similar functions of the proteins in hematopoiesis, it is likely that this complex is of extreme importance (Fig. (Fig.1)1) (68, 72, 118). This complex binds to the GATA-E-box motif in the upstream regulatory sequence (HS1) (Fig. (Fig.4)4) of the GATA1 gene, and the integrity of the GATA binding site is crucial for binding. However, the functional importance of these interactions remains unknown (114).

PU.1.

PU.1 is a member of the Ets family of transcription factors required for the development of the lymphoid and granulocytic-monocytic lineages (Fig. (Fig.1).1). Expression of PU.1 and GATA1 appears to be mutually exclusive, suggesting an antagonistic effect of these two transcription factors.

Several lines of evidence indicate that GATA1 and PU.1 functionally antagonize each other via direct physical interaction (74, 91, 134). PU.1 and GATA1 interaction takes place via the DNA-binding domains of both proteins (91, 134), but the mechanisms by which these transcription factors antagonize each other are quite distinct. GATA1 inhibits PU.1 by preventing it from interacting with its cofactor c-Jun (134), while PU.1 inhibits GATA1 by preventing its binding to DNA (135).

P300/CBP.

P300 and CBP are ubiquitously expressed proteins with histone acetyltransferase properties, known to interact with a large number of transcription factors. The mechanism by which P300 and CBP intervene in transcription regulation is not clear, and several models have been proposed. Binding of P300/CBP to transcription factors can be a way to recruit histone acetyltransferase to the vicinity of nucleosomes and induce an open chromatin configuration, thus stimulating transcription. CBP and P300 can also serve as a bridging molecule between components of the general transcription machinery and enhanceosome complexes (4). Furthermore, P300 and CBP are known to be responsible for the acetylation of transcription factors which may have a direct effect on their function (reviewed in reference 112). Indeed, mice homozygous for point mutations in the KIX domain of p300, disrupting the binding surface for the transcription factors c-Myb and CREB, display multilineage defects in hematopoiesis (49). It remains to be determined whether the interactions between GATA1 and CBP/P300 are of similar importance.

GATA1 binds P300 (6) and CBP (43) both in vitro and in vivo, and P300 and CBP acetylate GATA1 (Fig. (Fig.22 and and3)3) (6, 43). The involvement of P300/CBP in the recruitment of other transcription factors, cofactors, or chromatin-remodeling complexes to regulatory sequences bound by GATA1 may be envisaged.

PIASy.

The SUMO ligase PIASy interacts with GATA1 through recognition of amino-acid residues 136 to 139 (LKTE) of mouse GATA1 (Fig. (Fig.2)2) (13). The functional consequences of these interactions, and of SUMO modification of GATA1, are unknown.

GATA1 TARGET GENES

GATA sequences are quite abundant in the genome, and GATA consensus sequences can be found in the promoters of many genes. An increasing number of GATA1 target genes are being identified using functional assays and, more recently, high-throughput gene expression analysis afforded by DNA microarrays. In addition to those discussed in the section Protein-protein Interactions, a short overview of the most relevant of the growing number of known GATA1 target genes is given.

α- and β-globins.

GATA1 was first identified by its interaction with the β-globin gene enhancer and was soon shown to bind to multiple regulatory regions in both the α- and β-globin loci (22, 60, 117). Despite the absence of GATA1, GATA1 null erythroid cells are still able to produce hemoglobin, suggesting that GATA1 does not play a critical role in the transcription of the globin genes (120). Another possibility is that GATA1 is replaced by GATA2, which is known to be upregulated in GATA1 null cells, since GATA binding sites are essential for expression of β-LCR-driven transgenes (88).

Heme biosynthesis enzymes.

Hemoglobin, present in large quantities in erythrocytes, is the protein responsible for the transport of oxygen and carbon dioxide throughout the body. Hemoglobin is a tetrameric protein composed of two α-like and two β-like globin chains. Each globin chain carries a heme group, a ring-shaped molecule containing a central iron atom, which can reversibly bind oxygen. Heme is synthesized from glycin and succinyl coenzyme A via a series of steps involving the action of eight enzymes (reviewed in reference 90). Several of the genes encoding the enzymes involved in heme biosynthesis (ALA-S, ALA-D, PBG-D) are known GATA1 target genes (81, 93). The GATA1 target gene ABCme, encoding a mitochondrial transporter enzyme, is thought to mediate mitochondrial transport functions related to heme biosynthesis (96), emphasizing the important and broad function of GATA1 in erythroid cells.

Epo and EpoR.

Erythropoietin (Epo) is the major growth factor for erythroid cells. Epo interacts with the Epo receptor (EpoR), a cell surface receptor expressed in erythroid, megakaryocytic, and mast cells, triggering signaling cascades leading to the proliferation, differentiation, and survival of erythroid progenitors (reviewed in reference 53).

GATA1 was first reported to be involved in the regulation of the EpoR gene by Zon and colleagues (139). These authors showed that GATA1 could specifically bind and transactivate the EpoR promoter. A second report (10) also shows that GATA1 is expressed prior to the EpoR but that its expression is strongly enhanced by EpoR-mediated signals. Surprisingly, Weiss and colleagues (120) showed that EpoR is normally transcribed in GATA1 null erythroblasts, strongly suggesting a role for GATA2 in EpoR expression in early erythroid precursors.

In contrast to EpoR regulation results, GATA proteins negatively regulate Epo expression by binding to GATA sites in its promoter (44, 45).

Bcl-XL.

It has been hypothesized that GATA1, in collaboration with Epo, can act as a survival factor during erythroid differentiation. The mechanism by which that is accomplished is not known, but Bcl-x, a member of the Bcl2 gene family, is a good candidate to mediate survival during erythroid development. Due to alternative splicing the Bcl-X gene can produce two distinct mRNAs: Bcl-XL, a larger mRNA that codes for a protein with antiapoptotic properties, and Bcl-XS, a smaller mRNA that, surprisingly, codes for a proapoptotic protein. Bcl-XL expression increases in late stages of erythroid differentiation and appears to be dependent on the presence of Epo (30, 71, 98).

