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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1652-1655
HEMATOPOIESIS
The GATA-E box-GATA motif in the EKLF promoter is required for
in vivo expression
Kathleen P. Anderson,
Scott C. Crable, and
Jerry
B. Lingrel
From the Department of Molecular Genetics, Biochemistry, and
Microbiology, University of Cincinnati, Cincinnati, OH.
 |
Abstract |
The erythroid Krüppel-like factor (EKLF) is a key regulatory
protein in globin gene expression. This zinc finger transcription factor is required for expression of the adult  globin gene, and it
has been suggested that it plays an important role in the developmental
switch from fetal  to adult globin gene expression. We have
previously described a sequence element in the distal promoter region
of the mouse EKLF gene that is critical for the expression of this
transcription factor. The element consists of an E box motif flanked by
2 GATA-1 binding sites. Here we demonstrate that mutation of the E box
or the GATA-1 consensus sequences eliminates expression from the EKLF
promoter in transgenic mice. These results confirm the importance of
this activator element for in vivo expression of the EKLF gene.
(Blood. 2000;95:1652-1655)
© 2000 by The American Society of Hematology.
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Introduction |
The erythroid Krüppel-like factor (EKLF) has 2 zinc finger motifs in the C-terminal half and a proline-rich
transactivation domain in the N-terminus of the protein.1
It is the founding member of a family of transcription factors related
to each other through a high degree of homology in the zinc finger
region.2 This class of proteins has been termed the KLF
family for the conserved C2H2 finger regions, and it consists of 12 members expressed with varying degrees of tissue
specificity.1-13
EKLF is first expressed in yolk sac blood islands and remains erythroid
specific throughout development, with adult expression observed in the
spleen.14 Targeted disruption of the EKLF gene in mice has
demonstrated that this factor is critical for
hematopoiesis.15,16 Indeed, EKLF is required for expression
of the adult -hemoglobin gene, and it plays an important role in the
developmental switch from fetal to adult -globin
expression.17-19
We have been investigating the regulated expression of this important
erythroid-specific protein and have recently identified an interesting
activator motif in the distal promoter of the EKLF gene.20
The site consists of 3 consensus-binding sequences, a GATA site, an E
box, and another GATA site. The GATA-E box-GATA, or GEG, motif appears
to organize a protein complex rather than supporting independent
binding by individual factors. This conclusion arises from the
observation that a mutation at any 1 of the 3 sites in the motif
eliminates activation of the EKLF promoter. Consistent with this
functional data, there have been reports describing a physical
association in erythroid cells between GATA1, Tal1/E2A, Ldb1, and Lmo2,
where Lmo2 acts as a bridging molecule between GATA1 and
Tal1.21-25 Tal1/E2A are a helix-loop-helix heterodimer pair recognizing an E-box sequence motif.24,26,27 Lmo2
lacks the ability to bind DNA but does contain LIM domains for
protein-protein interactions.28,29 The Ldb1,
LIM domain binding, protein is a
recently characterized binding partner for Lmo2.23,30
Significantly, targeted ablations of the gene for either GATA1, Tal1,
or Lmo2 all result in a failure in development of the hematopoietic
system.31-35 With both the Tal1 and the Lmo2 genes, this
effect is manifested with embryonic lethality at approximately day
8.5 of gestation (E8.5); the GATA1 null embryos survive until E11. This
further implicates the interaction of these transcription factors in
the regulation of genes involved in the hematopoietic pathway.
Our previous study identifying the GEG motif in the distal EKLF
promoter was based on stable and transient transfection experiments in
MEL cells.20 The current work extends these studies and
demonstrates the importance of this combination of consensus sites for
in vivo erythroid expression from the EKLF promoter.
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Material and methods |
Plasmids
The wild-type  1150 EKLFCAT and the 1150 mutant
constructs have been previously described.20 Briefly, these
plasmids contain the mouse EKLF promoter region fused to a CAT reporter
cassette in a modified pBKCMV vector (Stratagene, LaJolla, CA). The
specific mutations in the GATA and E box binding sites for
1150(GMEGM)EKLFCAT,
1150(GEMG)EKLFCAT, and
1150(GMEMGM)EKLFCAT are
listed in Figure 1.
