Hum. Reprod. Advance Access originally published online on May 9, 2006
Human Reproduction 2006 21(10):2538-2544; doi:10.1093/humrep/del126
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Progesterone regulates HLA-G gene expression through a novel progesterone response element
Department of Gynecology and Obstetrics, Sunnybrook and Women’s College Health Sciences Center, Toronto, Ontario, Canada
1 To whom correspondence should be addressed at: 790 Bay Street, Suite 1100, Toronto, Ontario, Canada M5G 1N8. E-mail: cliffl{at}ican.net
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Abstract |
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BACKGROUND: We have previously demonstrated that progesterone has a stimulatory effect on HLA-G gene expression. Because this effect was abolished by the anti-progestin, RU486, we hypothesize that this effect is through receptor-mediated up-regulation of the HLA-G gene. The objective of this study was to explore the molecular mechanisms of this effect. METHODS: The transient transfection of a chloramphenicol acetyltransferase (CAT) construct containing a fragment of the HLA-G gene promoter into the JEG-3 choriocarcinoma cell line was performed. An electrophoretic mobility shift assay (EMSA) and a DNA fragment-binding enzyme-linked immunosorbent assay (ELISA) were carried out to locate a specific progesterone response element (PRE) in the HLA-G gene promoter region. RESULTS: Progesterone treatment of JEG-3 cells transfected with the HLA-G gene promoter-CAT construct resulted in an increase of CAT synthesis, whereas RU486 blocked this transcriptional activation. A novel PRE-binding site sequence, with 60% homology to that of wild-type mouse mammary tumour virus (MMTV) PRE, was discovered in this region. CONCLUSION: The effect of progesterone on HLA-G gene expression is through progesterone receptor (PR) activation, followed by binding to a novel PRE in the HLA-G promoter region. Therefore, one of the mechanisms of immunomodulation by progesterone during pregnancy may be through the regulation of HLA-G gene expression via this novel PRE.
Key words: gene regulation/HLA-G/novel progesterone response element/pregnancy/progesterone
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Introduction |
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HLA-G is a non-classical class I HLA antigen that may play an important role in maternal–fetal immune tolerance (Kovats et al., 1990
). Two reported mechanisms of action are the inhibition of natural killer (NK) cell lysis (Kovats et al., 1991; Chumble et al., 1994; McMaster et al., 1995) and the inhibition of cytotoxic T-cell activity (Deniz et al., 1994; Kapasi et al., 2000). An understanding of the regulation of HLA-G gene expression is essential to fully appreciate the functional aspects of this protein. The exact mechanisms by which HLA-G gene expression is regulated are still poorly understood.
For many years, progesterone has been suggested to be an important immune modulator during pregnancy (Stites and Siiteri, 1983). It has been reported that progesterone can also block cytotoxic T-cell activity (Mannel et al., 1990) and reduce NK-cell activity (Hansen et al., 1992). For these reasons, we hypothesized that one potential mechanism by which progesterone acts is indirectly through the modulation of placental HLA-G gene expression.
We previously demonstrated that progesterone has an enhancement effect, in a dose- and time-dependent manner, on HLA-G gene expression in the JEG-3 choriocarcinoma cell line and isolated first-trimester placental cytotrophoblasts in vitro (Yie et al., 2006). These in vitro findings suggest that progesterone may play a physiological role in the regulation of HLA-G gene expression in vivo.
It is well known that the physiological effects of progesterone are primarily mediated through progesterone receptor (PR) activation (Graham and Clarke, 1997), followed by the binding of this complex to a specific DNA sequence, the progesterone response element (PRE), resulting in the transcription of target genes (Giangrande and McDonnell, 1999). In our previous study, we reported that RU486 abolishes the stimulatory effect by progesterone, suggesting that progesterone regulates HLA-G gene expression via its intracellular receptor (Yie et al., 2006). However, the HLA-G gene promoter region has no classical PRE sequence. Therefore, the objectives of this study were to elucidate the molecular mechanisms of the effect by using transient transfection of JEG-3 cells by a HLA-G gene promoter fragment with a chloramphenicol acetyltransferase (CAT) reporter gene and to identify a PRE in the HLA-G gene promoter region by using an electrophoretic mobility shift assay (EMSA) and a DNA fragment-binding enzyme-linked immunosorbent assay (ELISA).
