FcεRIα gene -18483A>C polymorphism affects transcriptional activity through YY1 binding

Abstract

Three frequent genetic polymorphisms in the human high-affinity IgE receptor alpha-subunit (FcepsilonRIalpha) were shown to be associated with allergic disorders and/or total serum IgE levels in allergic patients. Two of these were previously demonstrated to affect FcepsilonRIalpha expression while the third -18483A>C (rs2494262) has not yet been subjected to functional studies. We hypothesized that the -18483A>C variant affects transcriptional activity of the FcepsilonRIalpha distal promoter in monocytes in which FcepsilonRIalpha transcription is driven through that regulatory region. Indeed, we confirmed preferential binding of the YY1 transcription factor to the -18483C allele, resulting in lower transcriptional activity when compared with the -18483A allele.

Full text

BRIEF COMMUNICATION
FcεRIαgene –18483A>C polymorphism affects
transcriptional activity through YY1 binding
Daniel P. Potaczek &Keiko Maeda &Qing-Hui Wang &Nobuhiro Nakano &
Shunsuke Kanada &Ewa Stepien &Agnieszka Branicka &Tatsuo Fukai &
Mutsuko Hara &Tomoko Tokura &Hideoki Ogawa &Anetta Undas &Ko Okumura &
Chiharu Nishiyama
Received: 13 April 2009 / Accepted: 27 July 2009 /Published online: 14 August 2009
#Springer-Verlag 2009
Abstract Three frequent genetic polymorphisms in the
human high-affinity IgE receptor α-subunit (FcεRIα) were
shown to be associated with allergic disorders and/or total
serum IgE levels in allergic patients. Two of these were
previously demonstrated to affect FcεRIαexpression while
the third –18483A>C (rs2494262) has not yet been
subjected to functional studies. We hypothesized that the
–18483A>C variant affects transcriptional activity of the
FcεRIαdistal promoter in monocytes in which FcεRIα
transcription is driven through that regulatory region.
Indeed, we confirmed preferential binding of the YY1
transcription factor to the –18483C allele, resulting in lower
transcriptional activity when compared with the –18483A
allele.
Keywords FcεRIα.Monocytes .Polymorphism .
YY1 .FCER1A
Considering the crucial role of the human high-affinity IgE
receptor (FcεRI; Zhang et al. 2007), it is not surprising that
Supported by a research grant from the Japan Society for the
Promotion of Science (JSPS)
Supported by a grant-in-aid for Scientific Research (C) from the
Ministry of Education, Culture, Sports, Science, and Technology of
Japan
Electronic supplementary material The online version of this article
(doi:10.1007/s00251-009-0391-x) contains supplementary material,
which is available to authorized users.
D. P. Potaczek :K. Maeda :Q.-H. Wang :N. Nakano :
S. Kanada :T. Fukai :M. Hara :T. Tokura :H. Ogawa :
K. Okumura :C. Nishiyama (*)
Atopy (Allergy) Research Center,
Juntendo University School of Medicine,
2-1-1 Hongo, Bunkyo-ku,
Tokyo 113-8421, Japan
e-mail: chinishi@juntendo.ac.jp
Q.-H. Wang
Department of Immunology, College of Basic Medical Sciences,
China Medical University,
No. 92 Beier Road, Heping District,
Shenyang 110001, China
S. Kanada :K. Okumura
Department of Immunology,
Juntendo University School of Medicine,
2-1-1 Hongo, Bunkyo-ku,
Tokyo 113-8421, Japan
E. Stepien :A. Branicka
John Paul II Hospital,
80 Pradnicka Str.,
31-202 Krakow, Poland
T. Fukai
Department of Dermatology,
Juntendo University School of Medicine,
2-1-1 Hongo, Bunkyo-ku,
Tokyo 113-8421, Japan
A. Undas
Institute of Cardiology,
Jagiellonian University School of Medicine,
80 Pradnicka Str.,
31-202 Krakow, Poland
Immunogenetics (2009) 61:649–655
DOI 10.1007/s00251-009-0391-x

FcεRI α-subunit (FcεRIα) gene variability was recently
studied in the context of allergies and allergic disorders.
