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RI
Promoter Region Affecting Transcription Activity: A Possible Promoter-Dependent Mechanism for Association between FcRI and Atopy1
* Atopy (Allergy) Research Center, Departments of
Dermatology and
Immunology, Juntendo University School of Medicine, Tokyo, Japan;
Advanced Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co. Ltd., Saitama, Japan;
¶ Biotechnology Research Center, University of Tokyo, Tokyo, Japan;
|| Department of Pediatrics, Yamaguchi University School of Medicine, Yamaguchi, Japan;
# Department of Dermatology, Tokyo Medical University, Tokyo, Japan; and
** Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
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Abstract |
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subunit of the high-affinity IgE receptor (Fc
RI) plays an important role in IgE-mediated allergic reactions as an amplifier for cell surface expression and signal transduction of FcRI. FcRI is presumed to be one of the genes linked with atopic diseases. However, the validity of the associations previously found between single nucleotide polymorphisms (SNPs) in FcRI and atopic diseases is questionable. In the present study, we found correlation between the SNP of FcRI at +6960A/G, resulting in a Glu237Gly amino acid substitution, and the cell surface expression level of FcRI on blood basophils, although it has been shown that the Glu237Gly mutation itself does not affect the surface expression or function of FcRI. We additionally found four SNPs in the promoter region of FcRI, among which –426T/C and –654C/T were tightly linked with +6960A/G. Reporter plasmids carrying the –426C and –654T promoter displayed higher transcriptional activity than those carrying the –426T and –654C promoter. We found that transcription factor YY1 preferentially bound and transactivated the –654T promoter. Furthermore, expression of FcRI -chain mRNA in basophils from individuals who have the minor heterozygous genotype was significantly higher than that of the major homozygous genotype. These results suggest that the SNPs in the FcRI promoter are causally linked with atopy via regulation of FcRI expression. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RI) expressed on mast cells and basophils plays a critical role in mediating allergic reactions induced by Ag-specific IgE Abs. FcRI is composed of three subunits: the IgE-binding 
-chain, the signal-transducing 
-chain, and the -chain. The -chain enhances cell surface expression of FcRI by association with the -chain and amplifies signal from an ITAM motif of the -chain. Therefore, the -chain is a key molecule in mediating allergic reactions. In addition, FcRI is thought to be one of the genes responsible for atopic diseases based on the observation that q13 of chromosome 11, where FcRI is also mapped, is associated with atopic disease (1). Several polymorphisms have been found in human FcRI. Among them, three single nucleotide polymorphisms (SNPs)3 in the coding region result in amino acid substitution (2, 3). Further studies have shown that two SNPs in exon 6 are often absent in certain populations, including the Japanese, whereas another SNP in exon 7, which causes an amino acid substitution, Glu237Gly, is more common (4, 5). Although some reports have presented positive association between the Glu237Gly polymorphism and atopic diseases (3, 4, 6, 7), other reports have not (8, 9). In contrast, it has also been demonstrated that the amino acid variations in the -chain, including the Glu237Gly mutation, does not affect the expression or function of FcRI in vitro (10, 11). These conflicting observations raise the possibility that unidentified polymorphisms in the noncoding region of FcRI, which are linked with the Glu237Gly polymorphism, may be responsible for the linkage between FcRI and atopic diseases. In this respect, the promoter region of FcRI is the most likely region that can directly affect the expression of FcRI. To test this hypothesis, we characterized the functions of novel SNPs in the FcRI promoter and revealed their linkage with the Glu237Gly polymorphism, FcRI expression level on basophils, and promoter activity. |
Materials and Methods |
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Genomic DNA was prepared from peripheral blood using a DNA quick kit (Dainippon Pharmaceutical, Osaka, Japan). Nucleotide sequencing of FcRI was conducted as previously reported for the -chain promoter (12). The following oligonucleotides were used as primers to amplify the -chain gene: 5'-CCACCAATTCCTGAAGAC-3' (–1098/–1081) and 5'-CACCGTGACTATGACTTC-3' (+225/+208) to amplify the promoter region; and 5'-AGCGTGGTGGCAGGTACCTGAGGTT-3' (+6203/+6227) and 5'-TTTCCAGTAGCCCCTTAACAAAACC-3' (+7062/+7038) to amplify exon 7. Oligonucleotides 5'-CCCATTCTTGCCACTGT-3' (–667/-651), 5'-ACAGTGGCAAGAATGGG-3' (–651/-667), 5'-CCAGAAGAAGGGCACATCTC-3' (–279/-260), 5'-GAGATGTGCCCTTCTTCTGG-3' (–260/-279), and 5'-ATGACAGAGAGCGTGAGACCCAGA-3' (+6770/+6793) were used as the sequencing primers.
