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RI 
-Chain Gene Expression by Multiple Transcription Factors
* Allergy (Atopy) Research Center, Departments of
Immunology and
Dermatology, Juntendo University School of Medicine, Tokyo, Japan;
Biotechnology Research Center, University of Tokyo, Tokyo, Japan; and
¶ Foods and Pharmaceuticals Research and Development Laboratory, Asahi Breweries, Ibaraki, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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RI
-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1
bound to the region close to that recognized by Elf-1. The -chain
promoter activity was up-regulated 
2-fold by exogenously expressed
YY1 or PU.1 and 7-fold by GATA-1, respectively, in KU812 cells. In
contrast, coexpression of GATA-1 with either of PU.1 or YY1
dramatically activated the promoter 41- or 27-fold, respectively.
Especially synergic activation by GATA-1 and PU.1 was surprising,
because these transcription factors are known to inhibit the respective
transactivating activities of each other. These up-regulating effects
of PU.1 and YY1 with GATA-1 were inhibited by overexpression of Elf-1,
indicating that Elf-1 serves as a repressor for the -chain gene
expression. Transcriptional regulation of the -chain gene through
four transcriptional factors is discussed. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RI triggers the release of a
variety of chemical mediators from activated mast cells, which results
in allergic responses. FcRI is a tetrameric receptor composed of one
-, one 
-, and two 
-chains. Among three subunits of FcRI,
the -chain is found in various kinds of cells, serving as a
component of other receptors, such as FcRIII, FcRI, and FcRI,
which is in contrast with the expression of FcRI in limited cells.
The -chain is shown to be unnecessary for the expression of
functional human FcRI on the cell surface. In contrast, the
-chain is necessary for the functional FcRI on cell surface, and
is expressed in only FcRI-positive cells. Recently, the expression
of FcRI was found to be up-regulated by IL-4 in human mast cells,
eosinophils, or monocytes (1, 2, 3, 4, 5, 6). In those studies,
increases in -chain mRNA and its product in response to IL-4
stimulation were demonstrated. Those results suggest that -chain
expression specifies the cell-type specific expression of FcRI and
determines FcRI expression by IL-4 stimulation. Therefore,
elucidation of the mechanisms for the FcRI -chain expression
could give us the important information on the prevention against the
allergic diseases.
Recently, we analyzed the regulation of the FcRI -chain gene
expression and found that Elf-1 and GATA-1 were involved in the
regulation (7). In that study, we found that introduction
of nucleotide substitution at putative Elf-1 binding site of the
-chain gene, which diminished the specific-binding of Elf-1 to the
DNA fragment, caused a significant decrease in the promoter-enhancing
ability (7). Therefore, we had speculated that Elf-1 could
serve as a transcriptional activator of the gene. However, we later
found that overexpression of Elf-1 in FcRI-positive cells did not
increase but decreased the -chain gene expression (8).
This suggests the possibility that other transcriptional activator(s)
whose recognition sequence overlaps with that of Elf-1 is involved in
the regulation of the -chain gene expression.
In this report, we describe that two additional transcription factors
PU.1 and YY1 could serve as the transactivators for FcRI -chain
gene expression.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PT18 and KU812 cells were cultured in RPMI 1640 medium (Life
Technologies, Rockville, MD) supplemented with 10% FCS (Life
Technologies) and 1% penicillin-streptomycin solution
(Sigma-Aldrich, St. Louis, MO). RBL-2H3 cells were grown
in -MEM (Life Technologies) supplemented with 10% FCS and
penicillin-streptomycin at 37°C in a 5% CO2
incubator.
Plasmid construction
All of the constructs, pGV-B2-NN0.6/M1–M10, in which 3–6 bp
were replaced with others were generated from pGV-B2-NN0.6
(9), which contains 634 bp (from -605 to +29) of
5'-flanking region of human FcRI -chain gene, by site-directed
mutagenesis using a Quickchange site-directed mutagenesis kit
(Stratagene, La Jolla, CA).