On the basis of these observations, Gregory and colleagues (32) analyzed the expression of Bcl-XL during erythroid differentiation in G1E GATA1 null erythroid progenitors rescued by the expression of GATA1. These data show that Bcl-XL is upregulated in a GATA1-dependent manner during erythroid differentiation. This suggests that GATA1, together with Epo, prevents apoptosis in differentiating erythroid cells by promoting the expression of antiapoptotic proteins such as Bcl-XL. A direct interaction between GATA1 and the BCL-X promoter has yet to be demonstrated.

Hematopoietic transcription factors. (i) GATA2.

GATA2 is an important regulator of hematopoiesis, its downregulation being crucial for hematopoietic differentiation. The first clue about a possible regulation of the GATA2 gene by GATA1 was the observation that GATA2 is upregulated in the absence of GATA1 (120). Further analysis of GATA1-regulated genes consistently identified GATA2 as being repressed by GATA1 (93, 96), but the mechanism through which repression is achieved remains unknown.

In a recent study (29), GATA1 was reported to bind to a region 2.4 kb upstream of the GATA2 1G promoter. The same report also shows that GATA2, together with CBP, can bind to the same regions as GATA1 in its absence and that displacement of GATA2 by GATA1 is the cause of repression (Fig. (Fig.5).5). This result suggests a mechanism by which GATA1 directly represses GATA2: GATA2, when bound to the kb −2.8 site of its own locus, recruits CBP to this region, leading to histone acetylation and, consequently, activation of transcription. GATA2 displacement by GATA1 leads to a loss of CBP and the establishment of a closed chromatin configuration. The displacement of GATA2 by GATA1 during erythroid differentiation has also been reported to occur at the α-globin locus (2); in this case, expression of the α-globin genes is activated after binding of GATA1.

(ii) MaFK and p45 NF-E2.

In addition to the results seen with other megakaryocyte-specific genes, the expression of the transcription factors MafK and p45 NF-E2 is significantly decreased in megakaryocytes expressing an N-finger mutant of GATA1 (V205G) and in GATA1-deficient megakaryocytes (96, 116). p45 NF-E2 p45 and small Maf factors are critical for terminal differentiation of megakaryocytes (71, 100). This suggests that the attenuated expression of the essential transcription factors NF-E2 p45 and MafK is a major cause of the megakaryocytic phenotype of GATA1 mutations.

Cell cycle core components and proliferation-related genes.

Overexpression studies have assigned a function to GATA1 in G1/S cell cycle progression (20, 127). Recently, Rylski and colleagues (93) have reported the identification of core cell cycle components as target genes of GATA1. The GATA1 null erythroid cell line G1E can be induced to differentiate by reintroduction of GATA1 (123). The authors used this model system to analyze the influence of GATA1 on the transcription of genes involved in activation and inhibition of cell cycle progression. GATA1 appeared to repress the expression of core cell cycle proteins such as Cyclin D2 and Cdk6 and activate transcription of cell cycle progression inhibitors such as p18INK4c and p27Kip1. Furthermore, GATA1 induced expression of growth inhibitors, including Btg2, Hipk2, JunB, and Crep, and downregulated the expression of genes with mitogenic properties such as Myc, Myb, and Nab2.

The experiments described above were not able to distinguish between a direct GATA1 target gene and genes that are differentially expressed due to secondary effects. To clarify this issue, the authors performed a more detailed analysis of the interactions between Myc and GATA1 and showed that GATA1 represses transcription of the Myc gene by directly binding to its promoter. Surprisingly, forced expression of Myc inhibited the GATA1-induced cell cycle arrest but not erythroid maturation. This suggests that Myc may be involved in the transcriptional control of cell cycle genes such as Cyclin D2 and p18INK4c and p27Kip1 but does not interfere with the control of genes involved in erythroid differentiation.

GATA1 MUTATIONS IN HUMAN DISEASE

Mutations in the N-terminal transactivation domain and the N-finger of GATA1 have been linked to human disease (Fig. (Fig.22 and and6).6). Acquired mutations in GATA1 are a hallmark of the transient myeloproliferative disorder (TMD) that occurs in ~10% of newborn children with constitutional trisomy 21 (Down syndrome) (119). In ~20% of the TMD cases, this is followed by Down syndrome-related acute megakaryocytic leukemia (DS-AMKL) later in life. The large majority of the mutations found introduce a premature stop codon in the N-terminal transactivation domain of GATA1, but splice site mutations also occur (reviewed in reference 34). These mutations result in the exclusive translation of the GATA1s isoform, lacking the N-terminal transactivation domain (Fig. (Fig.2).2). This truncated GATA1 protein has diminished transactivation potential in in vitro assays (119). Investigations of the GATA1.05 knockdown mutation in the mouse have demonstrated that reduced GATA1 activity prevents differentiation of the precursor cells but allows their survival. Interestingly, female mice heterozygous for the knockdown mutation develop a myeloproliferative disorder at high frequency (99). Together, these data strongly suggest that reduced GATA1 activity is an early event in the pathogenesis of DS-AMKL, allowing the expansion of TMD blast cells from which DS-AMKL develops after the apparent spontaneous remission.

FIG. 6.
Mutations in the N-terminal finger of GATA1 causing human disease. The figure was prepared using the file 1GNF.pdb (51) and Swiss-pdb viewer software (http://www.expasy.org/spdbv/) (33). The 3D structure of A201 to P240 of human and mouse GATA1 is displayed ...

Missense mutations in the N-finger of GATA1 have been found in patients with X-linked thrombocytopenia and anemia (3, 25, 26, 64, 75, 133). The majority of these mutations affect the FOG 1 interaction surface of the N-finger (Fig. (Fig.6),6), adversely affecting the binding of FOG-1 to the N-finger mutants (3, 25, 26, 64, 75, 133). This further emphasizes the importance of the FOG-1-GATA1 interaction. One mutation, R216Q, displays normal FOG-1 interaction. Compared to wild-type GATA1 results, this mutant binds with comparable affinity to single GATA sites but with decreased affinity to palindromic sites (133). This indicates that the DNA binding properties of the N-finger contribute to the overall function of GATA1. The severity of disease depends on the particular mutation: D218G results in macrothrombocytopenia and mild dyserythropoietic features but no marked anemia, while D218Y is a more severe mutation resulting in deep macrothrombocytopenia, marked anemia, and early mortality (26). These phenotypic differences correlate well with the stronger loss of affinity of the D218Y mutant for FOG1 binding compared with that seen with the D218G mutant.