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Materials and methods |
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Transient transfection and reporter gene assay
A 458 bp DNA fragment of the HLA-G gene promoter region, from nucleotide –458 to the ATG, was cloned into a vector containing the CAT reporter gene (gift kindly provided by Dr J. Cross). JEG-3 cells, purchased from American Type Culture Collection (ATCC, Rockville, MD, USA), were transfected using the N-[1-(2,3-dioleyloxy)propyl-N,N,N-trimethylammonium chloride (DOTMA) method (Felgner et al., 1987
). The cells were seeded in Roswell Park Memorial Institute (RPMI) 1640 medium containing 10% fetal calf serum (FCS) for 16–20 h before transfection. The transfection mixture contained 1 µg of HLA-G promoter-CAT reporter vector and 4 µl of the lipofectin reagents (Gibco/BRL, Burlington, Ontario, Canada) diluted in serum-free RPMI culture media (SFM). The mixture was incubated for 15 min at room temperature before it was added to the wells. The cells were then incubated for 6 h at 37°C and then re-fed with culture medium, with or without progesterone and/or RU486, for a further 24 h. JEG-3 choriocarcinoma cells were then harvested and lysed as described in Felgner et al.’s study (1987). CAT production was measured with a commercial CAT-ELISA kit (Roche Diagnosis, Laval, Quebec, Canada) according to the manufacturer’s manual.
Binding of PR to HLA-G gene promoter
Preparation of PR for DNA binding
The preparation method was adapted from the publication by Lieberman et al. (1993). Briefly, MCF-7 human breast cancer cells (ATCC) were grown in 10 cm-diameter culture dishes with RPMI 1640 media containing 10% FCS, 50 IU/ml of penicillin and 50 µg/ml of streptomycin until reaching a density of 
1 x 106 cells per dish. The cells were then treated with 40 nM RU486 (Sigma, St Louis, MI, USA) in SFM at 37°C for 1 h. Nuclei were prepared by homogenizing the cells at 4°C in TEDG2 [10 mM Tris–HCl, pH 7.5, 1 mM EDTA, 1 mM dithiothreitol (DTT), 10% glycerol, 150 mM potassium glutamate and Sigma proteinase inhibitor cocktail]. PRs were extracted from the nuclear pellet with 0.5 M NaCl in TEDG2 for 1 h, followed by centrifugation at 16 000 g for 30 min at 4°C. The supernatant (nuclear extract) was dialysed overnight against two changes of TEDG2 and then clarified by centrifugation at 16 000 g at 4°C for 30 min The receptor preparation was stored at –70°C and thawed only on the day of study to avoid the loss of DNA-binding activity.
Preparation of target DNA
JEG-3 cells were cultured as described above. The cell genomic DNA was isolated with a commercial DNA isolation kit (Qiagen,Hilden, Germany) according to the manufacturer’s manual. The concentration of purified DNA was determined by using 260/280 nm UV absorbance. The 458 bp DNA target fragment, located between –458 and the ATG of the HLA-G gene promoter region, and smaller fragments from the ATG to –100, from –101 to –220 and from –221 to –458 bases were generated and labeled with fluorecein-12-dUTP (Roche) by PCR with HLA-G specific primers (Table I) for 30 cycles with denaturation at 95 °C for 1 min, annealing at varied temperature for each pair of primers (Table 1) for 1 min and extension at 72 °C for 2 min. The PCR products were purified by using 1.2–2% agarose gel electrophoreses followed by a gel purification kit according to the manufacturer’s manual (Qiagen).
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EMSA
PR preparations (
5 µg protein) were incubated in 20 µl DNA-binding buffer (10 mM Tris–HCl, pH 7.5, 1 mM EDTA, 150 mM potassium glutamate, 5 mM DTT, 5% glycerol and 2 mM MgCl2) with 1 µg of poly(dI–C), 2 ng of fluorecein-labelled DNA fragment and either 200 ng of unlabelled DNA fragments or 200 ng of synthetic oligonucleotide for the mouse mammary tumour virus (MMTV) PRE for 30 min at 4°C. Samples were loaded onto a precooled polyacrylamide gel. A 5% gel was used for the binding reaction of PR and 458 bp DNA fragment, a 6% gel for PR and 220 or 230 bp DNA fragment and an 8% gel for PR and the 120 or 100 bp DNA fragment. Gels were run at 200 V for 3 h in 0.5x Tris–borate–EDTA (TBE) running buffer and then transferred to a nylon membrane in 0.5x TBE transfer buffer at 30 V for 1 h at room temperature. The membrane was blocked with 5% milk in 0.01% phosphate-buffered saline (PBS)/150 mM saline at 4°C overnight followed by incubation with a 1:500 dilution of anti-fluorescein–horse-radish peroxidase (HRP) conjugate (Roche) in 0.01% M PBS/Tween for 1 h at room temperature. After three 15 min washes with PBS/Tween at room temperature, the colour reaction was developed with diaminobenzidine (Sigma).