FcεRIα–344(–315)
1
C>T (rs2427827) polymorphism was
found to be associated with aspirin-induced urticaria (Bae et
al. 2007) and with total serum IgE levels in different groups
of allergic subjects (Shikanai et al. 2002; Potaczek et al.
2006,2007a,2007b; Bae et al. 2007). Its close genomic
neighbor, FcεRIαproximal promoter –95(–66)
1
T>C
(rs2251746) polymorphism, was shown to be associated
with atopic dermatitis (Hasegawa et al. 2003b). Both of
these frequent polymorphisms were demonstrated to
strongly affect FcεRIαexpression in mast cells and/or
basophils in an additive manner (Hasegawa et al. 2003b;
Bae et al. 2007; Kanada et al. 2008), thus providing a
partial mechanistic background for the genetic associations
described above. In addition, the frequent –18483A>C
(rs2494262) polymorphism was also found to be associated
with total serum IgE levels in allergic subjects (Potaczek et
al. 2007a,2007b); however, no functional studies on that
genetic variant have been conducted to date. Here, we
report the results of functional analysis of FcεRIα
–18483A>C polymorphism.
The FcεRIαgene is composed of five coding exons,
spanning about 6 kbp, directly preceded by the proximal
promoter while two additional untranslated exons (1A and
2A) are localized further upstream (about 12 and 18 kbp,
respectively; Nishiyama et al. 2001) and are under
transcriptional regulation of the distal promoter (Hasegawa
et al. 2003a; Fig. 1a). In contrast to basophils and/or mast
cells, in which the proximal promoter strongly works with
the GATA-1/PU.1 transcription factor-dependent activating
mechanism, in monocytes, transcription of FcεRIαis also
driven by the distal promoter (Hasegawa et al. 2003a).
Hence, in monocytes, any potential effects of –18483A>C
single-nucleotide polymorphism (SNP) on FcεRIαexpres-
sion through the distal promoter would not be easily
masked by strong activity of the proximal promoter and
the potent effects of –95T>C and/or –344C>T proximal
promoter polymorphisms (Hasegawa et al. 2003b; Bae et al.
2007; Kanada et al. 2008).
Coverage of the FcεRIαgene by the –18483A>C,
–344C>T, and –95T>C polymorphisms is shown in
Fig. 1a. Linkage disequilibrium (LD) data between FcεRIα
1
Polymorphisms in the present study are numbered according to the
translation start site; –95T>C and –344C>T polymorphisms were also
numbered according to the FcεRIαgene proximal promoter transcrip-
tion start site as –66T>C and –315C>T, respectively (Hasegawa et al.
2003b; Kanada et al. 2008).
b
a
Polish
population
Japanese
population
D’ D’
r
2
r
2
c

Fig. 1 Human high-affinity IgE receptor α-subunit (FcεRIα) gene –
18483A>C, –344C>T, and –95T>C polymorphisms. aCoverage of
FcεRIαgene by the three polymorphisms. bLinkage disequilibrium
data between the three FcεRIαpolymorphisms in Poles (n= 104) and
Japanese (n=102). D' values are plotted on the results of four game
test (cutoff value=0.0). D' is expressed as a percentage of maximal
value (1.0). Squares without numbers correspond to D'= 1.0. White
boxes indicate four possible two-marker haplotypes, whereas black
boxes correspond to≤three pairwise gametes. On the r
2
value plot,
numbers represent r
2
values expressed as a percentage of maximal
value (1.0). Squares without numbers correspond to r
2
=1.0. Shading
represents r
2
magnitude with a black-to-white gradient reflecting
higher-to-lower r
2
values. cThree FcεRIαpolymorphisms and their
haplotypes in Poles (n=104) and Japanese (n=102). Minor allele
frequencies of polymorphisms and proportions of haplotypes are
given. SNP denotes single-nucleotide polymorphism
650 Immunogenetics (2009) 61:649–655

–18483A>C, –344C>T, and –95T>C SNPs, estimated in
representative population groups of Polish Caucasians (n=