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| Fig 1.
Wild-type and mutant EKLF CAT transgenic constructs.
The mouse EKLF promoter from 1150 to +60 was fused to the CAT
reporter gene. The nucleotide sequence for GATA-E box-GATA motif is
shown above the wild-type construct. Each consensus-binding site is
underlined. Asterisks mark the mutations in subsequent constructs; the
nucleotide changes are shown in italics.
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Transgenic mice
EKLFCAT expression plasmids were purified (Qiagen, Santa Clarita,
CA) before injection, and transgenic animals were produced in the FVB/N
mouse strain.36 Putative transgenic animals were screened
by a polymerase chain reaction assay. DNA from established lines was
analyzed by Southern blotting to determine copy number and to ensure
the transgene was intact and free of rearrangements.
CAT assays
Blood was collected from F0 and F1 animals and placed in a
phosphate-buffered saline/heparin solution. The samples were
centrifuged, and the cell pellet was lysed by freeze-thaw in a 0.1 mol/L Tris, pH 7.5 solution. Tissue extracts were also prepared from
adult transgenic animals by homogenization in the Tris solution,
followed by freeze-thaw lysis. CAT assays were conducted as
previously described.2 Results were normalized for protein
levels using a bicinchoninic acid assay (Pierce Chemicals, Rockford, IL).
| |
Results |
The GATA-E box-GATA (GEG) element in the distal EKLF promoter was
originally identified based on studies in mouse erythroleukemia (MEL)
cells.20 This cell line has been used extensively to
analyze critical cis and trans regulatory elements required for the
expression of erythroid genes. Because of the complexity of the
hematopoietic system, however, complementary studies in transgenic mice
can provide a more rigorous test of the importance of such elements or
factors. With this view, we produced a series of transgenic animals to
ascertain the in vivo relevance of the GEG motif in the EKLF promoter.
Constructs containing either a wild-type or a mutated form of the mouse
EKLF promoter driving expression of a CAT reporter gene were introduced
into fertilized oocytes. Three mutant constructs were used in which
either the E box site was replaced (1150(GEMG)) or
point mutations were introduced to disrupt each of the flanking GATA
sites (1150(GMEGM)), or mutations at all
3 sites in the GEG motif were incorporated into a single construct
(1150(GMEMGM)). These
transgenes and the specific GEG sequence alterations are shown in
Figure 1.
Four lines of mice carrying the wild-type 1150 EKLFCAT construct
were obtained and analyzed. We have shown that this promoter can direct
correct tissue and developmentally specific expression of a
-galactosidase gene in transgenic mice.20 This finding was confirmed in our current study using the CAT reporter gene. The
1150(GMEGM) construct was used to
generate 12 lines of transgenic mice. The F0 animals carrying this
mutant transgene were analyzed for CAT expression in the blood.
Additionally, 11 of these lines were bred and analyzed as F1.
Similarly, we produced 14 F0 mice using the E box mutant construct,
1150(GEMG). All F0 lines were screened for transgene
expression in adult red cells, and 10 lines were bred for confirmation
of these results in F1 animals. The promoter construct with alterations
at all three binding sites was analyzed in two transgenic lines.
The results of transgene expression in adult F1 blood samples are shown
in Figure 2 and are quantitated in Table
1. All 4 wild-type EKLF promoter lines
expressed the reporter gene to varying degrees, in agreement with our
previous results.20 No expression was detected in the 6 representative lines carrying point mutations in the 2 GATA sites of
the GEG motif. Furthermore, all 7 of the F1 lines with the E box
disruption failed to express the transgene. Finally, as expected from
these results, no CAT activity was observed in the blood from the 2 lines in which all 3 sites were altered in the GATA-E box-GATA motif.
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| Fig 2.