Plasmids, pCR-Elf-1/type 1 and pCR-GATA-1, generated in our previous study (7, 8) were used to produce Elf-1 and GATA-1, respectively. Plasmid for the expression of YY1 or PU.1 was constructed as follows; rat cDNA was obtained by using mRNA from RBL-2H3 cells which was prepared by using TRIzol Reagent (Life Technologies) and an RT-PCR kit (Takara Shuzo, Kyoto, Japan). Two oligonucleotides, 5'-GGCCGTGGCGGCGGAGCCCTCAGCC-3' and 5'-GGTCGAGAAGGTCTTCTCTCTTCTTT-3', which were designed to have the nucleotide sequences of 5' and 3' noncoding regions based on the sequences of human and mouse YY1 cDNAs (10, 11), were used as the primers for PCR to clone rat YY1 cDNA, because the nucleotide sequence of rat YY1 has not been available until now. To amplify rat PU.1 cDNA, the following two oligonucleotides were used, 5'-GCTGGATGTTACAGGCGTGCAAAATG-3' and 5'-CCGGGCGAGGGCTTAATGCTATGGCC-3', which contained portions of human and mouse PU.1 cDNA sequences (12, 13). PCR was conducted by using an Advantage cDNA PCR kit (Clontech Laboratories, Palo Alto, CA). The amplified cDNA fragments were inserted into pCR3.1 (Invitrogen, Leek, The Netherlands) to generate expression plasmids pCR-YY1 and pCR-PU.1.
Transfection and luciferase assay
Harvested cells were suspended in the culture medium including an additional 10% FCS. The cells (5–10 x 106 cells in 0.5 ml) were cotransfected with 5 µg of the test construct and 25 ng of pRL-CMV (Promega, Madison, WI) by electroporation using Bio-Rad Gene Pulsar II (Bio-Rad, Hercules, CA) set at 300 V and 950 µF. The pRL-CMV plasmid was used for normalizing the transfection efficiency. The cells were harvested after a 24-h incubation, and treated with a PicaGene Dual SeaPansy Luminescence kit (Toyo Ink, Tokyo, Japan) for the measurement of luciferase activity. The luminescence was measured by a luminometer, MicroLumat Plus (Berthold, Postfach, Germany).
To analyze the transactivating abilities of Elf-1, GATA-1, PU.1, and
YY1, the coexpression experiment was conducted as follows: cells were
cotransfected with 3 µg of each expression plasmid and 3 µg of
reporter plasmid pGV-B2-NN0.6 under the same conditions as described
above. Total amount of the plasmid used for the transfection was
adjusted to 12 µg by the addition of the appropriate amount of the
empty plasmid pCR3.1-self (8, 9), because the transfection
efficiency is affected by the amount of plasmid DNA used. The cells
harvested after a 24-h cultivation were lysed by PicaGene Cell Culture
Lysis Reagent Luc (Toyo Ink), and the luciferase activity was measured
by a PicaGene Luminescence kit (Toyo Ink).
In vitro transcription and translation
In vitro transcription and translation were performed with TNT T7 Quick coupled transcription/translation system (Promega) using pCR-Elf-1 or pCR-PU.1 as the template for the reaction.
EMSA
Probe for EMSA was prepared by annealing rhodamine-labeled synthetic oligonucleotides, 5'-GATACAGAAAACATTTCCTTCTGCTTTTTGGTTTTAA-3' and 5'-TTAAAACCAAAAAGCAGAAGGAAATGTTTTCTGTATC-3'. Nuclear extract of PT18 cells was prepared as described previously (7, 9). EMSA was performed under the conditions almost the same as described previously (7); 10 µg instead of 4 µg of nuclear extract was used in this study. Anti-Elf-1, anti-GATA-1, anti-PU.1, anti-YY1, anti-USF1, and anti-USF2 Abs were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). For competition experiments, nonlabeled competitor oligonucleotides were added to the reaction mixture. Band shift on polyacrylamide gel was analyzed by a fluorescence detector, FMBIO-100 (Takara Shuzo) (9, 14).
