| Nucleic Acids Research | Pages |
Conserved elements containing NF-E2 and tandem GATA binding sites are required for erythroid-specific chromatin structure reorganization within the human [beta]-globin locus control region
Introduction
Materials And Methods
HS2 and HS3 mutant constructs
Nuclease sensitivity assays
Results
Mutational analysis of LCR HS2
Mutational analysis of LCR HS3
Local chromatin structure of HS2 and HS3
Discussion
The relationship between [beta]-globin LCR chromatin structure and function
Mechanism of LCR HS formation
Acknowledgements
References
Conserved elements containing NF-E2 and tandem GATA binding sites are required for erythroid-specific chromatin structure reorganization within the human [beta]-globin locus control region
ABSTRACT
INTRODUCTION
The human [beta]-globin gene locus contains five expressed globin genes (Fig.
Several lines of evidence indicate a link between the chromatin structure of the human [beta]-globin gene locus and human [beta]-globin gene regulation. These studies also suggest that the [beta]-globin LCR is the primary determinant of locus chromatin structure. For example, natural deletion mutations of the LCR result in complete silencing of structurally intact [beta]-globin genes (2,10). This effect is demonstrated by the Hispanic [gamma][delta][beta]-thalassemia mutation, in which LCR HSs 2, 3 and 4 are deleted but all of the globin genes are intact (11). Not only are none of the genes expressed, but none of the characteristic erythroid-specific chromatin structures of the locus are formed (3). Neither the remaining LCR HS (HS1) nor the promoter HSs are formed (3). Similarly, insertion of a hygromycin resistance gene between HS1 and HS2 of the human LCR in a mouse/human hybrid cell line resulted in silencing of globin gene expression and inhibition of HS formation downstream of the inserted gene (12). These results suggest that a primary function of the LCR is to establish an active chromatin structure throughout the locus. A second link between LCR function and [beta]-globin locus chromatin structure involves the ability of the LCR to direct position-independent expression of linked globin genes in transgenic mice. This ability appears to be due to the capacity of the LCR to form a normal, active chromatin structure irrespective of the location at which the transgene is incorporated into the host genome (13).
The formation of the LCR HSs is also likely to be important for the proper functioning of the LCR. These domains of locally altered chromatin structure are unique in that they are erythroid-specific, developmentally stable (5,6) and ~10- to 20-fold more sensitive to DNase I than the promoter-associated HSs (5,7,14). Perhaps most significant is the finding that the HSs are coincident with the functionally active core elements of the LCR (15-17). Similar results have been found for the chicken [beta]-globin 3[prime] enhancer, which is also able to confer position-independent expression in transgenic mice (18-20). As with most DNase I HSs, the erythroid-specific reorganization of local chromatin structure associated with the LCR HSs appears to be due to the disruption or displacement of nucleosomes (14,21). In other systems, similar changes have been shown to be necessary for the binding of the full complement of trans-acting factors to a specific cis-acting element (22).
As a step in understanding how the complex reorganization of [beta]-globin locus chromatin structure occurs we have focused on the mechanisms by which the LCR HSs are formed. In our initial experiments we used human HS4 as a model for studying this process. We demonstrated that a 1.3 kb fragment from the region of HS4 is able to direct the formation of HS4 in an erythroid-specific manner in transgenic mice (23). Subsequent truncation and deletion experiments indicated that an ~100 bp element near the center of HS4 is both necessary and sufficient for the formation of the HS (23). We have termed this element the HS-forming element or HSFE. Further analysis revealed that an NF-E2 binding site and tandem, inverted GATA sites are required for the formation of the native chromatin structure of HS4 (14). These binding sites are separated by ~50 bp. The finding that NF-E2 and GATA binding sites are required for LCR HS formation provided at least a partial basis for the erythroid specificity of these HSs. Examination of the DNA sequences of other LCR HS core regions revealed that similar NF-E2 and tandem, inverted GATA binding sites, also separated by ~50 bp, were found within the core region of each human LCR HS (14). These binding sites are evolutionarily conserved in the LCR HSs of chickens, rabbits, goats and mice (14,24).