104) and Japanese East Asians (n=102), are presented
Fig. 1b while the allelic frequencies and the distribution of
haplotypes of the three FcεRIαpolymorphisms are given
in Fig. 1c. In all cases, three pairwise haplotypes of
–18483A>C, –344C>T, and –95T>C polymorphisms
account for 97.7–100.0% of all haplotypes (Fig. 1c). In
addition, all of the pairwise D' values are high, ranging
from 0.85–1.0 (Fig. 1b). Therefore, it can be assumed that
protein U937 nuclear extract
competitor
- A C - C A
probe A C protein U937 in vitro
probe C
extract YY1 empty
Ab
Sp1
YY1
Sp1
YY1
Sp1
YY1
---
protein THP1 nuclear extract
competitor
- A C - C A
probe A C
Ab
IgG
YY1
12 3 4 5 6 7 8 9 10 12 3 4 5 6 7 8 9
12 3 4 5 6 7 8 9 10 11 12
abc
Fig. 2 Effect of human high-affinity IgE receptor α-subunit (FcεRIα)
gene –18483A>C polymorphism on transcription factor binding on
electrophoretic mobility shift assay (EMSA). aEffects of –18483A>C
polymorphism on EMSA profile and preferential –18483C allele
protein binding in U937 cells. EMSA was performed with FITC-
labeled –18494/–18471 double-stranded oligonucleotide probes car-
rying –18483A allele (lane 1)or–18483C allele (lane 6) and nuclear
extracts from U937. For competition assay, 25- or 50-fold levels of
–18483A (lanes 2,3,9, and 10)or–18483C (lanes 4,5,7, and 8)
competitors were used. Specific bands are indicated with by arrow-
heads.bIdentification of protein preferentially binding to –18483C
allele. A mixture of –18483C probe and nuclear extract from U937
was applied into wells 1–3 after addition of each antibody (Ab). Lane
1without Ab, lane 2 with anti-YY1 Ab, lane 3 with irrelevant anti-
Sp1 (control) Ab. Specific bands are indicated by arrowheads.
Binding of in vitro-translated YY1 to the –18483C probe (lanes 4–
9). The –18483C probe was mixed with in vitro-translated YY1 (lanes
4–6) or with in vitro transcription/translation mixture without template
cDNA (lanes 7–9). Lanes 4 and 7without Ab, lanes 5 and 8with anti-
YY1 Ab, lanes 6 and 9with irrelevant anti-Sp1 (control) Ab. cEffects
of –18483A>C polymorphism on EMSA profile and preferential
–18483C allele protein binding in THP-1 cells (lanes 1–10). Lanes 1–
10 identical description as for the left panel, except for the usage of
THP-1 nuclear extracts instead of those obtained from U937 cells.
Identification of protein preferentially binding to –18483C allele in
THP-1 (lanes 11 and 12). Lane 11 with IgG isotype control Ab, lane
12 with anti-YY1 Ab
Fig. 3 Genomic neighborhood of –18483A>C polymorphism (–18470/
–18499) aligned with YY1 consensus binding sequences as described by
Shrivastava and Calame (1994). Nucleotides are numbered 1to 30 for
the purposes of the present figure only. If the –18483C allele is present,
the sequence almost perfectly correlates with the YY1 consensus
repressor binding motif (Shrivastava and Calame 1994). C in position
19 of the genomic sequence does not fit T in the consensus motif;
however, the consensus rate for T in that position is 72%, and C can be
present in the YY1 binding repressor site (Shrivastava and Calame
1994). Nucleotides corresponding to the core of the YY1 binding motif
are underlined (Javahery et al. 1994). Replacement of first the C in the
core motif with A (position 14), corresponding to the –18483C→A
substitution, leads to a 3- to 4-fold reduction in YY1 binding (Javahery
et al. 1994)
Immunogenetics (2009) 61:649–655 651

there were no past pairwise recombination events (–344C>T|–
95T>C in Poles and Japanese and –18483A>C|–95T>C in
Japanese) or that their rates were low (–18483A>C|–344C>T
in Poles and Japanese and –18483A>C|–95T>C in Poles).
As a result, only four three-loci haplotypes account for
98.4% and 97.7% of all three-locus haplotypes in Poles and
Japanese, respectively (Fig. 1b, c).