Western blot analysis
Amount of transcription factors produced in recombinant cells was analyzed as follows. A volume of 1/40 of each total cell lysate was subjected to Western blotting analysis. The Abs the same as those for EMSA analyses were used as the primary Abs. Peroxidase-conjugated anti-mouse goat Abs were used as the secondary Abs. Membrane was soaked with the ECL Plus Western Blotting Detection Reagent (Amersham Pharmacia Biotech, Piscataway, NJ), and its chemiluminescence was detected by LAS-1000 (Fuji Film, Tokyo, Japan).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RI
-chain promoter
Ten mutant plasmids, pGV-B2-NN0.6/M1–M10, each containing 3–6
bp replacements that were introduced into the region between
-91 and -22 of the -chain gene, were constructed because this
region was shown to be necessary for the cell-type specific expression
of the gene in our previous study (7). Among them, the
luciferase activities directed by three altered promoters, M5, M6, and
M7 were markedly decreased in -chain producing cells, PT18 and
RBL-2H3 (Fig. 1
). This suggested that the
region around -56/-42 played an important role in the transcription
of the -chain gene. A significant decrease in the luciferase
activity was also found in the cells transfected with the plasmid M2
carrying the base substitution at the GATA motif around the -70
region. In contrast, the substitution of the AGATC sequence for the
TATAT sequence that was indicated as the putative TATA-box did not
decrease the activity in PT18 cells, but remarkably increased the
activities in both RBL-2H3 and KU812 cells (Fig. 1).
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To identify the nuclear protein(s) binding to the region required
for transcriptional activation, EMSA was conducted by using a
double-stranded oligonucleotide -68/-29 as the probe. As shown in
Fig. 2, two major shift bands (shown by
single and double asterisks) were observed in this assay. These bands
lost their intensity by addition of the cold probe, competitor 1
containing the original sequence, indicating that the competition
analysis on EMSA worked quite well. The upper band also lost intensity
by the addition of competitors 4 (lanes 9 and
10) and 5 (lanes 11 and 12).
However, the upper band was still found even when two oligonucleotides,
competitors 2 (lanes 5 and 6) and 3
(lanes 7 and 8), were added. This
indicated that the nuclear protein responsible for this band shift
recognized the region (-56/-50) into which the base substitutions
were introduced in competitors 2 and 3. In contrast, another shift band
(shown by an arrow with double asterisks) disappeared by addition of
competitors 1, 2, and 3, but was not significantly affected by addition
of competitors 4 and 5, indicating that the nuclear protein causing the
lower band shift bound to the regions -52/-42. In addition, a band
(an arrow with triple asterisks; see also Fig. 3) with very weak intensity was found in
the absence of any competitors or in the presence of competitors 3, 4,
and 5. Similar EMSA profiles were also observed using nuclear extract
from KU812 cells and RBL-2H3 cells (data not shown).
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To identify the nuclear protein binding to the region shown by the
above analysis, Abs against various transcription factors, Elf-1, YY1,
or PU.1, were added to the reaction mixture for EMSA and analyzed for
their effects on mobility shift. As shown in Fig. 3
, addition of
the anti-YY1 Ab caused disappearance of the shift band shown by
double asterisks. In contrast, the upper band (corresponding to the
single asterisk in Fig. 2) disappeared by addition of the Ab against
Elf-1, which coincided well with our previous observation
(7). The faint band marked with triple asterisks
disappeared in the presence of anti-PU.1 Ab. In contrast, addition
of anti-GATA-1, -USF1, or -USF2 Abs did not affect the EMSA profile
(data not shown). These results indicate that three shift bands, each
of which is shown by single, double, and triple asterisks, correspond
to specific binding of Elf-1, YY1, and PU.1, respectively, to the
probe DNA.