Subjects
All subjects were unrelated Japanese volunteers from the University of Tokyo (Departments of Biotechnology and Applied Biological Chemistry, Biotechnology Research Center) and from Juntendo University School of Medicine (Departments of Dermatology and Immunology, Atopy Research Center). We selected healthy individuals who had no symptoms or history of atopic dermatitis, atopic asthma, or allergic rhinitis for the determination of the cell surface expression of FcRI. This study was approved by the ethics committee of Juntendo University School of Medicine.
Measurement of FcRI level on blood basophils by flow cytometry
Basophils were enriched from 5 ml of peripheral blood using Polymorphoprep (AXIS-SHIED PoC, Oslo, Norway). As previously reported (13), cells were analyzed by flow cytometry on a FACSCalibur (BD Biosciences, Mountain View, CA) after staining with PE-conjugated anti-human CD3, CD7, CD9, CD14, and CD19 Abs (BD Pharmingen, San Diego, CA) and with FITC-conjugated anti-human FcRI -chain Ab CRA1, which does not compete with IgE (Cosmo Bio, Tokyo, Japan) or FITC-conjugated mouse IgG2b isotype control (BD Pharmingen). Mean fluorescence intensity (MFI) of the anti-FcRI staining on CD3–CD7–CD9–CD14–CD19– basophils was determined using CellQuest software (BD Biosciences).
Statistical analysis.
The p value was determined using a paired t test and <0.05 was considered to indicate statistical significance. The 
2 test was performed to analyze linkage between each polymorphism using SPSS software (version 11.0; SPSS, Chicago, IL). A p value of exact significance was used in the 2 test. Multiple linear regression analysis was performed to test for predictors of MFI by entering genotypes of SNPs into the model (SPSS).
Cell lines
Human mast cell lines, HMC-1 and KU812, a megakaryocyte cell line HML/SE, and a cervical carcinoma cell line, HeLa, were maintained and characterized as described previously (14, 15).
Reporter assay for promoter activity
Reporter plasmids carrying the whole -chain promoter of a major allele (–752T/–654C/–426T/–109T) and a minor allele (–752C/–654T/–426C/–109C) were generated from the reporter plasmid pGL(–1079/+102) (14) by site-directed mutagenesis using a QuikChange site-directed mutagenesis kit (Stratagene, La Jolla, CA). Three tandem repeats of each polymorphic sequence were introduced upstream of the human -chain minimal promoter (14) in a luciferase reporter plasmid (see Fig. 3C). In brief, 3 x (–121/–97) sequence, 3 x (–438/–414), 3 x (–666/–642), and 3 x (–764/–740) were used to examine the effect of –109C/T, –426T/C, –654C/T, and –752C/T SNPs, respectively, on promoter activity. The expression plasmid pCR-YY1 (16) was used for coexpression analysis. Cells were transfected with 5 µg of reporter plasmid to compare the effect of each SNP, or they were infected with 3 µg of reporter plasmid and 3 µg of expression plasmid for coexpression analysis. Transfection was performed by electroporation using a Bio-Rad Gene Pulsar II (Bio-Rad, Hercules, CA) as described previously (17). The luminescence of each cell lysate was measured using MicroLumat Plus (Berthold, Postfach, Germany) as described previously (14).