On the basis of these findings, we hypothesized that the NF-E2 and tandem, inverted GATA binding sites found in each of the human LCR HS cores are necessary for the formation of each of these domains of erythroid-specific chromatin structure. If true, this would be consistent with a common underlying chromatin structure for each of the LCR HSs and would support a common mechanism of formation of the individual HSs. To test this hypothesis we have performed site-directed mutagenesis of the NF-E2 and tandem, inverted GATA sites found within the core regions of human [beta]-globin LCR HSs 2 and 3. These elements were then stably transfected into MEL cells and pools of clones evaluated for the ability of the mutant HSs to form. Using micrococcal nuclease (MNase) we also performed a comparative analysis of the nucleosomal structures of the HSs.
MATERIALS AND METHODS
HS2 and HS3 mutant constructs
HS2 (1.45 kb, KpnI-BglII), HS3 (1.9 kb, HindIII-HindIII) and HS4 (1.4 kb, BamHI-SphI) fragments were subcloned into a previously described pUC-based plasmid containing a neomycin resistance gene (Fig.
Nuclease sensitivity assays
In vivo DNase I sensitivity assays were performed on nuclei isolated from pools of stable transfectants as previously described (14,23). For most experiments nuclei (200 µg DNA/reaction) were digested in a volume of 200 µl with DNase I at concentrations of 0, 0.1, 0.25, 0.5, 0.75, 1.0, 2.0, 3.0 and 4.0 µg/ml. In some experiments the higher DNase I concentrations are not shown due to complete DNA digestion. Reactions were performed at 37°C for 10 min. Following DNase I treatment, genomic DNA was isolated and digested to completion with XhoI/SalI for Southern blots of HS2 mutants and XhoI for Southern blots of HS3 (Fig.
Regions of DNase I sensitivity and nucleosome position were mapped by plotting the migration distance of the molecular weight markers versus the logarithm of their size in base pairs. These data points were then fitted to the equation
| fragment size (bp) = m[ei(migration distance in cm)]. |
This produced a straight line where m is the slope of the line and i is the y-intercept. Correlation coefficients for the plots were >0.99. By measuring the migration distances of the upper and lower limits of each DNase I HS or MNase cutting site and applying the above formula the size, and therefore location, of each HS within the parental fragment was determined.
Figure 1. (A) Chromatin structure of the human [beta]-globin gene locus. The five expressed [beta]-globin genes are shown. The horizontal arrow represents the tissue-specific nuclease sensitivity observed throughout the entire locus in erythroid cells. Small vertical arrows represent DNase I HSs associated with the promoters of the globin genes. Boxes represent the 5[prime] DNase I `super' HSs. 5[prime] HSs 1-4 are erythroid-specific, developmentally stable and comprise the [beta]-globin locus control region (LCR). (B) Plasmid-based constructs used to determine the cis-acting sequences necessary for HS2 and HS3 formation. Mutations of HS2 and HS3 were made within the p[Delta]HS2 and p[Delta]HS3 plasmids. Approximate locations of HSs are indicated by hatched boxes. Probes and restriction enzyme sites used in DNase I sensitivity assays are shown. X, XhoI; H, HindIII; S, SalI; B, BglII. To test our hypothesis that the NF-E2 and tandem, inverted GATA binding sites of each [beta]-globin LCR HS are necessary for the formation of the associated domains of altered chromatin structure, we performed a mutational analysis of human LCR HSs 2 and 3. To do this we constructed plasmids containing the wild-type HS sequences. Each plasmid also contained a second wild-type HS, either HS4 or HS3, to serve as an internal control for LCR HS formation and a neoR gene for the selection of stable clones (Fig. [beta]-Globin LCR HS2 is unique in that it contains a strong erythroid-specific enhancer (27,28). This enhancer function is mediated through tandem NF-E2 binding sites located within the active core of the element (29). Besides NF-E2, the binding sites are also able to bind the transcription factor AP-1 and NF-E2-related factors LCR-F1 and NRF2 (28,30,31). The tandem NF-E2 sites are located ~50 bp 5[prime] of tandem, inverted GATA binding motifs. Together they comprise the region homologous to the HS4 HSFE (14). To assess the role of the tandem NF-E2 sites and tandem, inverted GATA sites in LCR HS2 formation we performed site-directed mutagenesis of these binding elements. The results of these experiments are shown in Figure Figure 2. Mutations used to evaluate the roles of NF-E2 and GATA binding elements in HS2 and HS3 formation. Mutations were introduced into plasmids p[Delta]HS2 and p[Delta]HS3 by site-directed mutagenesis. HS2 contains tandem NF-E2 sites and tandem, inverted GATA binding sites. HS3 contains two sets of tandem, inverted GATA binding sites located ~50 and ~110 bp 5[prime] of the NF-E2 