Binding regions of two Ets-related proteins, Elf-1 and PU.1
For further confirmation of the identity of the nuclear protein
binding to the region, EMSA using in vitro translated transcription
factors was conducted. As shown in Fig. 4B, in vitro translated
products of Elf-1 and PU.1 caused distinct band shift. Both shift bands
showed the gel mobility which were the same as those observed with the
nuclear extract (data not sown). When a series of oligonucleotides with
3 bp substitution were used as competitors for EMSA, MB and MC did not
compete with the labeled probe upon Elf-1 protein binding. This
indicates that Elf-1 binds -55/-50 region of the -chain gene.
Similarly, PU.1 was shown to bind -52/-47 region. Thus, each
transcription factor belonging to the Ets family bound to the closely
located and overlapping portion of the -chain promoter.
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Transcription-activating ability of Elf-1, GATA-1, PU.1, and YY1
By the transient reporter assay (Fig. 1) and EMSA (
Figs. 2–4),
three transcription factors, Elf-1, PU.1, and YY1 were shown to
recognize the portions overlapping with each other. These findings
suggest that these three transcription factors regulate the expression
of the -chain gene in a complicated manner, in combination with
another transcriptional activator GATA-1 that recognizes the GATA motif
at -74/-69 (7). To investigate the roles of these
transcription factors on the -chain gene expression, Elf-1, GATA-1,
PU.1, and YY1 were expressed in various combinations in KU812 cells and
their effects on the -chain promoter activity were analyzed by using
luciferase gene as the reporter. To confirm that these effects on the
luciferase activity actually correlated to overproduction of each
factor, the amount of each factor was analyzed by Western blotting
using the Abs. As shown in Fig. 5A, all the factors were
overproduced at least 10 times more, when compared with endogenous
ones. The exogenously expressed GATA-1, PU.1, or YY1 up-regulated the
promoter 7-, 2-, or 2-fold, respectively (Fig. 5B,
top). Surprisingly, the promoter activity was dramatically
increased (27-fold) when GATA-1 was coexpressed with YY1. Moreover, the
coexpression of GATA-1 with PU.1 up-regulated the promoter activity up
to 41-fold. These results indicate that GATA-1 up-regulates the
-chain promoter in combination with YY1 or PU.1. In contrast,
overexpression of Elf-1 decreased up-regulating effects by YY1 and
PU.1; especially the inhibitory effects of Elf-1 are apparent when
coexpressed with GATA-1.
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-chain gene, we constructed two
different plasmids in which base-substituted promoters were placed
upstream of the luciferase gene, and used as the reporters for the
coexpression analysis. Promoters M6 and M7 carry the nucleotide
sequences almost similar to that of the original promoter, but contain
the base substitutions which are the same as those in the constructs M6
and M7 in Fig. 1. As shown in Fig. 5B, all three promoters
responded to exogenously expressed GATA-1 to an almost equal extent.
However, the up-regulating effect of exogenously expressed YY1 and PU.1
was drastically decreased for M7 and M6 promoters, respectively.
Similarly, the synergic up-regulating effect by GATA-1 with PU.1
was drastically decreased in M6 promoter and the cooperative
up-regulation by GATA-1 with YY1 was markedly decreased in M7 promoter,
while it was also moderately decreased in M6 promoter. These results
coincide well with the observations in Figs. 2 and 4 where PU.1 and YY1
are suggested to bind -52/-47 and -52/-42 in the -chain
promoter. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain promoter caused a marked decrease in the
promoter-enhancing activity. Those regions contained the sequences
recognizable by GATA-1 and Elf-1. EMSA containing Ab against GATA-1 and
Elf-1 affected profiles of shifted bands. From these observations, we
had concluded that GATA-1 and Elf-1 were involved in the up-regulation
of FcRI -chain (7). However, the detailed analysis
in the present study is emerging a more complex mechanism for the
regulation of the -chain gene expression mediated by two additional
transcription factors, PU.1 and YY1. Both Elf-1 and PU.1 belong to
Ets-family proteins that bind their target DNA sequences through their
conserved Ets domains. Ets-family proteins recognize a dsDNA with the
sequence of 5'-GGAA-3' as the core. EMSA using the nuclear protein and
anti-transcription factor Abs revealed that Elf-1 and PU.1 mainly
recognize -55/-50 and -52/-47 in the -chain promoter,
respectively (
Figs. 2–4). Considering the consensus motif of the
Ets-family protein, Elf-1 binds -54/-51 (5'-TTCC-3'), and PU.1
recognizes -50/-47 (5'-TTCT-3').