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The following oligonucleotides labeled with FITC at the 5' site were used as the probes for EMSA: 5'-GAGACTAACACAC/TACTCACTCACAT-3' corresponding to –438/-414 for –426C/T and 5'-CCATTCTTGCCAC/TTGTAAAGATCTA-3' corresponding to –666/-642 for –654C/T. Nuclear extracts and double-stranded oligonucleotide probes were prepared as described previously (18, 19). Abs against YY1 and USF1 were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). In vitro transcription and translation were performed with a TNT T7 Quick coupled transcription/translation system (Promega) using pCR-YY1 (16) as the template. The FITC-labeled probe was mixed with nuclear extract or the in vitro transcription/translation mixture and subjected to 4% PAGE as described in our previous report (14, 20). Fluorescent images were analyzed on a FluorImager 595 (Molecular Dynamics, Sunnyvale, CA).
Quantification of -chain mRNA
Basophils were purified by the MACS separation technique using a Basophil Isolation kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and a Vario MACS (Miltenyi Biotec) according to the manufacturer’s instructions. In brief, PBMC from 60 ml of peripheral blood, which was isolated by density gradient centrifugation, were treated with isotonic ammonium chloride buffer to lyse erythrocytes and then washed with PBS supplemented with 0.5% BSA and 2 mM EDTA. The PBMC suspension treated with reagents from a Basophil Isolation kit (FcR Blocking Reagent, Hapten-Antibody Cocktail, and MACS Anti-Hapten BicroBeads) was applied onto an LS+ column in the magnetic field of a Vario MACS. The purity of the isolated basophils, which were collected as negative fraction using the above magnetic separation system, was confirmed to be 
95% by flow cytometry. Total RNA was prepared from the basophils using TRIzol reagent (Invitrogen Life Technologies, Leek, The Netherlands). Reverse transcription was performed using a SuperScript III First-Strand Synthesis System for RT-PCR (Invitrogen Life Technologies). The Advantage 2 polymerase mix (BD Clontech, Palo Alto, CA) was used for semiquantitative PCR with the same primer sets for human FcRI -chain and -actin as used in our previous study (14). The thermal cycling condition was as follows: denaturalization at 95°C for 30 s, annealing at 55°C for 30 s, and extension at 68°C for 1 min. The amount of FcRI -chain mRNA was also quantified using a 7500 Real-Time PCR System (Applied Biosystems, Foster City, CA) with an Assays-on-Demand gene expression product (no. Hs00175091_m1# for human FcRI -chain) and TaqMan Universal PCR Master Mix (Applied Biosystems). The expression level of the FcRI -chain was shown as a ratio to that of GAPDH by calculation of cycle threshold (Ct) values in amplification plots with 7500 SDS software. The -chain mRNA expression level in Fig. 5B is the ratio to that of no. 1 of the –654C/C individual.
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-chain mRNA expression level (%) = 2((Ct value of FcRI -chain) – (Ct value of GAPDH)) – ((Ct value of FcRI -chain of –654C/C no. 1) –(Ct value of GAPDH of –654C/C no. 1)) x 100. |
Results |
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RI Glu237Gly polymorphism and cell surface expression level of FcRI on blood basophils
We first examined the correlation between FcRI polymorphism at Glu237Gly and the expression level of FcRI on peripheral blood basophils from nonatopic healthy individuals whose genotypes were determined by direct sequencing. Most of the Japanese population carried either GAA/GAA (Glu/Glu) (48 of 70 individuals) or GAA/GGA (Glu/Gly) (21 of 70 individuals) at +6960 (237). No basophils of the GGA/GGA (Gly/Gly) genotype were subjected to this analysis due to its extremely low allelic frequency (1 of 70 individuals). As shown in Fig. 1, basophils of the Glu/Gly (A/G) genotype expressed significantly higher levels of FcRI (MFI = 759 ± 78) than those of the Glu/Glu (A/A) genotype (MFI = 480 ± 46; p = 0.0037). However, we and others have previously demonstrated that the amino acid substitution Glu237Gly itself has no direct effect on the expression or function of FcRI (10, 11). In this context, we hypothesized that the Glu237Gly (+6960A/G) polymorphism might be linked with another polymorphism in the promoter region that was able to directly affect -chain gene expression.