In most cases, high D' values are not, however,
accompanied by r
2
values of a similar magnitude, which
reflects the substantial pairwise differences in allelic
frequencies between FcεRIαSNPs particularly for pairs
including the –95T>C SNP in Japanese (Fig. 1b, c). One
exception is the r
2
value for the –18483A>C|–344C>T pair
in Poles, although this is diminished by the presence of
recombinant haplotype –18483A|–344 T (1.0%), despite
the pairwise difference in allelic frequencies between
–18483A>C and –344C>T SNPs in that ethnic group being
relatively small. Nevertheless, in both Caucasians and East
Asians, the genomic relationships between the three
FcεRIαSNPs are close as reflected by the distribution of
haplotypes and high D' values.
The FcεRIα–18483A>C, –344C>T, and –95T>C SNPs
were genotyped by the polymerase chain reaction-
restriction fragment length polymorphism method, the
details of which can be found in the Supplementary
Materials. The structure and distribution of haplotypes
were analyzed using Thesias_3.1 software (http://genecan
vas.ecgene.net/uploads/Thesias_Java_interface/) (Tregouet
and Garelle 2007) while measures of LD were estimated
using Haploview_4.0 software (http://www.broad.mit.edu/
haploview/haploview-downloads; Barrett et al. 2005).
We speculated that the FcεRIα–18483A>C polymor-
phism affects the transcriptional activity of the distal
promoter localized immediately upstream (Nishiyama et
al. 2001; Hasegawa et al. 2003a). To verify our hypothesis,
we examined the potential of the –18483A>C polymor-
phism to affect the binding of transcription factors using
electrophoretic mobility shift assay (EMSA) as described
previously (Kanada et al. 2008; Fig. 2). Oligonucleotides,
antibodies, and basic vectors used in the present study are
shown in Supplementary Materials.
EMSA conducted using nuclear extracts from human
monocytic U937 cells with competitive oligonucleotides
showed preferential binding of nuclear protein(s) to the
–18483C allele (Fig. 2a). Thus, we analyzed the sequence
surrounding the –18483C allele and noted that it almost
perfectly matched the YY1 binding consensus repressive
motif while its homology to the consensus YY1 activating
site was comparatively low (Shrivastava and Calame 1994;
Fig. 3). Indeed, subsequent EMSA with specific antibodies
confirmed that the transcription factor binding to –18483C
allele was YY1 (Fig. 2b), which was further confirmed
using in vitro translated YY1 protein (Fig. 2b) obtained as
described previously (Hasegawa et al. 2003a; Kanada et al.
2008). Similar results were obtained using nuclear extracts
from human monocytic THP-1 cells (Fig. 2c).
In order to confirm YY1 binding in vivo, we performed
chromatin immunoprecipitation (ChIP) assay as described
previously (Wang et al. 2008). ChIP assay was conducted
using U937 cells confirmed by direct sequencing (Potaczek
et al. 2008) to possess –18483CC (Fig. 4). Significantly
larger amounts of chromosomal DNA around –18483 were
immunoprecipitated by YY1 antibody (Ab) as compared
with control Ab, which demonstrated the occurrence of
YY1 binding around the –18483C allele in vivo (Fig. 4,
center). Although two cis-control regions at ∼350 bp
upstream (Fig. 4, left) and downstream (Fig. 4, right)
exhibited significant binding with YY1, possibly due to the
presence of YY1-bindable sequences (marked with stars;
Nishiyama et al. 2001; Hasegawa et al. 2003a), the SNP
site showed the highest amount, thus suggesting that
detection of the SNP site was not dependent on YY1
binding to the YY1 sequences in the distal promoter and in
intron 1A. One cannot, however, exclude the possibility
that some of the SNP site detection was derived from the
fragments containing binding motifs in the distal promoter
or intron 1A.
YY1 Cnt YY1 Cnt YY1 Cnt
cis-control
(upstream)
cis-control
(downstream)
SNP site
Ex 1A
Relative input unit (%)
FCER1A
0.05
0.04
0.03
0.02
0.01
0
Fig. 4 In vivo binding of YY1 around the human high-affinity IgE
receptor α-subunit (FcεRIα) gene (FCER1A)–18483C allele in U937
cells having the –18483CC genotype. The amount of exon 1A region
(–18546/–18435) immunoprecipitated with anti-YY1 antibody (Ab)
was quantitatively analyzed by chromatin immunoprecipitation assay.