YY1 is a transcriptional regulator which has the DNA binding consensus
sequence motif of
5'-CCA/TTNTTNNNA/T-3'
(15). Similar sequence is found at the region -52/-42 as
5'-CCTTcTgcttT-3'. Considering the difference in the EMSA profiles
between the results using competitors 3 and 4 in Fig. 2, T(-49) was
suggested to be essential for the recognition by YY1. This result
coincides with the report that the oligonucleotide with mutation at the
core sequence (CA/TT) of
YY1 motif from CAT to CAG was not recognized by YY1 in terminal
transferase (TdT) promoter (16).
The -chain gene is thought to be transcribed by using 5'-TATATTT-3'
(-28/-22) as the "TATA-box" (17) (Fig. 6). However, the base substitutions to
alter the TATA sequence did not show apparent negative effect (M10 in
Fig. 1). On the contrary, the luciferase activity directed from this
altered promoter was much higher than that of the wild-type promoter in
RBL-2H3 and KU812 cells. This result suggests that the -chain gene
can be transcribed in a TATA-box-independent way. YY1 is known to
recognize the region close to the transcription start site of a
TATA-less promoter and initiate the transcription (18, 19). PU.1 is also shown to play an indispensable role in
transcriptional initiation by binding to the element at just upstream
of the transcription initiation site of a TATA-less promoter (20, 21). Interestingly, both PU.1 and YY1 are the transcription
factors capable of binding TATA-binding protein (22, 23). It would be interesting to test the transcription effect of
the promoter region -40/+1, which contains only the putative TATA-box,
and none of the enhancer elements, to see whether the TATA-box is
functional. We assume that further analysis of the mechanism for the
YY1- and PU.1-mediated transactivation of the -chain promoter might
elucidate the mechanism for TATA-independent transcription.
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-chain promoter was investigated by the transient coexpression
experiment (Fig. 5). Overexpression of GATA-1, PU.1, or YY1
significantly up-regulated the -chain promoter. The up-regulation
was synergically accelerated by coexpression of GATA-1 with either PU.1
or YY1. In contrast, in the coexpression experiment, overexpression of
Elf-1 decreased the positive effect induced by PU.1 and YY1, but did
not affect the positive effect directed by GATA-1. Based on the EMSA
analysis, we assume that Elf-1 functions as a repressor competing with
PU.1 and/or YY1 for the overlapping binding site (Fig. 6). YY1 and PU.1
also bind to the overlapping regions of the -chain promoter for the
up-regulation. Therefore, these transcription factors might not be able
to bind the region at the same time. The EMSA profile using the nuclear
extract suggests that YY1 is more abundant in cells than PU.1 (Fig. 2).
This may indicate that YY1 is a natural transactivator for the
-chain gene. In contrast with the case for YY1 that is ubiquitously
expressed in every cell, PU.1 is known to be expressed in limited
cells, B cells, macrophages, mast cells, neutrophils, and early
erythroblasts (24). Elf-1 is also a cell type-specific
transcriptional factor expressed in T cells, B cells, megakaryocytes,
mast cells, and macrophages (7, 8). Considering that human
FcRI -chain is expressed in mast cells, basophils,
megakaryocytes/platelets, eosinophils, Langerhans cells, and monocytes,
the cell type-specific expression of the -chain is regulated
probably by transcription factors which are expressed in a cell
type-specific manner. Therefore, we assume that PU.1 is still a
candidate of the factors which are involved in the regulation of the
expression of the -chain gene.