site. Figure 3. Formation of HS2 following mutation of NF-E2 and GATA binding sites. Several DNase I HSs are formed within each construct. These include HS2, the test HS in these experiments, 1° HS3, 2° HS3 and the neoR-associated HS, the positive controls for these experiments. The expected location of HS2 is shown by the open arrow. The probe is the 318 bp KpnI-SacI fragment from the 5[prime]-end of HS2. P, parental band, XhoI-SalI fragment from the p[Delta]HS2 plasmid (Fig. 1); M, molecular weight markers; a mixture of HindIII-digested [lambda] DNA and HaeIII-digested [phis]X174 DNA. Mutation of the tandem NF-E2 binding sites within the HS2 core (mutant H2M1) produces a decrease in the sensitivity of the HS2 region to DNase I. The intensity of HS2 is now approximately equivalent to that of 2° HS3. These results are similar to what we observed in our original mutational studies of HS4, where mutation of the NF-E2 binding motif also resulted in a decrease in the sensitivity of HS4 (14). Mutation of the tandem, inverted GATA sites (H2M2) also results in a decreased sensitivity of HS2. These findings are also similar to our previous results for HS4. Mutation of both the NF-E2 and GATA sites (H2M3) results in the complete loss of HS2. This is despite the fact that all other factor binding sites in the region of the HS2 core remain intact. These results recapitulate our findings for HS4 and support the hypothesis that the NF-E2 and GATA binding sites are critical for the formation of both HS2 and HS4. Experiments analyzing the role of NF-E2 and GATA binding sites in HS3 formation are shown in Figure Figure 4. Formation of HS3 following mutation of individual NF-E2 and GATA binding sites. Several DNase I HSs are formed within each construct. These include 1° HS3, the test HS in these experiments, and 2° HS3, HS4 and the neoR-associated HS, the positive controls for these experiments. The expected location of HS3 is shown by the open arrow. The probe is the 634 bp SacI-SacI fragment from the 5[prime]-end of HS4 (Fig. 1). P, parental band, XhoI-XhoI fragment from the p[Delta]HS3 plasmid (Fig. 1); M, molecular weight markers as described in Figure 3. Analysis of the HS3 wild-type construct again shows several HSs. These include the neoR-associated HS, the two HS3 sites and the internal control for these experiments, HS4. Note that in the wild-type construct the intensity of 1° HS3 is approximately equal to that of the neoR HS. Mutation of the NF-E2 binding site (H3M1) results in a minor decrease in the intensity of 1° HS3 when compared with the neoR internal control. The next panel (H3M2) shows that mutation of the proximal GATA sites has little effect on HS3 formation. However, when the distal GATA sites are mutated (H3M3), the intensity of 1° HS3 is dramatically reduced to less than the level of 2° HS3. 2° HS3 is unaffected by any of these mutations. In Figure Figure 5. Formation of HS3 following mutation of multiple factor binding sites. DNase I HSs include 1° HS3, the test HS in these experiments, and 2° HS3, HS4 and the neoR-associated HS, the positive controls for these experiments. The expected location of HS3 is shown by the open arrow. HS4 is obscured in mutants H3M6 and H3M7 by the presence of an artifactual band. This band is present in the `0' DNase I lane and does not change with increasing DNase I concentration. The probe is the 634 bp SacI-SacI fragment from the 5[prime]-end of HS4. P, parental band, XhoI fragment from the p[Delta]HS3 plasmid (Fig. 1); M, molecular weight markers as described in Figure 3. Figure 6. Local chromatin structure of LCR HS2 and HS3. (A) DNase I and MNase analysis of HS2. Here the parental band (P) is the 1.45 kb KpnI-BglII HS2 fragment. The probe is the 318 bp KpnI-SacI fragment from the 5[prime]-end of HS2. (B) DNase I and MNase analysis of HS3. The parental band (P) is the 1.9 kb HindIII HS3 fragment. The probe is the 259 bp HindIII-SacI fragment from the 5[prime]-end of HS3. For DNase I experiments the regions of preferential cutting are indicated by brackets. HS DNase I and MNase mapping studies are summarized showing areas of DNase I sensitivity (open boxes) and nucleosomal location as determined by MNase digestion (circles). Mapping was performed as described in Materials and Methods. Also shown are the locations of the NF-E2 (N) and tandem GATA (G) binding elements, the functional core elements of the HSs and previously characterized regions of protein binding. M (over gel), molecular weight markers as described in Figure 3. M with bracket on the nucleosome figure indicates the site of maximal MNase digestion. The finding of conserved NF-E2 and GATA elements which are required for local chromatin reorganization within each LCR HS suggests that there may also be a common underlying structure within each HS region. To investigate this possibility we next examined the nucleosomal structure of HS2 and HS3. These experiments