Thus far, only a few mutations in GATA1 causing human disease have been described. This likely reflects the lethality of mutations affecting the function of GATA1 more severely, as can be deduced from the studies in the mouse. Nevertheless, the mutations in the N-terminal transactivation domain and N-finger have revealed novel and sometimes unexpected aspects of GATA1 function, opening up new directions for future research such as the elucidation of the molecular mechanisms leading to leukemogenesis in Down syndrome.

GATA1: THE FUTURE LOOKS BRIGHT

The interactions with cofactors and/or regulatory complexes are important parameters in transcription factor regulation. A variety of proteins have already been identified as interaction partners of the GATA transcription factors. These proteins include other transcription factors, non-DNA binding cofactors, chromatin-remodeling factors, and proteins involved in cell cycle regulation. The interactions with each of these proteins were identified individually; such procedures are laborious and overall reveal only a small amount of information. Recently a new one-step purification technique for isolation of protein complexes was developed. This technique consists in tagging the protein of interest with a small peptide that is specifically recognized by the Escherichia coli biotin ligase BirA (17). The system enables one-step purification of the in vivo biotinylated protein and its interacting partners through binding to streptavidin-coated beads. Purified proteins can then identified by mass spectrometry. By use of this method several new GATA1-interacting proteins were identified, in addition to previously described interaction partners (P. Rodriguez, E. Bonte, J. Krijgsveld, K. Kolodziej, B. Guyot, A. J. R. Heck, P. Vyas, E. de Boer, F. Grosveld, and J. Strouboulis, submitted for publication). The interacting proteins are components of well-characterized complexes involved not only in transcriptional activation but also in repression. Genome-wide chromatin immunoprecipitation analysis will help to clarify the function of these distinct complexes at GATA1 target loci during erythroid development (2, 7). In addition, it will be interesting to isolate complexes with, for example, GATA1 mutants defective in particular posttranslational modifications. The comparison between complexes identified with wild-type and mutant GATA1 proteins may reveal specific functions of a particular posttranscriptional modification. Because there are many more elusive aspects of GATA1 biology, we expect that GATA1 will indeed remain in the floodlight of modern biology, as a paradigm for hematopoietic transcription factors in general and GATA factors in particular.

Acknowledgments

Work in our laboratories is supported by the Dutch organization for scientific research NWO and the Dutch cancer foundation KWF (R.F. and S.P.) and by JST ERATO, the Ministry of Education, Science, Sports and Culture (Advanced Research for Cancer and General Area), the Naito Foundation, and JSPS-RFTF (K.O. and M.Y.).

