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Pregnancy |
Harris Birthright Research Centre for Fetal Medicine,3 King's College Hospital Medical School, London SE5 9RS, United Kingdom
Department of Biological Sciences,4 Imperial College, London SW7 2AY, United Kingdom
Departments of Cellular Pathology5 and Obstetrics,4
and Gynaecology,6 St. George's Hospital Medical School, London SW17 ORE, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2.15 Mb from Syncytin (HERV-W) gene at 7q21.3, are implicated in choriocarcinoma and Silver-Russell syndrome. Here we have analyzed the temporal regulation of mRNA expression of these genes in placenta and demonstrate that Syncytin gene activation is highest in term placenta, PEG10, downregulated at early hypoxic phase, and highly activated at 11–12 wk of gestation. In contrast, transcription from SGCE remained unchanged throughout pregnancy, suggesting two neighboring imprinted genes are differentially regulated at very early pregnancy. Additionally, accumulation of two major species of mRNA (8 kb and 3.1 kb) encoded by HERV-W in placenta is regulated: 3.1 kb mRNA level remained unchanged throughout pregnancy, whereas the production of 8 kb species was highest in term placenta. Western blot and immunohistochemical staining of placental tissues with monoclonal antibodies revealed a marked reduction of syncytin glycoprotein synthesis in late pregnancy. Therefore, the relative levels of 3.1 kb and 8 kb mRNAs in trophoblasts could regulate syncytin protein synthesis, possibly by competition of the two mRNA species for translational apparatus.
gene regulation, placenta, pregnancy, syncytiotrophoblast, trophoblast
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2.15 kb away from syncytin (HERV-W), (Fig. 1, Ai) at 7q21.3. Unlike HERV-W, PEG10 contains no long terminal repeat sequences (Fig. 1A, ii). PEG10 mRNA is predominantly expressed in placenta and testis and to a lesser extent in brain and lung [5] and codes for a protein homologous to mouse MyEF-3 (myelin expression factor 3), which is presumed to be necessary for producing myelin-binding protein (MBP) and has been shown to participate in myelinating neurons [6].
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SGCE, the epsilon (
) member of the sarcoglycan family, is a component of the transmembrane dystrophin-glycoprotein (DGC) complex. It mediates muscle cytoskeleton-extracellular matrix communications by stabilizing membranes [7]. The transmembrane DGC complex often contains subcomplexes containing dystroglycans and sarcoglycans. -Sarkoglycan exhibits strong homology to 
-sarkoglycan [8, 9]; however, unlike -, -sarkoglycan is highly activated in placenta in addition to heart and skeletal muscle [10]. Although the abundance of HERV-W, PEG10, and SGCE transcripts in human placenta indicated their functional role, very little is known about their regulation during pregnancy, primarily because these studies were often carried out with late or full-term placental materials [3–5, 10–12]. Nevertheless, a specific function of syncytin in placental morphogenesis became apparent from recent work on aberrant pregnancies. For instance, reduced syncytin expression has been directly correlated with insufficient or late differentiation of STs in Down syndrome pregnancies [13–16], suboptimal invasion of trophoblast in pre-eclampsia, and hypertensive pregnancy disorders [11, 12]. Furthermore, two neighboring genes at 7q21.3 (SGCE and PEG10), implicated in Silver-Russell syndrome (SRS), characterized by intrauterine growth restriction [17–19] and choriocarcinoma [20, 21], are maternally imprinted [22, 23]. Therefore, future experiments investigating their functional link to placental and fetal development might be facilitated by understanding the regulation of these genes during normal pregnancies. Here we demonstrate that two neighboring imprinted genes (PEG10 and SGCE) are differentially regulated in placenta and that despite increased transcriptional activation of HERV-W, syncytin protein synthesis is markedly reduced in late pregnancy.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This study was approved by the local ethics committees of St. George's and King's College Hospitals, London, and written consent was obtained from patients before the collection of samples. Placental tissue was taken from patients undergoing termination of pregnancy with gestational age range of 7–12 wk. Full-term placental tissues were obtained after vaginal delivery or after cesarean section. Tissue was dissected and washed in PBS (Ca2+/Mg2+-free) until clean and villous material isolated by further dissection in a sterile Petri dish placed under a stereomicroscope. Embryonic tissue from a 12-wk pregnancy and decidual tissue were carefully dissected and repeatedly washed in PBS. Samples were stored in RNA Later (Ambion, Austin, TX) overnight at 4°C before transfer to storage at -20°C. Women undergoing chorionic villus sampling (CVS), for ultrasonographic indications, were asked to allow tissue in excess of that needed for cytogenetic analysis to be used for the study. These samples were stored and only materials from chromosomally normal pregnancies were used. Tissues were homogenized in TRIzol (Invitrogen, Carlsbad, CA) using the manufacturer's standard protocol for total RNA preparation. RNAs were stored as ethanol precipitates at -70°C.