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RI promoter and Glu237Gly polymorphism
We sequenced over 1 kb of FcRI promoter region from 70 individuals to identify polymorphic sites. As shown in Fig. 2, we found four SNPs at –109, –426, –654, and –752. Subsequently, we performed statistical analysis to examine their linkage to the +6960A/G polymorphism (Tables I–IV). When the polymorphisms were scored for association with each other, we found a high degree of linkage disequilibrium: –426T was closely associated with +6960A, while –426C was closely associated with +6960G (Table II, 2 = 117.81 with 4 df; p = 2.39 x 10–13). In addition, –654C and T were also closely associated with +6960A and +6960G, respectively (Table III, 2 = 110.01 with 4 df; p = 1.96 x 10–11). A SNP at –109 was also significantly associated with that at +6960 (Table I, 2 = 20.17 with 4 df; p = 0.00018). In contrast, no statistically significant association was found between –752T/C and +6960A/G (Table IV, p = 0.083). By the exact test from 2 x 2 contingency tables excluding heterozygous genotypes (Table V), significant association of the Glu237Gly polymorphism was observed with SNPs at –426 (p = 0.021) and –654 (p = 0.021) but not with those at –109 (p = 0.069) and –752 (p = 0.31). Association between the polymorphism at Glu237Gly (+6960A/G) and those in the promoter is summarized in Fig. 3A. We also found that the –752T/–654C/–426T/–109T/+690A genotype constitutes a typical major allele while the –752C/–654T/–426C/–109C/+6960G genotype constitutes a typical minor allele in the Japanese population.
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RI expression, we reanalyzed the data in Fig. 1 using a multiple linear regression model. A significant multiple linear regression equation was obtained (p = 0.0065), and the –109T (p = 0.0024), –426C (p = 0.0058), and –654T (p = 0.031) SNPs were significantly associated with higher FcRI expression. These results suggested that the higher expression of FcRI on basophils carrying the +6960A/G genotype was due to the effect of polymorphisms in the promoter that were tightly linked to the +6960A/G SNP. Effect of SNPs on promoter activity
To examine the effect of the four SNPs on the promoter activity, we performed the luciferase reporter assay in FcRI-positive KU812 cells (14), which were transiently transfected with the reporter plasmids containing the whole promoter (–1079/+102) of the major allele carrying –752T/–654C/–426T/–109T (TCTT), or the minor allele, carrying –752C/–654T/–426C/–109C (CTCC), just upstream of the luciferase gene. As shown in Fig. 3B, the minor allele (CTCC) promoter exhibited significantly higher activity than the major allele (TCTT) promoter in KU812 cells (p = 0.014).
To identify the SNP affecting the promoter activity, we constructed four pairs of reporter plasmids, in which three tandem repeats of 25-bp sequence around each SNP were placed just upstream of the minimal -chain promoter (–95/+102) containing a TATA box and Oct-1 binding sites (see Fig. 2) (14) as shown in Fig. 3C. FcRI-positive HML/SE cells (14) were transfected with these reporter plasmids, and luciferase activity in the cell lysates was measured. The sequence with –654T exhibited markedly higher cis-enhancing activity than that with –654C. The sequence with –426C also showed moderately higher activity than that with –426T. By contrast, no significant difference was observed between –109C and –109T or between –752C and –752T. These results indicate that both –426C and –654T in the minor allele, which were tightly linked with the +6960G genotype (Fig. 3A), had higher cis-enhancing activity than –426T and –654C in the major allele.