REFERENCES

1. Anderson, K. P., S. C. Crable, and J. B. Lingrel. 1998. Multiple proteins binding to a GATA-E box-GATA motif regulate the erythroid Kruppel-like factor (EKLF) gene. J. Biol. Chem. 273:14347-14354. [PubMed]
2. Anguita, E., J. Hughes, C. Heyworth, G. A. Blobel, W. G. Wood, and D. R. Higgs. 2004. Globin gene activation during haemopoiesis is driven by protein complexes nucleated by GATA-1 and GATA-2. EMBO J. 23:2841-2852. [PubMed]
3. Balduini, C. L., A. Pecci, G. Loffredo, P. Izzo, P. Noris, M. Grosso, G. Bergamaschi, V. Rosti, U. Magrini, I. F. Ceresa, V. Conti, V. Poggi, and A. Savoia. 2004. Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb. Haemostasis 91:129-140. [PubMed]
4. Barrett, D. M., K. S. Gustafson, J. Wang, S. Z. Wang, and G. D. Ginder. 2004. A GATA factor mediates cell type-restricted induction of HLA-E gene transcription by gamma interferon. Mol. Cell. Biol. 24:6194-6204. [PMC free article] [PubMed]
5. Blobel, G. A., T. Nakajima, R. Eckner, M. Montminy, and S. H. Orkin. 1998. CREB-binding protein cooperates with transcription factor GATA-1 and is required for erythroid differentiation. Proc. Natl. Acad. Sci. USA 95:2061-2066. [PubMed]
6. Boyes, J., P. Byfield, Y. Nakatani, and V. Ogryzko. 1998. Regulation of activity of the transcription factor GATA-1 by acetylation. Nature 396:594-598. [PubMed]
7. Buck, M. J., and J. D. Lieb. 2004. ChIP-chip: considerations for the design, analysis, and application of genome-wide chromatin immunoprecipitation experiments. Genomics 83:349-360. [PubMed]
8. Calligaris, R., S. Bottardi, S. Cogoi, I. Apezteguia, and C. Santoro. 1995. Alternative translation initiation site usage results in two functionally distinct forms of the GATA-1 transcription factor. Proc. Natl. Acad. Sci. USA 92:11598-11602. [PubMed]
9. Carter, D., L. Chakalova, C. S. Osborne, Y. F. Dai, and P. Fraser. 2002. Long-range chromatin regulatory interactions in vivo. Nat. Genet. 32:623-626. [PubMed]
10. Chiba, T., Y. Nagata, A. Kishi, K. Sakamaki, A. Miyajima, M. Yamamoto, J. D. Engel, and K. Todokoro. 1993. Induction of erythroid-specific gene expression in lymphoid cells. Proc. Natl. Acad. Sci. USA 90:11593-11597. [PubMed]
11. Clark, A. J., K. M. Doyle, and P. O. Humbert. 2004. Cell-intrinsic requirement for pRb in erythropoiesis. Blood 104:1324-1326. [PubMed]
12. Cohen-Kaminsky, S., L. Maouche-Chretien, L. Vitelli, M. A. Vinit, I. Blanchard, M. Yamamoto, C. Peschle, and P. H. Romeo. 1998. Chromatin immunoselection defines a TAL-1 target gene. EMBO J. 17:5151-5160. [PubMed]
13. Collavin, L., M. Gostissa, F. Avolio, P. Secco, A. Ronchi, C. Santoro, and G. Del Sal. 2004. Modification of the erythroid transcription factor GATA-1 by SUMO-1. Proc. Natl. Acad. Sci. USA 101:8870-8875. [PubMed]
14. Crispino, J. D., M. B. Lodish, J. P. MacKay, and S. H. Orkin. 1999. Use of altered specificity mutants to probe a specific protein-protein interaction in differentiation: the GATA-1:FOG complex. Mol. Cell 3:219-228. [PubMed]
15. Crossley, M., M. Merika, and S. H. Orkin. 1995. Self-association of the erythroid transcription factor GATA-1 mediated by its zinc finger domains. Mol. Cell. Biol. 15:2448-2456. [PMC free article] [PubMed]
16. Crossley, M., and S. H. Orkin. 1994. Phosphorylation of the erythroid transcription factor GATA-1. J. Biol. Chem. 269:16589-16596. [PubMed]
17. de Boer, E., P. Rodriguez, E. Bonte, J. Krijgsveld, E. Katsantoni, A. Heck, F. Grosveld, and J. Strouboulis. 2003. Efficient biotinylation and single-step purification of tagged transcription factors in mammalian cells and transgenic mice. Proc. Natl. Acad. Sci. USA 100:7480-7485. [PubMed]
18. De Maria, R., A. Zeuner, A. Eramo, C. Domenichelli, D. Bonci, F. Grignani, S. M. Srinivasula, E. S. Alnemri, U. Testa, and C. Peschle. 1999. Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature 401:489-493. [PubMed]
19. Drissen, R., R. J. Palstra, N. Gillemans, E. Splinter, F. Grosveld, S. Philipsen, and W. de Laat. 2004. The active spatial organization of the beta-globin locus requires the transcription factor EKLF. Genes Dev. 18:2485-2490. [PubMed]
20. Dubart, A., P. H. Romeo, W. Vainchenker, and D. Dumenil. 1996. Constitutive expression of GATA-1 interferes with the cell-cycle regulation. Blood 87:3711-3721. [PubMed]
21. Evans, T., and G. Felsenfeld. 1989. The erythroid-specific transcription factor Eryf1: a new finger protein. Cell 58:877-885. [PubMed]
22. Evans, T., M. Reitman, and G. Felsenfeld. 1988. An erythrocyte-specific DNA-binding factor recognizes a regulatory sequence common to all chicken globin genes. Proc. Natl. Acad. Sci. USA 85:5976-5980. [PubMed]
23. Fox, A. H., K. Kowalski, G. F. King, J. P. Mackay, and M. Crossley. 1998. Key residues characteristic of GATA N-fingers are recognized by FOG. J. Biol. Chem. 273:33595-33603. [PubMed]
24. Fox, A. H., C. Liew, M. Holmes, K. Kowalski, J. Mackay, and M. Crossley. 1999. Transcriptional cofactors of the FOG family interact with GATA proteins by means of multiple zinc fingers. EMBO J. 18:2812-2822. [PubMed]
25. Freson, K., K. Devriendt, G. Matthijs, A. Van Hoof, R. De Vos, C. Thys, K. Minner, M. F. Hoylaerts, J. Vermylen, and C. Van Geet. 2001. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood 98:85-92. [PubMed]
26. Freson, K., G. Matthijs, C. Thys, P. Marien, M. F. Hoylaerts, J. Vermylen, and C. Van Geet. 2002. Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation. Hum. Mol. Genet. 11:147-152. [PubMed]
27. Fujiwara, Y., C. P. Browne, K. Cunniff, S. C. Goff, and S. H. Orkin. 1996. Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc. Natl. Acad. Sci. USA 93:12355-12358. [PubMed]
28. Ghirlando, R., and C. D. Trainor. 2003. Determinants of GATA-1 Binding to DNA: the role of non-finger residues. J. Biol. Chem. 278:45620-45628. [PubMed]
