Molecular Human Reproduction, Vol. 6, No. 12, 1141-1145,
December 2000
© 2000 European Society of Human Reproduction and Embryology
Pregnancy |
Application of a functional genomics approach to identify differentially expressed genes in human myometrium during pregnancy and labour
1 Department of Obstetrics, Gynecology and Reproductive Sciences, Bressler Research Building 11–048, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Abstract
The molecular mechanisms regulating uterine relaxation and contraction during pregnancy are poorly understood. In the present study, we used for the first time a functional genomics approach applying gene array technology to identify novel candidate genes involved in the regulation of uterine quiescence and contractility during pregnancy. The purpose of this approach was to obtain a molecular snapshot of the expression profile of gene transcripts as a function of the time dependent process regulating myometrial quiescence. Using this approach, we found several genes whose expression in human myometrium was altered with the onset of labour. For example, the expression of insulin-like growth factor (IGF)-II, calgranulin A and B, and G-protein coupled receptor were decreased while the expression of IGF-binding proteins, Ca2+/CaM binding protein kinase C substrate, and angiotensin converting enzyme were increased in the labouring, compared with non-labouring, pregnant myometrium. The differentially-expressed genes include several genes whose roles in myometrial quiescence are yet to be understood, although they have been reported to regulate vascular smooth muscle tone. Our findings illustrate the advantage of a functional genomics approach over a single gene analysis in identifying a large number of novel and potentially important genes mediating uterine smooth muscle contractile activity.
array technology/labour/myometrium/pregnancy/uterine quiescence
Introduction
During the course of pregnancy, the myometrium undergoes quiescence (a state of relaxation) until late in gestation when labour (a state of contraction) begins. This relative state of uterine quiescence has been attributed to the release of several factors [prostacyclin, parathyroid hormone-related peptide (PTHr-P), corticotrophin-releasing hormone (CRH), calcitonin gene-related peptide (CGRP), progesterone, nitric oxide, carbon monoxide, etc] originating in gestational tissues and acting in autocrine and paracrine fashions on the myometrium (Keelan et al., 1997
; Morimoto et al., 1997; Acevedo and Ahmed, 1998; Smith and Brien, 1998; Dong et al., 1999; Grammatopoulos and Hillhouse, 1999; Wu et al., 1999). Despite intensive study of these factors, the cellular and molecular mechanisms mediating uterine quiescence remain poorly understood.
We propose that, in addition to the above known genes, the underlying mechanisms of myometrial quiescence involved the expression of other, as yet, unidentified genes. Our objective was to identify these genes using a functional genomics approach. Functional genomics may be described as the simultaneous study of thousands of genes whose functions are already known, thus providing a molecular snapshot of the expression profiles of various genes for a given tissue (Nadeau and Dunn, 1998; Schena et al., 1998; Wen et al., 1998). It is based on the rationale that there is a close relationship between the function of the gene product and its expression pattern. Typically, and apart from housekeeping genes, a gene is only expressed in a specific tissue when its gene-product contributes to the overall fitness of the tissue and organism under that specific condition (Brown and Botstein, 1999). In this study, functional genomics was used to identify previously unknown genes which are expressed in the myometrium and may participate in myometrial quiescence. Thus, knowledge of the expression profile of gene transcripts in the myometrium obtained from non-labouring and labouring women may provide important information on the biochemical and regulatory pathways operative at the time of sampling.
Using this functional genomics approach, we have identified many new genes previously reported to regulate vascular smooth muscle tone, but not as yet known to play a role in myometrial smooth muscle contraction. Thus, the approach provides a novel and efficient method for screening of gestational age-dependent changes in gene expression which may contribute to the mechanisms of myometrial quiescence.
Materials and methods
Sample collection
Human pregnant myometrial samples were obtained at the time of Caesarean section performed for medical reasons in two groups of women at term either not in labour (non-labouring myometrium) or in active labour (labouring myometrium). The clinical history of the patients was obtained and information on gestational age, and the occurrence of labour, based on spontaneous regular uterine contractions (four times/10 min) and cervical dilatation (>4 cm) was noted. Both groups of women, apart from their labour status (i.e. labouring versus non-labouring), had similar clinical characteristics, e.g. age (range 25–38 years), parity (range 0–2) and gestational age (range 38–39.5 weeks gestation). None of the women received any therapeutic intervention for their labouring condition. The samples were obtained from the upper edge of the hysterotomy in the transverse lower uterine segment. The tissue was frozen rapidly in liquid nitrogen and stored at –80°C until used. The Institutional Review Board approved the study and informed consent was obtained from each patient.
RNA and probe preparation
The total RNA was extracted from the tissue sample using Qiagen RNA isolation kit (Qiagen, Valencio, CA, USA) following its recommended protocol. Genomic DNA contamination was removed by incubating the sample RNA with DNAse 1 (10 IU/µg of RNA) for 30 min at 37°C. The mRNA was isolated from the DNAse 1-treated RNA sample using Qiagen mRNA Kit (Qiagen). The mRNAs of both labouring and non-labouring myometrium were converted to cDNA using Atlas cDNA synthesis protocol (Atlas cDNA Kit; Clontech, Palo Alto, CA, USA) in the presence of [
-32P]-dCTP. The labelled cDNAs were purified from the free [32P]-dCTP using Chromaspin-200 columns (Clontech).