Specific transactivation of the –654T allele by YY1
The significant effects of SNPs at –426 and –654 on the promoter activity suggested that some unidentified transcription factor may be differentially recognizing these SNPs. We then performed EMSA with nuclear extracts from FcRI-positive cell lines (HMC-1, KU812, and HML/SE) or a negative cell line (HeLa) using double-stranded 25-bp oligonucleotides corresponding to –426T/C (–438/–414) or –654C/T (–666/–642) as probes. No apparent difference was observed with the –426C and –426T probes (data not shown). In contrast, a specific band was observed with the –654T probe but not with the –654C probe (Fig. 4A, indicated by arrow). This band specifically disappeared by the addition of excess unlabeled –654T probe but not –654C probe as a competitor (Fig. 4B). These results indicate the presence of a nuclear protein, which specifically bound to the –654T allele. This nuclear protein was found not only in FcRI-positive cells but also in FcRI-negative HeLa cells (Fig. 4A), suggesting that it is ubiquitously expressed. We noticed that the nucleotide substitution of T for C at –654 generated a potential YY1-binding motif, CCAT, at this position. To test the involvement of YY1, we added anti-YY1 Ab to the EMSA mixture and found that the target band disappeared in the presence of anti-YY1 Ab but was still present after addition of irrelevant anti-USF1 Ab to the assay mixture (Fig. 4B). Furthermore, when YY1 produced by in vitro transcription/translation was used instead of nuclear extract, a band showing the same mobility was observed (Fig. 4C, indicated by arrow). This band disappeared in the presence of anti-YY1 Ab.
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RI minimal promoter (see Fig. 3C). The luciferase activity driven by the promoter with (–654T)x3 sequence was significantly higher than that driven by the (–654C)x3 sequence in KU812 cells (p = 0.029; Fig. 4D) as well as in HML/SE cells (Fig. 3C). Overexpression of YY1 moderately up-regulated the promoter with the (–654C)x3 sequence (p = 0.058; Fig. 4D). This was probably due to a nonspecific effect of exogenous YY1, because a similar effect of exogenous YY1 was observed when a promoter-less plasmid, pGL3-Basic, was used as the reporter plasmid (data not shown). In contrast, the promoter with (–654T)x3 sequence was markedly up-regulated by overexpression of YY1 (p = 0.00053; Fig. 4D). When the fold induction was compared between (–654C)x3 and (–654T)x3, the effect of coexpressed YY1 on (–654T)x3 (2.27-fold) was statistically higher than that on (–654C)x3 (1.77-fold; p = 0.021). These results suggested that the higher transcriptional activity of the minor allele promoter was partly due to specific transactivation by YY1 via the site containing –654T.
Expression level of the FcRI -chain in blood basophils from –654C/C and –654C/T individuals
To analyze the effect of the SNPs on the expression level of the FcRI -chain, we compared the amount of FcRI -chain mRNA in basophils between –654C/C individuals (n = 4) and –654C/T individuals (n = 5). The amount of FcRI -chain mRNA in basophils isolated from peripheral blood was analyzed by semiquantitative PCR (Fig. 5A) and real-time PCR (Fig. 5B). The expression of FcRI -chain mRNA in basophils from individuals who have the minor heterozygous allele was significantly higher than that of those with the major homozygous genotype, as determined by quantitative PCR (Fig. 5B). A similar conclusion was obtained using semiquantitative PCR, as interpreted using the intensity of the bands in the agarose gel profile (Fig. 5A). These results indicate that the minor allele at –654 of FcRI increases FcRI -chain transcription in basophils.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RI, which results in the Glu237Gly polymorphism, has been implicated in atopic diseases as a predisposing genetic factor (3, 4, 6, 7). In the present study, we found significant association between the Glu237Gly polymorphism and the expression level of FcRI on blood basophils (Fig. 1). However, we and others have demonstrated that the amino acid substitution of the Glu237Gly dose not affect either expression or function of FcRI (10, 11), suggesting that this polymorphism is genetically linked with other polymorphisms that can directly affect the expression of -chain. We have now found four SNPs in the FcRI promoter (Fig. 2), of which two SNPs, –426T/C and –654C/T,are most tightly linked with the Glu237Gly polymorphism (Tables I–V) and directly affect transcriptional activity (Fig. 3).