29. Grass, J. A., M. E. Boyer, S. Pal, J. Wu, M. J. Weiss, and E. H. Bresnick. 2003. GATA-1-dependent transcriptional repression of GATA-2 via disruption of positive autoregulation and domain-wide chromatin remodeling. Proc. Natl. Acad. Sci. USA 100:8811-8816. [PubMed]
30. Gregoli, P. A., and M. C. Bondurant. 1997. The roles of Bcl-X(L) and apopain in the control of erythropoiesis by erythropoietin. Blood 90:630-640. [PubMed]
31. Gregory, R. C., D. J. Taxman, D. Seshasayee, M. H. Kensinger, J. J. Bieker, and D. M. Wojchowski. 1996. Functional interaction of GATA1 with erythroid Kruppel-like factor and Sp1 at defined erythroid promoters. Blood 87:1793-1801. [PubMed]
32. Gregory, T., C. Yu, A. Ma, S. H. Orkin, G. A. Blobel, and M. J. Weiss. 1999. GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-xL expression. Blood 94:87-96. [PubMed]
33. Guex, N., and M. C. Peitsch. 1997. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18:2714-2723. [PubMed]
34. Gurbuxani, S., P. Vyas, and J. D. Crispino. 2004. Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome. Blood 103:399-406. [PubMed]
35. Gutierrez, L., F. Lindeboom, A. Langeveld, F. Grosveld, S. Philipsen, and D. Whyatt. 2004. Homotypic signalling regulates Gata1 activity in the erythroblastic island. Development 131:3183-3193. [PubMed]
36. Guyot, B., V. Valverde-Garduno, C. Porcher, and P. Vyas. 2004. Deletion of the major GATA1 enhancer HS 1 does not affect eosinophil GATA1 expression and eosinophil differentiation. Blood 104:89-91. [PubMed]
37. Hannon, R., T. Evans, G. Felsenfeld, and H. Gould. 1991. Structure and promoter activity of the gene for the erythroid transcription factor GATA-1. Proc. Natl. Acad. Sci. USA 88:3004-3008. [PubMed]
38. Harigae, H., S. Takahashi, N. Suwabe, H. Ohtsu, L. Gu, Z. Yang, F. Y. Tsai, Y. Kitamura, J. D. Engel, and M. Yamamoto. 1998. Differential roles of GATA-1 and GATA-2 in growth and differentiation of mast cells. Genes Cells 3:39-50. [PubMed]
39. Reference deleted.
40. Heyworth, C., S. Pearson, G. May, and T. Enver. 2002. Transcription factor-mediated lineage switching reveals plasticity in primary committed progenitor cells. EMBO J. 21:3770-3781. [PubMed]
41. Hirasawa, R., R. Shimizu, S. Takahashi, M. Osawa, S. Takayanagi, Y. Kato, M. Onodera, N. Minegishi, M. Yamamoto, K. Fukao, H. Taniguchi, H. Nakauchi, and A. Iwama. 2002. Essential and instructive roles of GATA factors in eosinophil development. J. Exp. Med. 195:1379-1386. [PMC free article] [PubMed]
42. Reference deleted.
43. Hung, H. L., J. Lau, A. Y. Kim, M. J. Weiss, and G. A. Blobel. 1999. CREB-binding protein acetylates hematopoietic transcription factor GATA-1 at functionally important sites. Mol. Cell. Biol. 19:3496-3505. [PMC free article] [PubMed]
44. Imagawa, S., N. Suzuki, K. Ohmine, N. Obara, H. Y. Mukai, K. Ozawa, M. Yamamoto, and T. Nagasawa. 2002. GATA suppresses erythropoietin gene expression through GATA site in mouse erythropoietin gene promoter. Int. J. Hematol. 75:376-381. [PubMed]
45. Imagawa, S., M. Yamamoto, and Y. Miura. 1997. Negative regulation of the erythropoietin gene expression by the GATA transcription factors. Blood 89:1430-1439. [PubMed]
46. Ito, E., T. Toki, H. Ishihara, H. Ohtani, L. Gu, M. Yokoyama, J. D. Engel, and M. Yamamoto. 1993. Erythroid transcription factor GATA-1 is abundantly transcribed in mouse testis. Nature 362:466-468. [PubMed]
47. Iwasaki, H., S. Mizuno, R. A. Wells, A. B. Cantor, S. Watanabe, and K. Akashi. 2003. GATA-1 converts lymphoid and myelomonocytic progenitors into the megakaryocyte/erythrocyte lineages. Immunity 19:451-462. [PubMed]
48. Jacks, T., A. Fazeli, E. M. Schmitt, R. T. Bronson, M. A. Goodell, and R. A. Weinberg. 1992. Effects of an Rb mutation in the mouse. Nature 359:295-300. [PubMed]
49. Kasper, L. H., F. Boussouar, P. A. Ney, C. W. Jackson, J. Rehg, J. M. van Deursen, and P. K. Brindle. 2002. A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis. Nature 419:738-743. [PubMed]
50. Ko, L. J., and J. D. Engel. 1993. DNA-binding specificities of the GATA transcription factor family. Mol. Cell. Biol. 13:4011-4022. [PMC free article] [PubMed]
51. Kowalski, K., R. Czolij, G. F. King, M. Crossley, and J. P. Mackay. 1999. The solution structure of the N-terminal zinc finger of GATA-1 reveals a specific binding face for the transcriptional co-factor FOG. J. Biomol. NMR 13:249-262. [PubMed]
52. Kulessa, H., J. Frampton, and T. Graf. 1995. GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. Genes Dev. 9:1250-1262. [PubMed]
53. Lacombe, C., and P. Mayeux. 1999. The molecular biology of erythropoietin. Nephrol. Dial. Transplant. 14(Suppl. 2):22-28. [PubMed]
53a. Lecointe, N., O. Bernard, K. Naert, V. Joulin, C. J. Larsen, P. H. Romeo, and D. Mathieu-Mahul. 1994. GATA-and SP1-binding sites are required for the full activity of the tissue-specific promoter of the tal-1 gene. Oncogene 9:2623-2626. [PubMed]
54. Lee, E. Y., C. Y. Chang, N. Hu, Y. C. Wang, C. C. Lai, K. Herrup, W. H. Lee, and A. Bradley. 1992. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359:288-294. [PubMed]
55. Leonard, M., M. Brice, J. D. Engel, and T. Papayannopoulou. 1993. Dynamics of GATA transcription factor expression during erythroid differentiation. Blood 82:1071-1079. [PubMed]
56. Lindeboom, F., N. Gillemans, A. Karis, M. Jaegle, D. Meijer, F. Grosveld, and S. Philipsen. 2003. A tissue-specific knockout reveals that Gata1 is not essential for Sertoli cell function in the mouse. Nucleic Acids Res. 31:5405-5412. [PMC free article] [PubMed]
57. Lipinski, M. M., and T. Jacks. 1999. The retinoblastoma gene family in differentiation and development. Oncogene 18:7873-7882. [PubMed]