utilized DNase I, which preferentially digests nuclear DNA in regions of disrupted or displaced nucleosomes, and micrococcal nuclease (MNase), which preferentially cuts linker DNA between nucleosomes, as probes of local chromatin structure (21). Using these techniques the locations of specific regions of nuclease hypersensitivity and the positions of individual nucleosomes can be determined. Our previous mapping studies of LCR HS4 demonstrated that this HS is composed of an intense central band of DNase I sensitivity covering ~200 bp (14,23). This central area of sensitivity is flanked by less intense DNase IHS bands. MNase analysis of HS4 demonstrated that in erythroid cells a single nucleosome was disrupted or displaced from the central region of the DNase I HS and that nucleosomes formed a positioned array spanning several hundred base pairs (14). The HS4 HSFE is located near the 5[prime] boundary of the region of open chromatin which closely corresponds to the functional core of HS4 when analyzed for its ability to direct copy number-dependent expression in transgenic mice (15). To determine whether the local chromatin structures of HS2 and HS3 are similarly organized, we performed DNase I and MNase mapping experiments on these two HSs. The results of these experiments are shown in Figure Results for HS2 show that, similar to HS4, a broad intense central band is formed with DNase digestion (Fig. When a similar analysis is applied to HS3 we see a different picture (Fig. Our experiments were designed to test the hypothesis that the NF-E2 and tandem, inverted GATA binding elements found in each [beta]-globin LCR HS core region are necessary for the formation of the HSs. Our results indicate that, just as for HS4, mutation of these sites within HS2 and HS3 causes a marked reduction in the DNase I sensitivity of the HSs. These changes are most dramatic when both the NF-E2 and GATA binding motifs are mutated. Our results support the conclusion that the evolutionarily conserved NF-E2 and tandem inverted GATA sites found in each of the human LCR functional core regions play a critical and similar role in the formation of the individual HSs. Our experiments are based on the idea that the combination of an NF-E2 site and tandem, inverted GATA sites comprises a conserved element which is necessary for establishing the normal chromatin structure of the active elements of the LCR. A related hypothesis is that the formation of the LCR HS structures is necessary for LCR function. Since the initial description of the [beta]-globin LCR, studies of LCR function have been performed in a variety of experimental contexts. If formation of HS chromatin structures is necessary for LCR function, then these studies should demonstrate the importance of the same NF-E2 and GATA binding sites in LCR function. Studies aimed at defining the minimal LCR elements necessary for high level and position-independent expression of linked globin genes have been performed for HSs 2, 3 and 4. As shown in Figure Functional studies examining the effects of mutating individual binding sites within HS2 and HS3 have also been performed. Philipsen and colleagues found that a 98 bp fragment of HS3 extending from the 5[prime] set of tandem GATA sites through the 3[prime] set of tandem GATA sites was able to confer copy number-dependent expression in transgenic mice. These are the same sites mutated in the current study. Deletion of either of these sets of tandem GATA sites from their test construct resulted in markedly decreased expression and loss of copy number dependence (32). Specific mutation of the tandem NF-E2 elements of HS2 resulted in a 4-fold decrease in average expression when assayed as stable integrants in MEL cells (17). Mutation of these sites in transient assays results in the complete loss of HS2 enhancer activity (29). Deletion of the tandem NF-E2 sites in the context of a 1.9 kb HS2 fragment in transgenic mice resulted in a 20-fold decrease in expression levels but copy number dependence was maintained (33). Taken together, these results indicate that the specific NF-E2 and tandem GATA sites we have studied in HSs 2, 3 and 4 are not only required for the formation of the native chromatin structures of the HSs, but are also important for the functional activities of the LCR. Numerous studies have shown that the DNase I HSs associated with the [beta]-globin LCR are erythroid specific (5-7). Other studies have shown that the initial formation of the HSs may occur very early in erythroid differentiation or even prior to the onset of erythroid differentiation (37,38). Our own experiments, as well as those of Boyes and Felsenfeld on the formation of the chicken [beta]-globin enhancer HS, show that even after NF-E2 and GATA sites are mutated, a very weak HS often persists (14,20). These investigators used a quantitative restriction endonuclease assay of HS formation to show that the weak HS which