Mutations in either the E box or the GATA sites eliminate
expression in adult blood.
Samples from the blood of F1 mice carrying wild-type or mutant EKLFCAT
constructs were assayed for CAT activity. All 4 wild-type lines are
included. Six representative lines for the E box mutant construct and 7 lines with the GATA site mutations are shown. Additional data are
summarized in Table 1.
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As indicated in Table 1, the initial characterization of the F0 mice
revealed 1 of 12 GMEGM animals and 2 of 14 GEMG mice with expression of the transgene in adult blood
at a level significantly exceeding the wild-type values. We suspected
this expression resulted from a position effect wherein the transgene integrated near a strong enhancer element. Subsequent analysis from 1 of these lines confirmed this, with high levels of CAT activity present
in extracts from lung, heart, and spleen, and lower levels in liver and
brain. Activity arising from blood contamination of the organs was
ruled out by assaying similar tissue samples from a mouse carrying the
wild-type EKLFCAT construct. All tissues were negative with this
wild-type promoter, with the exception of a low level in the spleen as
shown in Figure 3. These results are in
agreement with our previous data demonstrating the tissue specificity
of this wild-type EKLF promoter, and they support the premise that the
infrequent instances of CAT activity arising from the mutant promoter
are correlated with unregulated ectopic expression. In addition to
reconfirming the tissue-specific expression of the wild-type EKLF
promoter, we also assayed tissue extracts from developmental time
points. No expression was observed from any samples, either yolk sac
or fetal liver, obtained from mutant lines (data not shown). In
contrast, the 1150 EKLFCAT construct was appropriately expressed
in fetal liver as expected. Therefore, it is not that the mutant
transgenes are active early and subsequently shut down in the adult
hematopoietic tissue, but, rather, they are never
expressed if the GEG site is not intact.
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| Fig 3.
Ectopic expression infrequently occurred in some mutant
constructs, whereas expression from the wild-type EKLF promoter
remained tissue specific.
The tissue specificity was assayed for 1 of the E box mutant lines
expressed in adult blood (see Table 1) and was compared against the
expression from a wild-type construct. Tissues collected from adult F1
animals were assayed for CAT activity as described.
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| |
Discussion |
Our previous studies identified a critical sequence element
in the distal EKLF promoter comprised of a consensus E box flanked by 2 GATA sites.20 Studies using various promoter constructs in
erythroid and nonerythroid cells indicated that a mutation in any
one of these three protein-binding sites would eliminate enhanced
expression from the EKLF promoter. The current study extends those
findings by demonstrating the in vivo importance of the GEG
element. Generally only those transgenic animals carrying the
wild-type EKLF promoter expressed the reporter gene at all.
Any expression observed from a mutant promoter construct was high
level and nonerythroid specific, suggesting a transgenic position effect.
It is particularly interesting that the transgene with a mutation in
the E box consensus site is silent. The identification of a
multiprotein complex in which Lmo2 acts as a bridge between Tal1 and
GATA1 has been identified in erythroid cells,21-25 which might lead one to anticipate that Tal1 is the protein that binds this
functional E box in the EKLF promoter. Our attempts to confirm this
speculation have as yet been unsuccessful. Supershift assays using the
GEG sequence and erythroid cell nuclear extracts with antibodies
directed against Tal1 have yielded neither a complex with an altered
mobility nor an inhibition of complex formation. In addition, we
performed transfection experiments in an effort to up-regulate CAT
expression from the EKLF promoter by overexpressing Tal1 in either
erythroid or nonerythroid cells. No evidence for a direct effect by
Tal1 was observed. Conversely, Vyas et al25 have recently
described an E box-GATA site upstream of the erythroid-specific promoter for GATA-1. In DNA-binding studies, this site binds a complex
containing Tal1 in supershift assays. Our studies certainly do not rule
out Tal1 as the E box-binding component of the complex associating with
the GEG site in the EKLF promoter. The use of a different anti-Tal1
antibody, for example, could explain the lack of an effect in
supershift assays. Alternatively, however, the presence of 2 GATA
sites may change the binding site configuration, and one might also
then consider the possibility that another helix-loop-helix
protein may be involved.