DNA fragment-binding ELISA
A total of 50 µl per of PR preparations (10 µg/ml) were used to coat a 96-well ELISA plate (Corning, NY, USA) overnight and blocked by 5% milk at room temperature for 2 h. Fluorecein-labelled DNA fragments were incubated in 100 µl of PBS per well with and without unlabelled DNA fragments or the synthetic MMTV PRE oligonucleotide as well as a 15 bp oligonucleotide within the ATG to –100 region of the HLA-G gene for 1 h at room temperature. The plates were washed four times, with PBS/Tween, followed by incubation with 50 µl per well of 1:2000 anti-fluorecein–HRP conjugate for 1 h at room temperature. The plates were again washed, and 100 µl of tetramethylbenzidine solution (Sigma) was added to each well. Absorbance at 450 nm was obtained on the automated ELISA plate reader after incubation for 10–15 min at room temperature followed by stopping the reaction with 50 µl per well of 1 M HCl.
Statistical analysis
All experiments were performed in triplicate, and all experiments were repeated at least three times on different occasions. All data were analysed for the comparison of group means using one-way analysis of variance. A P value of <0.05 was considered statistically significant.
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Results |
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Effects of progesterone and RU486 on HLA-G promoter-driven CAT reporter gene expression
Using the HLA-G gene promoter-reporter construct, we found that progesterone, at 100 and 1000 ng/ml, the same concentrations as in our previous paper (Yie et al., 2006
), significantly increased the steady state of HLA-G gene promoter transcriptional activity in a dose-dependent way, after exposure for 24 h (Figure 1A) (F = 5.94, P = 0.0045). Figure 1B shows that addition of 100 or 1000 ng/ml of RU486 blocked this progesterone effect.
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The specific binding site for PR complex in promoter region
After studying the HLA-G promoter region sequence, no typical PRE sequence was identified. To define any novel specific binding site in the HLA-G gene promoter region, an EMSA and a DNA-binding ELISA were performed. Figure 2 shows a schematic diagram of the experiments used to identify a specific binding site for the PR complex within the 458 bp DNA fragment of HLA-G gene promoter region. Figure 3A shows a schematic diagram of sequences of the 458, 238, 220, 120 and 100 bp DNA fragments used in the experiments. Specific binding to the 458 bp DNA fragment by RU486–PR complex was demonstrated by both the DNA-binding ELISA and EMSA (Figures 4 and 5). The location of PR-specific binding was narrowed down to a 100 bp DNA fragment by using sequentially smaller fragments (Figures 4 and 5).
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A novel PRE found in the promoter region
Within the 100 bp DNA fragment, we found a sequence (GTTCTAAAGTCCTCG) which has 60% homology to the wild-type MMTV PRE sequence (GTTACAAACTGTTCT) (Lieberman et al., 1993
), with variation at positions of –4, –3, +1, +3, +4 and +7 (Figure 3B). This sequence overlaps the HLA-G TATA box. A similar sequence overlap was also found for thyroid hormone response elements and TATA box in the rat GH gene (Kim et al., 1992). Specific binding of PR complexes to the 458, 220 and 100 bp labelled DNA fragments was specifically inhibited, and to the same extent, by the HLA-G PRE, the MMTV PRE and unlabelled fragments (Figure 5). A search of online databases revealed no complete genomic matches for this novel PRE in the human or other species genomes. |
Discussion |
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It is well known that PRs activate gene transcription through binding of the PR complex to a PRE contained in the promoter region of target genes (Shibata et al., 1997). This study demonstrates that a 15 bp sequence located between –100 and ATG in the HLA-G gene promoter contains a specific binding site for the PR complex (Figures 2–
5). This binding site has a weaker affinity for PR complexes than the MMTV PRE (Figure 5). This 15 bp sequence was the only RP like binding site we could find between –458 and the ATG of the HLA-G gene promoter region. PR binding to this 458 bp fragment elicited a response in the CAT reporter gene assay, and this response was abrogated specifically by RU486 (Figure 1).