Two regions upstream (–18901/–18753) and downstream (–18117/–
18015) were also analyzed. Black stars in the schematic drawing of
FCER1A gene represent the locations of identified YY1-binding
sequences in previous studies [upstream (Hasegawa et al. 2003a) and
downstream (Nishiyama et al. 2001)] and in the present study (SNP).
The results are expressed as means +SEM for three real-time PCRs
with duplicate samples. Similar results were observed in an additional
independent experiment. Closed bars specific YY1 Ab, open bars
control Ab (Cnt)
652 Immunogenetics (2009) 61:649–655

Next, we examined the potential effects of –18483A>C
substitution on transcriptional activity by performing lucifer-
ase reporter assay as described previously (Kanada etal. 2008;
Wang et al. 2008). We used tandem repeated constructs
based on the pGL4.23 [luc2/miniP] plasmid to evaluate the
effect of this SNP on transcriptional activity. Briefly, triple
motif CCT(A/C)CATGCTACTAAG (–18486/–18471), con-
taining the –18483A>C polymorphism within its genomic
neighborhood and covering in length for repressive or
activator YY1 consensus binding sites (Shrivastava and
Calame 1994), was XhoI/HindIII subcloned upstream of the
minimal promoter of pGL4.23 [luc2/miniP] plasmid. In
human monocytic THP-1 cells, the luciferase activity of the
–18483C allele-specific construct was significantly lower
when compared with that of both the –18483A allele-
specific construct and the basic (containing no genomic
insert) plasmid (Fig. 5a).
Confirmatory analyses were conducted in human baso-
philic KU812 cells (Fig. 5b), rat basophilic RBL-2H3 cells
(Fig. 5c), and mouse mastocytic PT18 cells (Fig. 5d). In all
cases, reporter activity of the –18483C allele-specific vector
Fig. 5 Effects of FcεRIαgene –18483A>C polymorphism on
transcriptional activity analyzed by luciferase assay using pGL4.23
[luc2/miniP]-based constructs in human monocytic THP-1 cells (a),
human basophilic KU812 cells (b), rat basophilic RBL-2H3 cells (c),
and mouse mastocytic PT18 cells (d). Triple motif CCT(A/C)
CATGCTACTAAG (–18486/–18471), containing the –18483A>C
polymorphism within its genomic neighborhood, was cloned upstream
of the minimal promoter of pGL4.23 [luc2/miniP] plasmid. Basic
plasmid denotes the pGL4.23 [luc2/miniP] vector with no genomic
insert. Relative luciferase activity is represented as the ratio of activity
to that of the basic pGL4.23 [luc2/miniP] plasmid. The results are
expressed as means +SEM for four (a), three (d), or two (b,c)
independent experimental series conducted in triplicate. One-way
ANOVA followed by post hoc Duncan's test was used for compar-
isons. Only significant results (P<0.05) on post hoc testing are shown
Relative Luciferase Activity
Cnt YY1 Cnt YY1 Cnt YY1
Basic 18483A 18483C
P
= 0.002
1.5
1
0.5
0
Fig. 6 Effects of YY1 siRNA on –18483C allele-mediated transcrip-
tional suppression. Each reporter plasmid of pGL4.23-based series
was introduced with YY1 siRNA or control siRNA using Nucleo-
fector II. YY1 siRNA significantly upregulated C-allele vector-driven
activity (P<0.005 on unpaired Student's ttest). Significant differences
between the A-allele (Cnt) and C-allele (Cnt; P<0.025 on post hoc
Duncan's test) were eliminated by YY1 siRNA treatment [P= 0.18
between A-allele (YY1) and C-allele (YY1)]
Immunogenetics (2009) 61:649–655 653

was significantly lower when compared with that of both
the –18483A allele-specific construct and the basic plasmid
(Fig. 5b–d). In KU812 and PT18 cells, the luciferase activity
of the –18483A allele-specific vector was also lower when
compared with that of the basic plasmid (Fig. 5b, d). If the C
allele is present in the –18483 locus, the nucleotide sequence
surrounding the –18483A>C polymorphism possesses strong
homology with the YY1 recognition repressor sequence
(Shrivastava and Calame 1994) while replacement of C by A
in the core YY1 binding motif, corresponding to replacement
of the –18483C allele by the –18483A variant, results in a 3–
4-fold reduction in YY1 binding (Javahery et al. 1994;
Fig. 3). Therefore, YY1 binding to the –18483C allele would
be expected to result in a lower transcription rate when
compared with the –18483A allele. Indeed, in all four cell
lines, the luciferase activity of the –18483C allele-specific
vector was lower when compared with both the –18483A
allele-specific and basic vectors (Fig. 5a–d).