forms in the absence of NF-E2 and/or GATA sites is due to a decrease in the proportion of HS regions which, within a cell population, are in a DNase I-hypersensitive conformation (20). Thus, binding of as yet unspecified factors may result in the initial remodeling of a small proportion of HS regions. The subsequent binding of NF-E2 and GATA factors would then stabilize this structure and shift the equilibrium from the nuclease-insensitive to the nuclease-sensitive conformations of the HS. Supporting this model are recent unpublished results from our laboratory suggesting that the NF-E2 and tandem, inverted GATA sites are, on their own, insufficient for HS formation in nuclear chromatin. While we have largely focused on the cis-acting sequences necessary for LCR HS formation, the trans-acting factors which mediate these structural changes are also relevant. In MEL cells, GATA-1 is the only readily detectable GATA family member (39,40). This implies that GATA-1 is able to mediate HS formation. Other GATA proteins such as GATA-2, which is expressed earlier in erythroid differentiation, may also be able to participate in LCR HS formation (41). NF-E2 and, to a lesser extent, AP-1 comprise the NF-E2 consensus sequence binding activity in MEL cells (42). Mutation of DNA bases required for NF-E2 binding, but not for AP-1 binding, within the HS4 core resulted in decreased DNase I sensitivity (14). These results suggest that NF-E2 is also a necessary trans-acting factor for full LCR HS formation. Supporting this conclusion are experiments performed by Armstrong and Emerson in a cell-free system, which demonstrated the ability of NF-E2 to disrupt local nucleosomal structure, and by Gong et al., which showed that the tandem NF-E2 sites of HS2 were necessary for HS formation on an Epstein-Barr-derived minichromosome in K562 cells (43,44). MEL cells lacking NF-E2 have been shown to form LCR HSs (45). However, our results and those of the Felsenfeld laboratory predict that the loss of NF-E2 would not abolish the HS, but would result only in a decrease in its DNase I sensitivity (14,20). Factors interacting with the tandem GATA binding elements appear to play a special role in LCR HS formation. For example, while ~90 in vitro DNA-protein interactions have been identified within or near the HS3 core region (35), the mutation of only the 3[prime] set of tandem GATA sites results in the near complete loss of the HS. Similar results were seen in our studies of HSs 2 and 4. The apposition of the tandem, inverted GATA binding elements may result in a unique interaction between GATA binding proteins which stabilizes the chromatin structure of the HS. This potential structural role of GATA proteins is distinct from their previously described transcriptional functions (46) and raises the possibility that one of the key functions of GATA-1 may be the maintenance of an open or active chromatin structure surrounding erythroid-specific gene loci. The active elements of the LCR have several features in common (i.e. they are contained within developmentally stable, erythroid-specific DNase I HSs, they confer copy number-dependent expression in multi-copy transgenic mice and they are evolutionarily conserved). Despite these functional similarities, little structural similarity has been found between the HSs, other than the observation that they contain clusters of similar DNA binding factors (47,48). Our finding of evolutionarily conserved, similarly arranged NF-E2 and GATA binding elements within HSs 2, 3 and 4 which appear to serve the common function of tissue-specific local chromatin structure reorganization raises two possibilities. The first is that the active elements of the LCR may be related by more than just the fact that they contain clusters of similar trans-factor binding sites. A common, multi-protein structure may be formed at the center of each LCR element. Potential functions of this structure include mediating interactions between individual HS elements (as in the holocomplex model of LCR function) or between the HS elements and distant globin gene promoters. Another potential function of the common structure might be to open local chromatin to allow assembly of the full complement of DNA binding factors necessary for LCR function. Our findings also raise the possibility that the LCR HSs may share a common evolutionary heritage. Just as the individual globin genes arose by gene duplication and subsequent divergence, the LCR HSs may also have arisen from a common `ancestor' regulatory element, followed by evolutionary divergence of protein binding sites around the central core region, leading to different functional roles for each HS. We wish to thank Dr J. McInerney for helpful discussions and M. Layon for assistance in data preparation. This research was supported by National Institutes of Health grant no. HL52243, the Cooley's Anemia Foundation and the Marie Wilkinson Fund.