The classical PRE has a 15 bp core sequence, and the positions from +2 to +7 in the sequence have been recognized as fixed half sites of steroid hormone response elements (Clark et al., 1992). Mutations at certain positions of the 15 bp sequence, including the fixed half site, decrease PR-binding affinity as compared with wild-type MMTV PRE (Lieberman et al., 1993). However, most of those mutations do not affect transcriptional response, as determined by a CAT reporter gene assay (Lieberman et al., 1993). These observations, together with our present results, suggest that the novel PR-binding sequence that we have identified in the HLA-G gene promoter region may be a transcriptional activation site for HLA-G by progesterone in vivo. Although we did not find any other binding sites in this area, through our experiments or by scanning the sequence database, we cannot be certain that this is the only PRE in the HLA-G promoter region.
It is now clear that a successful pregnancy requires a number of immune modulation factors from both mother and fetus. Progesterone has been suggested to be an important immune modulator during pregnancy (Stites and Siiteri, 1983). However, the exact underlying mechanism as to how progesterone modulates the immune system is still not completely clear. Growing evidence indicates that progesterone has many effects on the immune system during pregnancy, such as triggering suppressor-cell generation (Brierley and Clark, 1987), blocking cytotoxic T-cell activity (Mannel et al., 1990), reducing NK-cell activity (Hansen et al., 1992), inducing lymphocyte-blocking proteins (Barakonyi et al., 1999) and modifying the cytokine response (Parronchi et al., 1995; Piccinni et al., 1995; Choi et al., 2000). Whether these effects are through a PR mechanism remains controversial (Szekeres-Bartho et al., 1989; Mansour et al., 1994; Schust et al., 1996). Interestingly, HLA-G has also been demonstrated to have immunomodulation functions similar to those of progesterone, such as resistance to NK-cell lysis (Chumble et al., 1994; Deniz et al., 1994), the inhibition of cytotoxic T-cell activity (Sander et al., 1991; Kapasi et al., 2000), the modification of the balance between Th1 and Th2 cytokines (Clark, 1997) and the activation of 
/
T cells (Heyborne et al., 1992; Suzuki et al., 1995). Soluble HLA-G protein has also been implicated as an important factor in maternal–fetal immune intolerance (Kovats et al., 1990; McMaster et al., 1995). Thus, we hypothesize that one of the mechanisms through which progesterone immunomodulation occurs may be indirectly through the up-regulation of HLA-G gene expression in cytotrophoblasts.
The restricted expression of HLA-G in cytotrophoblasts at the maternal–fetal interface and changes of expression levels with the stage of pregnancy strongly suggest cell-specific and stage regulation for HLA-G gene expression (Kovats et al., 1990; McMaster et al., 1995). The mechanisms that control restricted HLA-G gene expression are unknown. Chaing and Main (1994) reported that trophoblasts have a tissue-specific nuclear-binding factor that may down-regulate classical class I HLA expression upon binding to a negative regulatory element (NRE) sequence 180 bp 5' to transcription initiation. The HLA-G gene does not have the NRE, thus enabling its expression by trophoblasts. Schmidt et al. (1993) demonstrated that the HLA-G gene contains an important positive regulatory element. These data suggested that transcriptional mechanisms are likely to play an important role in the cell-specific regulation of HLA-G gene expression (Kirszenbaum et al., 1994; Onno et al., 1994). It is interesting to note that HLA-G gene contains a PRE, whereas classical class I HLA genes have neither a classical PRE sequence nor the novel binding site identified here. This suggests that progesterone may also be involved in cell-specific regulation of the HLA-G gene. Furthermore, Shanker and Rao (1999) observed that the number of PRs in the human placenta decreases during late gestation, suggesting that progesterone may also be involved in the pregnancy stage-specific regulation of HLA-G gene expression.
In summary, this study demonstrates that HLA-G gene expression is up-regulated by progesterone through PR complex binding to a unique PRE sequence in the promoter region. Therefore, our findings further support the hypothesis that some of the immunomodulatory effects of progesterone during pregnancy may be mediated indirectly through modulation of HLA-G gene transcription.
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Submitted on November 18, 2005; resubmitted on February 27, 2006; accepted on March 29, 2006.
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