An erythroid-specific DNase-hypersensitive site has recently been
mapped to a region overlapping the GEG motif.37 These investigators localized the enhancer activity of this segment of the
EKLF promoter to sequences from 715 to 666, whereas the element we have described spans the region 687 to 650.
The discrepancy in these results may stem from a nucleotide change that
eliminates the 3' GATA site in the constructs of the former
group. Based on our previous analysis, this GATA site is critical for
enhanced activation of the EKLF promoter and appears to bind the GATA1 protein with a higher affinity than the GATA sequence that resides 5' of the E box. We have verified our analysis of the EKLF
promoter by determining the nucleotide sequence from the genomic DNA of 3 mouse strains, FVB/N, Musculus spretus,
and C57BL/6, and from ES cells. Although 2 other single-base
polymorphisms were present, all 3 samples possessed the GATA-E box-GATA
motif (Anderson KP, unpublished data).
Various investigators have now provided evidence for the
formation of a transcription factor complex in erythroid cells that apparently contacts the DNA through the GATA1 and Tal1
proteins.21-25 The exact stoichiometry and complete list of
components is still unclear, however. For example, gel mobility shift
assays have been used to demonstrate the presence of GATA1 in these
complexes, and our results provide evidence for the functional role of
the GATA sites in the EKLF promoter. However, it is also known that EKLF and a number of other erythroid-specific genes are still expressed
in GATA1 null embryos.38 One explanation for this apparent
inconsistency is compensation by GATA2 because the levels of this
protein are increased 50 time more those seen in wild-type embryos.38 Whether GATA2 is normally also involved in
complex formation and gene regulation is still an unanswered question.
The GEG site in the EKLF gene represents one of the first examples of a
potential binding site for this complex in a hematopoietic promoter.
Expression of the EKLF gene is a critical event in hematopoiesis, and
thus the presence of a GATA-E box-GATA motif in the promoter of this
gene is intriguing. The finding that both the GATA and the E box
binding sites are required for expression of this gene in vivo further
substantiates the view that multiple proteins must interface with the
DNA and each other to achieve correct transcriptional activation.
| |
Acknowledgments |
We thank Jon Neumann and Karen Yaeger for the generation of the
transgenic mice. We also thank Maureen Lehrmann for maintaining the
mouse colonies.
| |
Footnotes |
Submitted June 16, 1999; accepted November 4, 1999.
Supported by National Institutes of Health Sickle Cell Center
grant HL58421.
Reprints: Kathleen P. Anderson, Department of Molecular
Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Bethesda Avenue, ML 524, Cincinnati, OH 45267; e-mail:
kathleen.anderson{at}uc.edu.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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J. J. Welch, J. A. Watts, C. R. Vakoc, Y. Yao, H. Wang, R. C. Hardison, G. A. Blobel, L. A. Chodosh, and M. J. Weiss
Global regulation of erythroid gene expression by transcription factor GATA-1
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[Abstract]
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L. Xue, X. Chen, Y. Chang, and J. J. Bieker
Regulatory elements of the EKLF gene that direct erythroid cell-specific expression during mammalian development
Blood,
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R. Lahlil, E. Lecuyer, S. Herblot, and T. Hoang
SCL Assembles a Multifactorial Complex That Determines Glycophorin A Expression
Mol. Cell. Biol.,
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C. M. Kiekhaefer, J. A. Grass, K. D. Johnson, M. E. Boyer, and E. H. Bresnick
Hematopoietic-specific activators establish an overlapping pattern of histone acetylation and methylation within a mammalian chromatin domain
PNAS,
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[Abstract]
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P. E. Mead, A. E. Deconinck, T. L. Huber, S. H. Orkin, and L. I. Zon
Primitive erythropoiesis in the Xenopus embryo: the synergistic role of LMO-2, SCL and GATA-binding proteins
Development,
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Top
Abstract
Introduction