58. Mackay, J. P., K. Kowalski, A. H. Fox, R. Czolij, G. F. King, and M. Crossley. 1998. Involvement of the N-finger in the self-association of GATA-1. J. Biol. Chem. 273:30560-30567. [PubMed]
59. Marin, M., A. Karis, P. Visser, F. Grosveld, and S. Philipsen. 1997. Transcription factor Sp1 is essential for early embryonic development but dispensable for cell growth and differentiation. Cell 89:619-628. [PubMed]
60. Martin, D. I., and S. H. Orkin. 1990. Transcriptional activation and DNA binding by the erythroid factor GF-1/NF-E1/Eryf 1. Genes Dev. 4:1886-1898. [PubMed]
61. Martin, D. I., L. I. Zon, G. Mutter, and S. H. Orkin. 1990. Expression of an erythroid transcription factor in megakaryocytic and mast cell lineages. Nature 344:444-447. [PubMed]
62. McDevitt, M. A., Y. Fujiwara, R. A. Shivdasani, and S. H. Orkin. 1997. An upstream, DNase I hypersensitive region of the hematopoietic-expressed transcription factor GATA-1 gene confers developmental specificity in transgenic mice. Proc. Natl. Acad. Sci. USA 94:7976-7981. [PubMed]
63. McDevitt, M. A., R. A. Shivdasani, Y. Fujiwara, H. Yang, and S. H. Orkin. 1997. A “knockdown” mutation created by cis-element gene targeting reveals the dependence of erythroid cell maturation on the level of transcription factor GATA-1. Proc. Natl. Acad. Sci. USA 94:6781-6785. [PubMed]
64. Mehaffey, M. G., A. L. Newton, M. J. Gandhi, M. Crossley, and J. G. Drachman. 2001. X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood 98:2681-2688. [PubMed]
65. Merika, M., and S. H. Orkin. 1993. DNA-binding specificity of GATA family transcription factors. Mol. Cell. Biol. 13:3999-4010. [PMC free article] [PubMed]
66. Merika, M., and S. H. Orkin. 1995. Functional synergy and physical interactions of the erythroid transcription factor GATA-1 with the Kruppel family proteins Sp1 and EKLF. Mol. Cell. Biol. 15:2437-2447. [PMC free article] [PubMed]
67. Migliaccio, A. R., R. A. Rana, M. Sanchez, R. Lorenzini, L. Centurione, L. Bianchi, A. M. Vannucchi, G. Migliaccio, and S. H. Orkin. 2003. GATA-1 as a regulator of mast cell differentiation revealed by the phenotype of the GATA-1low mouse mutant. J. Exp. Med. 197:281-296. [PMC free article] [PubMed]
68. Mikkola, H. K., J. Klintman, H. Yang, H. Hock, T. M. Schlaeger, Y. Fujiwara, and S. H. Orkin. 2003. Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene. Nature 421:547-551. [PubMed]
69. Miller, I. J., and J. J. Bieker. 1993. A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Kruppel family of nuclear proteins. Mol. Cell. Biol. 13:2776-2786. [PMC free article] [PubMed]
70. Molkentin, J. D. 2000. The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J. Biol. Chem. 275:38949-38952. [PubMed]
71. Motoyama, N., F. Wang, K. A. Roth, H. Sawa, K. Nakayama, I. Negishi, S. Senju, Q. Zhang, S. Fujii, et al. 1995. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267:1506-1510. [PubMed]
71a. Mouthon, M. A., O. Bernard, M. T. Mitjavila, P. H. Romeo, W. Vainchenker, and D. Mathieu-Mahul. 1993. Expression of tal-1 and GATA-binding proteins during human hematopoiesis. Blood 81:647-655. [PubMed]
72. Mukhopadhyay, M., A. Teufel, T. Yamashita, A. D. Agulnick, L. Chen, K. M. Downs, A. Schindler, A. Grinberg, S. P. Huang, D. Dorward, and H. Westphal. 2003. Functional ablation of the mouse Ldb1 gene results in severe patterning defects during gastrulation. Development 130:495-505. [PubMed]
73. Reference deleted.
74. Nerlov, C., E. Querfurth, H. Kulessa, and T. Graf. 2000. GATA-1 interacts with the myeloid PU. 1 transcription factor and represses PU. 1-dependent transcription. Blood 95:2543-2551. [PubMed]
75. Nichols, K. E., J. D. Crispino, M. Poncz, J. G. White, S. H. Orkin, J. M. Maris, and M. J. Weiss. 2000. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat. Genet. 24:266-270. [PubMed]
76. Nishikawa, K., M. Kobayashi, A. Masumi, S. E. Lyons, B. M. Weinstein, P. P. Liu, and M. Yamamoto. 2003. Self-association of Gata1 enhances transcriptional activity in vivo in zebra fish embryos. Mol. Cell. Biol. 23:8295-8305. [PMC free article] [PubMed]
77. Nuez, B., D. Michalovich, A. Bygrave, R. Ploemacher, and F. Grosveld. 1995. Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene. Nature 375:316-318. [PubMed]
78. Omichinski, J. G., G. M. Clore, O. Schaad, G. Felsenfeld, C. Trainor, E. Appella, S. J. Stahl, and A. M. Gronenborn. 1993. NMR structure of a specific DNA complex of Zn-containing DNA binding domain of GATA-1. Science 261:438-446. [PubMed]
79. Onodera, K., S. Takahashi, S. Nishimura, J. Ohta, H. Motohashi, K. Yomogida, N. Hayashi, J. D. Engel, and M. Yamamoto. 1997. GATA-1 transcription is controlled by distinct regulatory mechanisms during primitive and definitive erythropoiesis. Proc. Natl. Acad. Sci. USA 94:4487-4492. [PubMed]
80. Onodera, K., K. Yomogida, N. Suwabe, S. Takahashi, Y. Muraosa, N. Hayashi, E. Ito, L. Gu, M. Rassoulzadegan, J. D. Engel, and M. Yamamoto. 1997. Conserved structure, regulatory elements, and transcriptional regulation from the GATA-1 gene testis promoter. J. Biochem. (Tokyo) 121:251-263. [PubMed]
81. Orkin, S. H. 1992. GATA-binding transcription factors in hematopoietic cells. Blood 80:575-581. [PubMed]
82. Osada, H., G. Grutz, H. Axelson, A. Forster, and T. H. Rabbitts. 1995. Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1. Proc. Natl. Acad. Sci. USA 92:9585-9589. [PubMed]
83. Osada, H., G. G. Grutz, H. Axelson, A. Forster, and T. H. Rabbitts. 1997. LIM-only protein Lmo2 forms a protein complex with erythroid transcription factor GATA-1. Leukemia 11(Suppl. 3):307-312. [PubMed]
84. Partington, G. A., and R. K. Patient. 1999. Phosphorylation of GATA-1 increases its DNA-binding affinity and is correlated with induction of human K562 erythroleukaemia cells. Nucleic Acids Res. 27:1168-1175. [PMC free article] [PubMed]