We also found that the single nucleotide change at –654 from C (major allele) to T (minor allele) created a YY1 motif, CCAT, and that this motif was actually recognized by YY1 (Fig. 4). YY1 strictly discriminated the –654C allele from the –654T allele. Such strict recognition of the core motif is a typical feature of YY1, as shown in other studies where mutation at the T of the CCA/TT core sequence completely abolished the binding of YY1 (17, 21). Although YY1 is a multifunctional transcription factor involved in both positive and negative regulation of gene expression, YY1 functioned as a positive regulator for the -chain promoter (Fig. 4D). Our present results suggest that the specific transactivation by YY1 is at least partly responsible for the higher activity of the minor allele promoter containing –654T. In our previous study, MZF-1 was identified as a transcription factor which determines the cell type-specific expression of the FcRI -chain (22). At the same time, we also found that the promoter activity of the -chain was affected by an ubiquitous transcription factor Oct-1 (14). Considering that YY1 is a ubiquitously expressed transcription factor, we concluded that YY1 does not determine the cell type-specific expression of FcRI, but rather affects the activity of the promoter, similar to the case of Oct-1.
In the present study, we were unable to detect or identify a nuclear protein differentially binding the –426T/C SNP. C at –426 of the minor allele forms an increased CA repeat sequence in this position (see Fig. 2), which has a high potential to form the Z-DNA structure (23, 24). The structural transition from a right-handed B-DNA conformation to a left-handed Z-DNA conformation has been shown to regulate gene transcription (25, 26). It should also be noted that SNPs altering gene expression and those associated with diseases are often found in the CA repeat sequences (27, 28, 29). At present, we assume that the SNP at –426 may affect -chain gene expression through rearrangement of DNA structure. Further studies are required to address this possibility.
The serum IgE level is known to affect the cell surface expression of FcRI. To determine whether the effect of SNPs on FcRI expression is independent of the IgE level, we analyzed the serum IgE levels of the individuals in Fig. 1 and found a positive correlation between the polymorphism and serum IgE level; the concentration of serum IgE of Glu/Gly (+6960A/G; 84 ± 48 IU/ml) was higher than that of Glu/Glu (+6960A/A; 58 ± 14 IU/ml, p = 0.0088), although these values were significantly lower than those of atopic dermatitis patients but still in the normal range for the healthy controls. Association between the Glu237Gly polymorphism and IgE level has been previously observed in the Japanese population (4, 7), and our observation that the promoter SNPs directed increased expression of the FcRI -chain associated with the IgE level is consistent with the previous observations. Although the mechanism for controlling IgE concentration in serum by -chain SNPs is still unclear, we propose that the SNPs in the -chain promoter are a possible cause of disease through the increased expression of the -chain. To verify this hypothesis, further study, including analysis of the SNPs of atopic patients, will be required.
Consistent with the notion that –426T/C and –654C/T SNPs in the promoter are responsible for the association with atopic diseases, the –426T/C and –654C/T SNPs in the promoter were more closely associated with atopic dermatitis than the +6960A/G polymorphism in our preliminary study (unpublished observation). Further studies are now underway to address the association with other allergic diseases such as atopic asthma and nasal allergy.
During preparation of this manuscript, linkage disequilibrium within FcRI was studied by Traherne et al. (30). Their report indicating that SNPs from –654 to +14050 (they labeled them –756 to +13948) exhibited linkage disequilibrium with each other is consistent with our present study demonstrating the linkage among –654, –426, and +6960, although they did not analyze the actual effects of candidate transcription factors.