Genetic Map, mRNAs, and cDNA Amplification by Reverse Transcription-Polymerase Chain Reaction
The relative positions of HERV-W, maternally imprinted neighboring PEG10, and SGCE at 7q21.3 and their corresponding mRNAs are shown in Figure 1A. HERV-W codes for two major species of mRNA, 8 kb and 3.1 kb, but in testis, only the 8-kb species is transcribed to produce syncytin glycoprotein and therefore defined as testis syncytin (SynT). Although both 8-kb and 3.1-kb mRNAs are produced in human placenta, the latter is translated to produce the functional envelope glycoprotein, syncytin [4]. To distinguish 8-kb from 3.1-kb mRNA, the latter is described as placental syncytin mRNA (SynP).
RNAs were treated with DNase I (Sigma, St. Louis, MO) in 30 mM Tris-Cl (pH 7.8), 50 mM NaCl, and 10 mM MgCl2, in the presence of 40 U RNaseOUT (Invitrogen) for 30 min before phenol-chloroform extraction and ethanol precipitation. First-strand cDNA was synthesized from 5 µg of total RNA using Superscript II reverse transcriptase (RT) (Invitrogen), primed with oligo (dT)12–18 (Invitrogen) according to the manufacturer's recommended protocol, and then treated with RNase H (Invitrogen) for 30 min prior to heat inactivation (70°C for 15 min) and cDNA amplification. Standard polymerase chain reaction (PCR) profile for all reactions: 94°C, 5-min initial denaturation followed by 94°C, 45 sec, 50–58°C (depending upon primer set; Table 1) annealing, 30 sec, 72°C extension, 90 sec for 15 cycles (to maintain exponential amplification), and a final extension cycle at 72°C for 10 min. Unlike Northern blot, RT-PCR analysis in a multiplex allows quantitative analysis of several mRNA species in a single exponential amplification reaction under defined experimental conditions in which the yield of amplified products in the multiplex is comparable to that of each single species alone (data not shown). All multiplex experiments were optimized so that the yield of each product in the multiplex reaction matched the yield of individual primer sets under the same conditions (data not shown). PCR products were resolved on 1.5%–2.0% agarose gels before Southern blotting by alkaline transfer to nylon membranes (Nytran-Plus, Schleicher and Schuell, Keene, NH).
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RNA and DNA Blot Hybridization
Approximately 15 µg of total RNA was resuspended in loading buffer containing 1x MOPS, 50% deionized formamide, and 2.2 M formaldehyde and separated on agarose gels containing formaldehyde (2.2 M) buffered with MOPS (40 mM MOPS, 10 mM sodium acetate, 1 mM EDTA, pH 7.2), transferred to a nylon membrane (Nytran-Plus, Schleicher and Schuell), washed in 2x saline sodium citrate, and baked to reverse the formaldehyde reaction.
The syncytin probe was a 1.7-kb EcoRI fragment from a cDNA clone (kindly provided by Dr. F. Mallet). SynP, SynT, PEG10, SGCE, and ß-actin probes were generated from RT-PCR products. All probes were gel purified by electroelution and concentrated by Elutip-D columns as described previously [24]. Two hundred nanograms of probe was radiolabeled using Megaprime kit (Amersham, Bucks, U.K.), column purified (NAP5, Pharmacia, Bucks, U.K.), denatured, and added to the hybridization solution. For multiplex analysis, SynP plus SynT was cohybridized after stripping, with ß-actin. SGCE was hybridized before stripping and subsequent cohybridization of PEG10 and ß-actin. Following overnight hybridization at 65°C, membranes were washed extensively (1% SDS, 50 mM PO4 at room temperature) and autoradiographed. For sequential hybridization, filters were stripped by boiling in 1% SDS solution.
Densitometry and Data Analysis
At least three exposures of each autoradiogram were scanned from each experiment, and only those scans exhibiting linearity were used to generate data points. Densitometry was carried out using a 1D-Multi Lane Densitometry program in an AlphaImager (1220 version 5.5, Alpha Innotech Corp., San Leandro, CA). For autodetection of pixel density in a peak, the scan width as well as baseline values were maintained constant for each exposure. Scan data (experimental and control) were transferred to Microsoft Excel (Redlands, WA) in which pixel density of each experimental lane was normalized to its corresponding ß-actin value. Each experiment was repeated at least twice, and average values for each data point were plotted.