RESULTS
Mutational analysis of LCR HS2
Mutational analysis of LCR HS3
Local chromatin structure of HS2 and HS3
DISCUSSION
The relationship between [beta]-globin LCR chromatin structure and function
Mechanism of LCR HS formation
ACKNOWLEDGEMENTS
REFERENCES
This article has been cited by other articles:
This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: www-admin{at}oup.co.uk
Last modification: 3 Dec 1998
Copyright©Oxford University Press, 1998.
CiteULike 
Connotea 
Del.icio.us What's this?
Y. Cho, S.-H. Song, J. J. Lee, N. Choi, C. G. Kim, A. Dean, and A. Kim
The role of transcriptional activator GATA-1 at human {beta}-globin HS2
Nucleic Acids Res.,
June 27, 2008;
(2008)
gkn368v1.
[Abstract]
[Full Text]
[PDF]
S. Barchetta, A. La Terza, P. Ballarini, S. Pucciarelli, and C. Miceli
Combination of Two Regulatory Elements in the Tetrahymena thermophila HSP70-1 Gene Controls Heat Shock Activation
Eukaryot. Cell,
February 1, 2008;
7(2):
379 - 386.
[Abstract]
[Full Text]
[PDF]
A. Kim, S.-h. Song, M. Brand, and A. Dean
Nucleosome and transcription activator antagonism at human {beta}-globin locus control region DNase I hypersensitive sites
Nucleic Acids Res.,
September 27, 2007;
35(17):
5831 - 5838.
[Abstract]
[Full Text]
[PDF]
W. Hong, A. Y. Kim, S. Ky, C. Rakowski, S.-B. Seo, D. Chakravarti, M. Atchison, and G. A. Blobel
Inhibition of CBP-Mediated Protein Acetylation by the Ets Family Oncoprotein PU.1
Mol. Cell. Biol.,
June 1, 2002;
22(11):
3729 - 3743.
[Abstract]
[Full Text]
[PDF]
G. T. F. Schwenger, R. Fournier, C. C. Kok, V. A. Mordvinov, D. Yeoman, and C. J. Sanderson
GATA-3 Has Dual Regulatory Functions in Human Interleukin-5 Transcription
J. Biol. Chem.,
December 14, 2001;
276(51):
48502 - 48509.
[Abstract]
[Full Text]
[PDF]
K. M. Leach, K. Nightingale, K. Igarashi, P. P. Levings, J. D. Engel, P. B. Becker, and J. Bungert
Reconstitution of Human {beta}-Globin Locus Control Region Hypersensitive Sites in the Absence of Chromatin Assembly
Mol. Cell. Biol.,
April 15, 2001;
21(8):
2629 - 2640.
[Abstract]
[Full Text]
J. C. McDowell and A. Dean
Structural and Functional Cross-Talk between a Distant Enhancer and the varepsilon -Globin Gene Promoter Shows Interdependence of the Two Elements in Chromatin
Mol. Cell. Biol.,
November 1, 1999;
19(11):
7600 - 7609.
[Abstract]
[Full Text]
[PDF]
C. D. Trainor, R. Ghirlando, and M. A. Simpson
GATA Zinc Finger Interactions Modulate DNA Binding and Transactivation
J. Biol. Chem.,
September 1, 2000;
275(36):
28157 - 28166.
[Abstract]
[Full Text]
[PDF]
S. Iwamoto, H. Suganuma, T. Kamesaki, T. Omi, H. Okuda, and E. Kajii
Cloning and Characterization of Erythroid-specific DNase I-hypersensitive Site in Human Rhesus-associated Glycoprotein Gene
J. Biol. Chem.,
August 25, 2000;
275(35):
27324 - 27331.
[Abstract]
[Full Text]
[PDF]
A. J. Goodwin, J. M. McInerney, M. A. Glander, O. Pomerantz, and C. H. Lowrey
In Vivo Formation of a Human beta -Globin Locus Control Region Core Element Requires Binding Sites for Multiple Factors Including GATA-1, NF-E2, Erythroid Kruppel-like Factor, and Sp1
J. Biol. Chem.,
July 13, 2001;
276(29):
26883 - 26892.
[Abstract]
[Full Text]
[PDF]
This Article 
Abstract
Print PDF (313K)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (13)
Commercial Re-use Guidelines
for Open Access NAR Content
Google Scholar
Articles by Pomerantz, O.
Articles by Lowrey, C. H.
Search for Related Content
PubMed
PubMed Citation
Articles by Pomerantz, O.
Articles by Lowrey, C. H.
Social Bookmarking
What's this?