85. Perkins, A. C., A. H. Sharpe, and S. H. Orkin. 1995. Lethal beta-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF. Nature 375:318-322. [PubMed]
86. Pevny, L., C. S. Lin, V. D'Agati, M. C. Simon, S. H. Orkin, and F. Costantini. 1995. Development of hematopoietic cells lacking transcription factor GATA-1. Development 121:163-172. [PubMed]
87. Pevny, L., M. C. Simon, E. Robertson, W. H. Klein, S. F. Tsai, V. D'Agati, S. H. Orkin, and F. Costantini. 1991. Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature 349:257-260. [PubMed]
88. Philipsen, S., S. Pruzina, and F. Grosveld. 1993. The minimal requirements for activity in transgenic mice of hypersensitive site 3 of the beta globin locus control region. EMBO J. 12:1077-1085. [PubMed]
89. Philipsen, S., and G. Suske. 1999. A tale of three fingers: the family of mammalian Sp/XKLF transcription factors. Nucleic Acids Res. 27:2991-3000. [PMC free article] [PubMed]
90. Ponka, P. 1997. Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells. Blood 89:1-25. [PubMed]
91. Rekhtman, N., F. Radparvar, T. Evans, and A. I. Skoultchi. 1999. Direct interaction of hematopoietic transcription factors PU. 1 and GATA-1: functional antagonism in erythroid cells. Genes Dev. 13:1398-1411. [PubMed]
92. Romeo, P. H., M. H. Prandini, V. Joulin, V. Mignotte, M. Prenant, W. Vainchenker, G. Marguerie, and G. Uzan. 1990. Megakaryocytic and erythrocytic lineages share specific transcription factors. Nature 344:447-449. [PubMed]
93. Rylski, M., J. J. Welch, Y. Y. Chen, D. L. Letting, J. A. Diehl, L. A. Chodosh, G. A. Blobel, and M. J. Weiss. 2003. GATA-1-mediated proliferation arrest during erythroid maturation. Mol. Cell. Biol. 23:5031-5042. [PMC free article] [PubMed]
94. Sapetschnig, A., G. Rischitor, H. Braun, A. Doll, M. Schergaut, F. Melchior, and G. Suske. 2002. Transcription factor Sp3 is silenced through SUMO modification by PIAS1. EMBO J. 21:5206-5215. [PubMed]
95. Shimizu, R., S. Takahashi, K. Ohneda, J. D. Engel, and M. Yamamoto. 2001. In vivo requirements for GATA-1 functional domains during primitive and definitive erythropoiesis. EMBO J. 20:5250-5260. [PubMed]
96. Shirihai, O. S., T. Gregory, C. Yu, S. H. Orkin, and M. J. Weiss. 2000. ABC-me: a novel mitochondrial transporter induced by GATA-1 during erythroid differentiation. EMBO J. 19:2492-2502. [PubMed]
97. Shivdasani, R. A., Y. Fujiwara, M. A. McDevitt, and S. H. Orkin. 1997. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J. 16:3965-3973. [PubMed]
98. Silva, M., D. Grillot, A. Benito, C. Richard, G. Nunez, and J. L. Fernandez-Luna. 1996. Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood 88:1576-1582. [PubMed]
99. Takahashi, S., T. Komeno, N. Suwabe, K. Yoh, O. Nakajima, S. Nishimura, T. Kuroha, T. Nagasawa, and M. Yamamoto. 1998. Role of GATA-1 in proliferation and differentiation of definitive erythroid and megakaryocytic cells in vivo. Blood 92:434-442. [PubMed]
100. Takahashi, S., K. Onodera, H. Motohashi, N. Suwabe, N. Hayashi, N. Yanai, Y. Nabesima, and M. Yamamoto. 1997. Arrest in primitive erythroid cell development caused by promoter-specific disruption of the GATA-1 gene. J. Biol. Chem. 272:12611-12615. [PubMed]
101. Tjandra, N., J. G. Omichinski, A. M. Gronenborn, G. M. Clore, and A. Bax. 1997. Use of dipolar 1H-15N and 1H-13C couplings in the structure determination of magnetically oriented macromolecules in solution. Nat. Struct. Biol. 4:732-738. [PubMed]
102. Tolhuis, B., R. J. Palstra, E. Splinter, F. Grosveld, and W. de Laat. 2002. Looping and interaction between hypersensitive sites in the active beta-globin locus. Mol. Cell 10:1453-1465. [PubMed]
103. Towatari, M., M. Ciro, S. Ottolenghi, S. Tsuzuki, and T. Enver. 2004. Involvement of mitogen-activated protein kinase in the cytokine-regulated phosphorylation of transcription factor GATA-1. Hematol. J. 5:262-272. [PubMed]
104. Trainor, C. D., R. Ghirlando, and M. A. Simpson. 2000. GATA zinc finger interactions modulate DNA binding and transactivation. J. Biol. Chem. 275:28157-28166. [PubMed]
105. Tsai, S. F., D. I. Martin, L. I. Zon, A. D. D'Andrea, G. G. Wong, and S. H. Orkin. 1989. Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells. Nature 339:446-451. [PubMed]
106. Tsai, S. F., E. Strauss, and S. H. Orkin. 1991. Functional analysis and in vivo footprinting implicate the erythroid transcription factor GATA-1 as a positive regulator of its own promoter. Genes Dev. 5:919-931. [PubMed]
107. Tsang, A. P., Y. Fujiwara, D. B. Hom, and S. H. Orkin. 1998. Failure of megakaryopoiesis and arrested erythropoiesis in mice lacking the GATA-1 transcriptional cofactor FOG. Genes Dev. 12:1176-1188. [PubMed]
108. Tsang, A. P., J. E. Visvader, C. A. Turner, Y. Fujiwara, C. Yu, M. J. Weiss, M. Crossley, and S. H. Orkin. 1997. FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell 90:109-119. [PubMed]
109. Valge-Archer, V. E., H. Osada, A. J. Warren, A. Forster, J. Li, R. Baer, and T. H. Rabbitts. 1994. The LIM protein RBTN2 and the basic helix-loop-helix protein TAL1 are present in a complex in erythroid cells. Proc. Natl. Acad. Sci. USA 91:8617-8621. [PubMed]
110. Valverde-Garduno, V., B. Guyot, E. Anguita, I. Hamlett, C. Porcher, and P. Vyas. 2004. Differences in the chromatin structure and cis-element organization of the human and mouse GATA1 loci: implications for cis-element identification. Blood 104:3106-3116. [PubMed]
111. Verger, A., J. Perdomo, and M. Crossley. 2003. Modification with SUMO. A role in transcriptional regulation. EMBO Rep. 4:137-142. [PubMed]
112. Vo, N., and R. H. Goodman. 2001. CREB-binding protein and p300 in transcriptional regulation. J. Biol. Chem. 276:13505-13508. [PubMed]