Western Blot and Immunohistochemistry
Proteins from placental villous tissue, dissected as described above, were extracted in T-Per (Pierce, Rockford, IL) following the recommended protocol. Protein concentrations were measured (Bradford assay, BioRad, Hercules, CA), and 10 µg of extract was resolved in 8% SDS-polyacrylamide gel and transferred to polyvinyl difluoride membrane. Immunostaining was carried out with primary 6A2B2 monoclonal antibody (1 in 3000 dilution) and anti-mouse secondary antibody. Reactions were detected using enhanced chemiluminescence reagents (Roche, Nutley, NJ) and fluorography. Subsequently, blots were stained with 0.25% Coomassie brilliant blue R in 40% methanol, destained, and photographed.
Placental tissue from 7-, 8-, and 12-wk and full-term pregnancies was fixed in 4% (v/v) freshly prepared paraformaldehyde in PBS (Ca2+/Mg2+-free) for 4 h at room temperature. The samples were cryoprotected, embedded in paraffin, and frozen in liquid nitrogen. Multiple sections (7 µm width) were cut and immunostained using ChemMate Detection kit (DAKO, Glostrup, Denmark). Following deparaffinization, slides were immersed in MS unmasker buffer (Microm Microtech, Francheville, France) and placed in a microwave (800 W) for three cycles (5 min each). Endogenous peroxidase activity was blocked (3% H2O2, 10 min) prior to incubation with monoclonal mouse anti-human syncytin (6A2B2, 1:100) followed by biotinylated goat anti-mouse immunoglobulin (30 min) and streptavidin peroxidase (30 min). The slides were developed by adding substrate-chromogen mixture (DAKO) for 7 min at room temperature. Reactions were stopped by repeated washing in distilled water followed by brief counterstaining (1 min) with freshly prepared and filtered Mayer hematoxylin (Merck, Middlesex, UK) followed by rinsing in 1% acid-alcohol. The slides were dehydrated in ascending ethanol series prior to mounting. For negative controls, the primary antibody was replaced with nonspecific isotype controls (negative control reagents, IgG1, monoclonal; DAKO). The sections were visualized in a Nikon E400 microscope and images were captured using Lucia version 4.21 system for image processing and analysis.
Statistical Analysis
Densitometric data were transferred to Microsoft Excel Worksheet and means, SDs, and variance (analysis of variance) for each data set were computed using Analysis ToolPak software. Values are shown as mean ± SEM. To compare gene expression in early and late placenta, the average value for early samples was compared with the average value for the full-term samples. A value for the level of significance (P value) was calculated using Poisson statistic. P < 0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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11 wk, and this high level of expression was maintained and was significantly increased (P < 0.05) in term placenta, compared with that in early pregnancy (Fig. 1C). In addition to the 6.3-kb full-length PEG10 mRNA, a 2.1-kb species was detected in all stages of pregnancy. The transcription of the 2.1-kb band increased as the pregnancy progressed (Fig. 1C). This transcript also hybridized to another PEG10 probe (Fig. 1A, ii and data not shown) and we suspect that it could have originated from a cryptic splice site within the full-length 6.3-kb mRNA or that its transcription was initiated at an internal site in PEG10. Rehybridization of the same blot (Fig. 1C) with SGCE cDNA probe (Fig 1A, iii) showed that this gene was active at all stages of pregnancy. To verify the Northern blot hybridization data, we examined the relative expression of SynP, SynT, PEG10, SGCE, and ß-actin mRNAs by semiquantitative RT-PCR. To achieve accurate estimates, cDNAs were amplified exponentially together, using two or three pairs of gene-specific primers (multiplex) for only 15 cycles before the products were resolved in agarose gels and identified by sequential or cohybridization with specific probes followed by densitometric measurement. Representative examples of these experiments for each probe are shown in Figure 2, A, B, and E. To estimate total syncytin expression and accumulation, SynP plus SynT (SynPT), cDNAs from placenta at various stages of pregnancy were amplified with primers at the 3' end of HERV-W (see Table 1 and Fig. 1A, i) and ß-actin primers in multiplex (Fig. 2A). Notably, the HERV-W primer set, by virtue of its location at the 3' end of the gene, will amplify both SynP (3.1 kb) and SynT (8 kb) cDNAs; therefore, the amplified products are called SynPT. As expected, the cDNA from whole embryo failed to amplify SynPT (Fig. 2A, lane 12). The total syncytin expression was highest in term placenta and was significantly higher (P < 0.01) when compared with the yield at early stages of pregnancy (Fig. 2C). We suspected that SynPT level in early placenta was due primarily to the amplification of SynP cDNA, whereas in late placenta, the products were contributed by both SynP and SynT cDNAs. Because both SynP and SynT could be translated to produce syncytin protein in placenta and testis, respectively [3, 4], and could potentially compete with each other for protein synthesis apparatus, we examined the relative level of translatable SynP mRNA available in early and term placentae. Such measurement is possible if one could estimate the contribution by SynT cDNA to the total amplified products (SynPT). To achieve this, a set of primers (Table 1 and Fig. 1A, i) was used where the forward and reverse primers were placed at a region that could amplify only 8 kb (SynT) cDNA. To examine the relative level of translatable SynP mRNA synthesis, cDNAs were coamplified (Fig. 2B). The relative level of translatable SynP mRNA synthesis was determined by subtracting SynT from SynPT for each experimental time point (Fig. 2B) and is shown in Fig. 2D. Assuming that two mRNA species compete, the level of SynP mRNA available to produce syncytin protein significantly decreased (P < 0.01) in term placenta, compared with that in early pregnancy (Fig. 2, B and D).