Recently, inhibitory effects of PU.1 (GATA-1) on GATA-1
(PU.1)-associated transcriptional activation were reported from several
laboratories (25, 26, 27, 28). This might contradict our results.
However, cell lines used in those studies produce only either of the
two transcription factors, and the promoters analyzed have only either
of the recognition sequences for the factors. On the contrary, the
-chain-producing cells are known to produce both of the
transcription factors, and the -chain promoter has the sequences
recognizable by these factors. We assume that these differences could
be the causes for the apparently contradicting results. It should be
noted that similar synergic transcriptional activation by GATA-1 and
PU.1 in mast cell was also found for the enhancer elements in the
second intron of IL-4 gene (29).
In this study, Elf-1, YY1, and PU.1 were identified to bind the
overlapping regions which are essential for the expression of human
FcRI -chain gene. In addition to the two regions around -70 and
-50, base substitution around the region -40 also resulted in a
moderate decrease in the luciferase activity (see M8 in Fig. 1),
suggesting the presence of another unidentified transcription factor
involved in the regulation of the -chain gene expression.
Considering that the activity of transcription factors of the Ets
family is regulated by phosphorylation of several Ser residues, a more
complicated mechanism would be present in the -chain gene
expression. For detailed elucidation of the regulation of the -chain
promoter, analysis with a knockout mouse of either of the transcription
factors in combination with site-directed mutant at the phosphorylation
sites would be required.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Molecular Cell Immunology and Allergology, Advanced Medical Research, Nihon University School of Medicine, 30-1 Ohyaguchikami-machi, Itabashi-ku, Tokyo, 173-8610, Japan.
Received for publication November 15, 2001. Accepted for publication February 21, 2002.
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RI -chain messenger RNA in eosinophils. J. Allergy Clin. Immunol. 96:1161.[Medline]
RI) on human mast cells by IL-4. Int. Immunol. 8:1367.RI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells. J. Clin. Invest. 99:1492.[Medline]
receptor type I expression in recombinant human stem cell factor-dependent fetal liver-derived human mast cells. J. Immunol. 159:2911.[Abstract]
-chain gene. J. Immunol. 163:623.RI chain expression via CAGCTG element in the first intron. Eur. J. Immunol. 31:590.[Medline]
, a transcription factor that binds to downstream elements in several polymerase II promoters, is a functionally versatile zinc-finger protein. Proc. Natl. Acad. Sci. USA 88:9799.RI -chain and its transcriptional regulation. Biochem. Biophys. Res. Commun. 284:1056.[Medline]
RI) -chain. J. Immunol. 151:6166.[Abstract]
RIIIA promoter. EMBO J. 13:3852.[Medline]
responsiveness and basal expression of the myeloid human FcR1b gene is mediated by a functional PU.1 site and a transcription initiator consensus. J. Exp. Med. 179:1985.This article has been cited by other articles:
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M. Hasegawa, C. Nishiyama, M. Nishiyama, Y. Akizawa, K. Takahashi, T. Ito, S. Furukawa, C. Ra, K. Okumura, and H. Ogawa Regulation of the Human Fc{epsilon}RI {alpha}-Chain Distal Promoter J. Immunol., April 1, 2003; 170(7): 3732 - 3738. [Abstract] [Full Text] [PDF]
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K. Maeda, C. Nishiyama, T. Tokura, Y. Akizawa, M. Nishiyama, H. Ogawa, K. Okumura, and C. Ra Regulation of Cell Type-Specific Mouse Fc{epsilon}RI {beta}-Chain Gene Expression by GATA-1 Via Four GATA Motifs in the Promoter J. Immunol., January 1, 2003; 170(1): 334 - 340. [Abstract] [Full Text] [PDF]
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