In the case of KU812 and PT18 cells, –18483A allele-
specific constructs also demonstrated lower luciferase activ-
ity when compared with the basic vector (Fig. 5b, d). This
may be explained by low-affinity binding of the YY1
transcription factor to the –18483A allele, which could be
also observed in EMSA (Fig. 2a, c), resulting in a repressive
effect on transcriptional activity in some cells. Nevertheless,
in all the cases, luciferase activity of –18483C allele-specific
constructs was lower than that of –18483A allele-specific
vectors (Fig. 5a–d). Although the –18483A>C polymor-
phism is located downstream of the distal promoter
transcription start site, it would not be surprising that binding
of YY1 downstream of the transcription initiation site can
affect gene expression (Griffioen et al. 2000).
Finally, in order to confirm the effects of YY1 on –
18483C allele-mediated transcriptional suppression, report-
er assay was performed under YY1 knockdown conditions.
Briefly, YY1 siRNA or control siRNA was introduced into
THP-1 cells with a reporter plasmid using Nucleofector II
(Amaxa, Cologne, Germany) as described previously
(Maeda et al. 2006). As shown in Fig. 6, luciferase activity
driven by a plasmid carrying the C allele was significantly
upregulated by the introduction of YY1 siRNA, whereas
the other two promoters, basic and carrying the A allele,
were not affected by YY1 siRNA, thus suggesting that
transcriptional suppression depending on the C allele at the
–18483 locus is regulated by YY1.
YY1 was previously reported to be involved in regula-
tion of several important allergy-related genes. Briefly,
Silverman et al. (2004) demonstrated that, being associated
with variant YY1 binding and thus altering transcriptional
activity, the –509C>T polymorphism of transforming
growth factor-β
1
was associated with asthma. Guo et al.
(2001) and Mordvinov et al. (1999) showed that YY1
transcription factor regulates T cell cytokine gene expres-
sion and allergic immune responses. Finally, some members
of our group demonstrated the involvement of YY1 in
transcriptional regulation of FcεRI subunit expression. Brief-
ly, variant YY1 factor binding to FcεRI β-subunit (FcεRIβ)–
654C>T polymorphism was shown to affect its expression
(Nishiyama et al. 2004). Moreover, YY1 was demonstrated
to contribute to the regulation of FcεRIαtranscription
through proximal and distal promoters (Nishiyama et al.
2001,2002;Hasegawaetal.2003a).
In summary, we demonstrated preferential binding of YY1
to the FcεRIαgene –18483C allele resulting in lower
transcriptional activity. The differences in transcriptional
activity between –18483C and –18483A alleles are not
apparently striking, but they may potentially be of some
biological importance in monocytes in which the potential
effect of –18483A>C variant on the distal promoter would
not be easily masked by strong activity of the proximal
promoter (Hasegawa et al. 2003a) and/or potent influences
of –344C>T/–95T>C polymorphisms (Hasegawa et al.
2003b; Bae et al. 2007; Kanada et al. 2008). The
associations between FcεRIαpolymorphism and serum IgE
levels and/or allergic disorders (Shikanai et al. 2002;
Hasegawa et al. 2003b; Potaczek et al. 2006,2007a,
2007b; Bae et al. 2007) may result from haplotypic interplay
between functional (Hasegawa et al. 2003b; Bae et al. 2007;
Kanada et al. 2008)–344C>T, –
95T>C, and –18483A>C
polymorphisms. A hypothetical mechanism by which alter-
ations in FcεRI(α) expression could affect IgE synthesis/
levels remains unknown. Therefore, further functional
studies focusing on this issue are necessary.
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