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These results are consistent with the data obtained by Northern blot hybridization (Fig. 1B). A similar analysis of PEG10 and SGCE mRNA expression at different stages of gestation revealed that activation of PEG10 began to increase at the end of the first trimester and was highest in term placenta, but SGCE transcription remained unchanged throughout pregnancy (Fig. 2, E and F). Placental tissues are difficult to obtain from voluntary termination of normal pregnancies following 12 wk of gestation. Therefore, clinically normal CVS were used for analysis (12–14 wk) in these experiments. Together, these results show that production of HERV-W mRNAs (SynP plus SynT) is maximum in full-term placenta and PEG10 gene is downregulated during very early hypoxic development, and the stage of pregnancy has no significant effect on SGCE regulation.
To investigate whether the syncytin mRNA data correlate with the synthesis/accumulation of syncytin protein, Western blots and immunohistochemistry were performed. Proteins extracted from early (7–12 wk) and term placentae (late, both cesarean and vaginal deliveries) were immunoblotted with a mouse monoclonal antibody [4] against syncytin (see Materials and Methods). Following antibody staining, membranes were briefly stained with Coomassie brilliant blue R to estimate the relative quantity of protein transferred in each lane (Fig. 3A). A visual examination of the blot suggests that unglycosylated (Mr, 55 x 103; 55, ugp), partially glycosylated (60 x 103; 60, pgp), and fully glycosylated (Mr, 85 x 103; 85, gp) syncytin precursor proteins were present in each lane (Fig. 3A). However, quantitative analysis of the bands revealed that the production of all three species of synctin was significantly increased (P < 0.01) in early pregnancy, compared with that in term (late) placentae (Fig. B). The 55–60 x 103 bands migrate as a single band in shorter runs or in 12% gels (data not shown). To further verify these results, immunohistochemistry was performed, using the same monoclonal antibody against syncytin, on placental sections from 7-wk, 8-wk, 12-wk, and term pregnancies. The intensity of staining was highest in 7- and 8-wk sections, somewhat reduced in 12-wk placenta, and was very weak in full-term placenta, compared with that in early pregnancy (Fig. 3C). These data are in agreement with the results obtained by Western blotting. Notably, both extravillous trophoblasts and STs reacted equally with the antibody. Although faint staining of intravillous cytotrophoblasts is detectable in 12-wk placental tissues, we did not detect immunostaining of inner villous vascular cells. Therefore, despite a quantitative increase in total syncytin mRNA (SynPT) expression in late placenta (Figs. 1A and 2, A, B, and E), syncytin protein synthesis was inhibited at this stage of pregnancy. Antibodies against PEG10 and human SGCE are currently unavailable. Therefore, expression of these proteins in human placenta would require future investigation.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The critical finding of this study is that syncytin mRNA production (which includes both placenta and testis-specific species, SynP and SynT) is highest in term placenta, but the protein synthesis is lowest, compared with that in early pregnancy. Moreover, steady-state SynP mRNA level remained unchanged throughout pregnancy and SynT is overproduced in term placenta. Given that SynP mRNA is generated by splicing of SynT precursors [3, 4], it is possible that SynT is overexpressed or stabilized in late placenta, compared with that in early pregnancy. Marked reduction of envelope glycoprotein synthesis most likely was due to the competition between placenta (3.1 kb)- and testis (8.0 kb)-specific mRNAs for ribosomes [27]. Such posttranscriptional regulation of a fusogenic surface glycoprotein in trophoblasts could be a physiological necessity to sustain pregnancy following implantation. Excessive accumulation of STs could lead to uncontrolled invasion, a phenomenon (placenta percreta) quite opposite to the superficial implantation in pre-eclampsia. Two independent reports [11, 12] have demonstrated a marked reduction of syncytin expression in pre-eclamptic trophoblasts, leading to suboptimal invasion, compared with that of gestational age-matched normal pregnancies. Whether the low level of syncytin protein in pre-eclampsia is due to hyperactivation of SynT transcription (mRNA competition for translational apparatus) remains to be determined. Interestingly, increased production of superoxide dismutase 1 and reduced syncytin expression in Down syndrome early pregnancies have been postulated to be associated with poor differentiation of STs, hypoplasia, and hypovascularity of the placenta [13–16, 28].