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Acknowledgments |
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Footnotes |
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1 This work was supported in part by a Grant-in-Aid for Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to C.N.). 
2 Address correspondence and reprint requests to Dr. Chiharu Nishiyama, Atopy (Allergy) Research Center, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. E-mail address: chinishi{at}med.juntendo.ac.jp
3 Abbreviations used in this paper: SNP, single nucleotide polymorphism; MFI, mean fluorescence intensity; Ct, cycle threshold.
Received for publication March 9, 2004. Accepted for publication September 10, 2004.
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References |
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subunit of the high-affinity IgE receptor (FcRI) on chromosome 11q. Lancet 341:332.[Medline]
subunit of the high-affinity immunoglobulin E receptor. Nat. Genet. 7:125.[Medline]
subunit of the high-affinity receptor for immunoglobulin E (FcR- E237G): associations with measures of atopy and bronchial hyper-responsiveness. Hum. Mol. Genet. 5:959.RI in a Japanese population. Hum. Mol. Genet. 5:1129.RI-. Adv. Exp. Med. Biol. 409:355.[Medline]
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receptor I -chain promoter affecting the transcription activity: possible relationship to allergic diseases. J. Immunol. 171:1927.RI and FcRI in human blood basophils. J. Allergy Clin. Immunol. 107:832.[Medline]
RI chain gene expression by Oct-1. Int. Immunol. 15:549.RI -chain distal promoter. J. Immunol. 170:3732.RI -chain gene expression by multiple transcription factors. J. Immunol. 168:4546.-chain gene. J. Immunol. 163:623.RI chain expression via a CAGCTG element in the first intron. Eur. J. Immunol. 31:590.[Medline]
RI -chain gene expression by GATA-1 via four GATA motifs in the promoter. J. Immunol. 170:334.-chain gene expression via an intronic element. J. Immunol. 171:2478. and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood 98:1594.RI-. Hum. Mol. Genet. 12:2577.This article has been cited by other articles:
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  T. Ito, C. Nishiyama, N. Nakano, M. Nishiyama, Y. Usui, K. Takeda, S. Kanada, K. Fukuyama, H. Akiba, T. Tokura, et al. Roles of PU.1 in monocyte- and mast cell-specific gene regulation: PU.1 transactivates CIITA pIV in cooperation with IFN-{gamma} Int. Immunol., July 1, 2009; 21(7): 803 - 816. [Abstract] [Full Text] [PDF]
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 S. Kanada, N. Nakano, D. P. Potaczek, K. Maeda, N. Shimokawa, Y. Niwa, T. Fukai, M. Sanak, A. Szczeklik, H. Yagita, et al. Two Different Transcription Factors Discriminate the -315C>T Polymorphism of the Fc{epsilon}RI{alpha} Gene: Binding of Sp1 to -315C and of a High Mobility Group-Related Molecule to -315T J. Immunol., June 15, 2008; 180(12): 8204 - 8210. [Abstract] [Full Text] [PDF]
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C. Nishiyama, T. Ito, M. Nishiyama, S. Masaki, K. Maeda, N. Nakano, W. Ng, K. Fukuyama, M. Yamamoto, K. Okumura, et al. GATA-1 is required for expression of Fc{varepsilon}RI on mast cells: analysis of mast cells derived from GATA-1 knockdown mouse bone marrow Int. Immunol., July 1, 2005; 17(7): 847 - 856. [Abstract] [Full Text] [PDF]
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T. Ito, C. Nishiyama, M. Nishiyama, H. Matsuda, K. Maeda, Y. Akizawa, R. Tsuboi, K. Okumura, and H. Ogawa Mast Cells Acquire Monocyte-Specific Gene Expression and Monocyte-Like Morphology by Overproduction of PU.1 J. Immunol., January 1, 2005; 174(1): 376 - 383. [Abstract] [Full Text] [PDF]
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RI