113. Vyas, P., K. Ault, C. W. Jackson, S. H. Orkin, and R. A. Shivdasani. 1999. Consequences of GATA-1 deficiency in megakaryocytes and platelets. Blood 93:2867-2875. [PubMed]
114. Vyas, P., M. A. McDevitt, A. B. Cantor, S. G. Katz, Y. Fujiwara, and S. H. Orkin. 1999. Different sequence requirements for expression in erythroid and megakaryocytic cells within a regulatory element upstream of the GATA-1 gene. Development 126:2799-2811. [PubMed]
115. Wadman, I., J. Li, R. O. Bash, A. Forster, H. Osada, T. H. Rabbitts, and R. Baer. 1994. Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia. EMBO J. 13:4831-4839. [PubMed]
116. Wadman, I. A., H. Osada, G. G. Grutz, A. D. Agulnick, H. Westphal, A. Forster, and T. H. Rabbitts. 1997. The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. EMBO J. 16:3145-3157. [PubMed]
117. Wall, L., E. deBoer, and F. Grosveld. 1988. The human beta-globin gene 3′ enhancer contains multiple binding sites for an erythroid-specific protein. Genes Dev. 2:1089-1100. [PubMed]
118. Warren, A. J., W. H. Colledge, M. B. Carlton, M. J. Evans, A. J. Smith, and T. H. Rabbitts. 1994. The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development. Cell 78:45-57. [PubMed]
119. Wechsler, J., M. Greene, M. A. McDevitt, J. Anastasi, J. E. Karp, M. M. Le Beau, and J. D. Crispino. 2002. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat. Genet. 32:148-152. [PubMed]
120. Weiss, M. J., G. Keller, and S. H. Orkin. 1994. Novel insights into erythroid development revealed through in vitro differentiation of GATA-1 embryonic stem cells. Genes Dev. 8:1184-1197. [PubMed]
121. Weiss, M. J., and S. H. Orkin. 1995. GATA transcription factors: key regulators of hematopoiesis. Exp. Hematol. 23:99-107. [PubMed]
122. Weiss, M. J., and S. H. Orkin. 1995. Transcription factor GATA-1 permits survival and maturation of erythroid precursors by preventing apoptosis. Proc. Natl. Acad. Sci. USA 92:9623-9627. [PubMed]
123. Weiss, M. J., C. Yu, and S. H. Orkin. 1997. Erythroid-cell-specific properties of transcription factor GATA-1 revealed by phenotypic rescue of a gene-targeted cell line. Mol. Cell. Biol. 17:1642-1651. [PMC free article] [PubMed]
124. Welch, J. J., J. A. Watts, C. R. Vakoc, Y. Yao, H. Wang, R. C. Hardison, G. A. Blobel, L. A. Chodosh, and M. J. Weiss. 2004. Global regulation of erythroid gene expression by transcription factor GATA-1. Blood 104:3136-3147. [PubMed]
125. Whyatt, D., F. Lindeboom, A. Karis, R. Ferreira, E. Milot, R. Hendriks, M. de Bruijn, A. Langeveld, J. Gribnau, F. Grosveld, and S. Philipsen. 2000. An intrinsic but cell-nonautonomous defect in GATA-1-overexpressing mouse erythroid cells. Nature 406:519-524. [PubMed]
126. Whyatt, D. J., E. deBoer, and F. Grosveld. 1993. The two zinc finger-like domains of GATA-1 have different DNA binding specificities. EMBO J. 12:4993-5005. [PubMed]
127. Whyatt, D. J., A. Karis, I. C. Harkes, A. Verkerk, N. Gillemans, A. G. Elefanty, G. Vairo, R. Ploemacher, F. Grosveld, and S. Philipsen. 1997. The level of the tissue-specific factor GATA-1 affects the cell-cycle machinery. Genes Funct. 1:11-24. [PubMed]
128. Reference deleted.
129. Yamamoto, M., L. J. Ko, M. W. Leonard, H. Beug, S. H. Orkin, and J. D. Engel. 1990. Activity and tissue-specific expression of the transcription factor NF-E1 multigene family. Genes Dev. 4:1650-1662. [PubMed]
130. Yang, H. Y., and T. Evans. 1992. Distinct roles for the two cGATA-1 finger domains. Mol. Cell. Biol. 12:4562-4570. [PMC free article] [PubMed]
131. Yomogida, K., H. Ohtani, H. Harigae, E. Ito, Y. Nishimune, J. D. Engel, and M. Yamamoto. 1994. Developmental stage- and spermatogenic cycle-specific expression of transcription factor GATA-1 in mouse Sertoli cells. Development 120:1759-1766. [PubMed]
132. Yu, C., A. B. Cantor, H. Yang, C. Browne, R. A. Wells, Y. Fujiwara, and S. H. Orkin. 2002. Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo. J. Exp. Med. 195:1387-1395. [PMC free article] [PubMed]
133. Yu, C., K. K. Niakan, M. Matsushita, G. Stamatoyannopoulos, S. H. Orkin, and W. H. Raskind. 2002. X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood 100:2040-2045. [PMC free article] [PubMed]
134. Zhang, P., G. Behre, J. Pan, A. Iwama, N. Wara-Aswapati, H. S. Radomska, P. E. Auron, D. G. Tenen, and Z. Sun. 1999. Negative cross-talk between hematopoietic regulators: GATA proteins repress PU. 1. Proc. Natl. Acad. Sci. USA 96:8705-8710. [PubMed]
135. Zhang, P., X. Zhang, A. Iwama, C. Yu, K. A. Smith, B. U. Mueller, S. Narravula, B. E. Torbett, S. H. Orkin, and D. G. Tenen. 2000. PU. 1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding. Blood 96:2641-2648. [PubMed]
136. Zon, L. I., C. Mather, S. Burgess, M. E. Bolce, R. M. Harland, and S. H. Orkin. 1991. Expression of GATA-binding proteins during embryonic development in Xenopus laevis. Proc. Natl. Acad. Sci. USA 88:10642-10646. [PubMed]
137. Zon, L. I., S. F. Tsai, S. Burgess, P. Matsudaira, G. A. Bruns, and S. H. Orkin. 1990. The major human erythroid DNA-binding protein (GF-1): primary sequence and localization of the gene to the X chromosome. Proc. Natl. Acad. Sci. USA 87:668-672. [PubMed]
138. Zon, L. I., Y. Yamaguchi, K. Yee, E. A. Albee, A. Kimura, J. C. Bennett, S. H. Orkin, and S. J. Ackerman. 1993. Expression of mRNA for the GATA-binding proteins in human eosinophils and basophils: potential role in gene transcription. Blood 81:3234-3241. [PubMed]
139. Zon, L. I., H. Youssoufian, C. Mather, H. F. Lodish, and S. H. Orkin. 1991. Activation of the erythropoietin receptor promoter by transcription factor GATA-1. Proc. Natl. Acad. Sci. USA 88:10638-10641. [PubMed]

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