Unlike Syncytin, very little is known about the PEG10 gene products. The predicted amino acid sequences from PEG10 (ORF1) have significant homology to mouse MyEF-3, an activator of MBP, which participates in myelinating neurons [6]. Because database searches for PEG10 genomic sequences show homology only to a BAC (AC069292) containing human PEG10 and SGCE, it is highly unlikely that extra bands (Fig. 1C) were due to cross-hybridization. Notably, two open reading frames (ORF1 and ORF2), encoded by PEG10 mRNA, have some amino acid sequence homology to gag (ORF1) and pol (ORF2) proteins of Sushi-ichi, a retrotransposon from pufferfish [5]. PEG10 is downregulated at early hypoxic phase of placental growth and is induced at 11–12 wk of gestation (Figs. 1 and 2), suggesting that the gene product could be essential for trophoblast differentiation and uterine implantation.
SGCE is constitutively expressed in early and late human placenta, indicating that the gene product could be essential for cell-to-cell signal transduction during proliferation, differentiation, and uterine invasion of trophoblasts. This conjecture is consistent with the observation that mice carrying homozygous deletion (dystroglykin-/-) die prior to implantation (d6.5) because of disruption of Reichert membrane [29], whereas in adults, heterozygous loss-of-function mutations in SGCE are linked to Myoclonus-dystonia syndrome characterized by myoclonic jerks of arms (writer's cramp) and axial muscles. Notably, SGCE and PEG10 exhibit very little coordinated activation at the hypoxic phase of placental growth (6–10 wk) (Fig. 2, E and F). Because the two genes are organized in a head-to-head (opposite) orientation and are differentially activated at early hypoxic phase of placental growth, it is possible that they share common regulatory elements capable of interacting with gene-specific transactivator/inhibitor [30].
Genomic imprinting in mammals is proposed to have evolved to maintain balanced growth and development through monoallelic expression of the genes in the placenta as well as embryo [25]. The early studies on the developmental potential of androgenetic and gynogenetic mouse embryos have shown that paternal and maternal haploid chromosomes, in general, contribute to the development of extraembryonic tissues (placenta) and the embryo proper, respectively [31, 32]. Partial hydatiform moles in human triploid pregnancies with paternal (diandy) or maternal (digyny) duplication of haploid chromosomes have two distinct developmental phenotypes, suggesting their parent-of-origin effect on growth and differentiation of human placenta [33]. Despite a catalogue of imprinted genes identified through genetic and molecular analysis of uniparental disomies in mouse [34, 35] we know very little about their regulation as well as specific role in human placental growth, embryogenesis, or both. HERV-W maps very close to two neighboring maternally imprinted (paternal expression) genes, SGCE and PEG10 at 7q21 [5]. Because imprinted genes are clustered [26], coordinately regulated through neighboring chromatin domains [36], and both PEG10 and HERV-W are retroelements, it is possible that Syncytin could be paternally expressed. Genetic polymorphism analysis of placental cDNAs from pregnancies with maternal iso- and heterodisomy of chromosome 7 [17–19] and triploidy might help to settle this issue. Our recent analysis revealed relaxation of imprinting of SGCE and PEG10 in placenta from a variety of genetically compromised pregnancies including Down syndrome (unpublished results).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Subhasis Banerjee, Harris Birthright Research Centre for Fetal Medicine, King's College Hospital Medical School, Denmark Hill, London SE5 9RS, United Kingdom. FAX: 44 0207 733 9534; dr_sbanerjee{at}hotmail.com
Received: 5 November 2002.
First decision: 12 December 2002.
Accepted: 11 February 2003.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-sarcoglycan is highly related to -sarcoglycan (adhalin), the limb girdle muscular dystrophy 2D gene. FEBS Lett 1998 422:27-32[CrossRef][Medline]-sarcoglycan are maternally imprinted genes: identification by a subtractive screen of novel uniparental fibroblast lines. Mol Cell Biol 2000 20:3308-3315This article has been cited by other articles:
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