Hybridization and analysis
Identical cDNA array blots (Atlas Human Blot; Clontech), containing 588 known genes (arranged in six functional groups with each gene printed twice, side by side, with 8–10 ng of cDNA/dot), were individually hybridized with their corresponding labelled cDNA probes. In all, six cDNA probes (isolated from three labouring and three non-labouring myometrial tissue) were hybridized separately with six cDNA array blots. The Atlas cDNA array blots were placed in separate glass bottles and prehybridized with 15 ml of ExpressHyb buffer (Clontech) for 2 h at 60°C in a rotating hybridization chamber. The labelled cDNA probes (2x106 cpm) were denatured at 95°C for 5 min, added to a fresh lot of 10 ml of pre-warmed (60°C) ExpressHyb buffer and mixed thoroughly. After decanting the old buffer from the glass bottles, the buffer containing the probes was added to the cDNA array blots and was hybridized at 60°C overnight. The blots were washed stringently (seven washes of 0.2x sodium chloride/sodium citrate, 0.5% sodium dodecyl sulphate) and autoradiographed for 12 h. To compare the expression of rare gene transcripts between labouring and non-labouring myometrial tissue, the blots were kept for an additional 4 days for autoradiography. The expression levels of the gene transcripts were directly quantified using a phosphoimager (GS-525; BioRad), and normalized as a percentage of the expression of several housekeeping genes (GAPDH, actin, ubiquitin, phospholipase) that were also arrayed in the blots. Expression levels were then obtained for both labouring (n = 3) and non-labouring myometrium (n = 3) and the values for labouring myometrium were normalized as a percentage change to the values of non-labouring myometrium. Consistent increases (at least 100%) or decreases (at least 50%) in gene expression levels, relative to non-labouring myometrium, were measured and expressed as mean ± SD.
Results
The transcript expression profile of labouring and non-labouring human myometrium is illustrated in Figure 1. The arrows indicate altered expression of some of the highlighted genes. The last two columns (right hand side) and the bottom row of the cDNA array blots were spotted with genomic DNA and hence all the spots were hybridized to labelled cellular cDNAs (as observed here). These spots provide a positive signal and also aid proper orientation of the membrane. The housekeeping genes were spotted in the second row from the bottom of the cDNA array blot and were equally expressed in the labouring and non-labouring myometrium (Figure 1). This suggests that both membranes were hybridized with the same amount of labelled cDNA probes. A magnified view of two cDNA array blots is shown in Figure 2.
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The cDNA array blot revealed a number of genes whose expression levels in the labouring human myometrium were either increased or decreased, compared with those in non-labouring pregnant myometrium (Table I
). As a reference point, we present the changes in gene expression levels in the labouring myometrium, compared with non-labouring pregnant myometrium. Although we observed altered expression of many genes, only the gene transcripts that were increased or decreased by >100 or 50% respectively were listed. These acceptance levels have been an established norm for selecting the differentially expressed genes in the field of genomics and cDNA array analyses. Genes displaying a smaller percentage change in expression levels may also be important (as in the case of transcription factors), but determining a statistical significance between labouring and non-labouring myometrium would require a larger sample size. Some of the genes (Table I) exhibiting a lower expression in the labouring myometrium were previously reported to inhibit smooth muscle contraction in tissues other than uterus, while a number of the genes which were increased in expression in labouring myometrium have been shown to facilitate contraction in many tissues and some have even been implicated in the myometrium.
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Discussion
Applying a functional genomics approach, we demonstrate for the first time the simultaneous expression profile of numerous gene transcripts in myometrium from labouring and pregnant non-labouring women. It is important to note that none of the women were under any therapeutic intervention that may affect gene expression within the myometrium. Interestingly, several genes previously shown to be involved in the maintenance of vascular smooth muscle tone (contraction as well as relaxation) were also found in our analysis to be differentially expressed in the labouring and non-labouring human myometrium. For example, the expression levels of IGF-binding proteins (IGF-BP) are increased (308%) while the levels of IGF-II are decreased (84%) in myometrium of labouring compared to pregnant non-labouring women. It has been demonstrated that IGF reduces vascular smooth muscle contraction (Hsai et al., 1998; Izhar et al., 2000), although its role in the regulation of myometrial smooth muscle tone remains to be explored. Since IGF-binding proteins bind to IGF-II, a higher level of IGF-binding protein in the labouring myometrium (compared to non-labouring) would ensure a lower level of unbound IGF-II available for cellular interaction and may enhance in smooth muscle contraction.
Further, we identified several gene transcripts (e.g. the G-protein coupled receptors, and calgranulin A and B) that are decreased in their expression in the labouring myometrium compared to non-labouring pregnant myometrium. A variety of factors and ion channels (such as parathyroid hormone, corticotrophin-releasing hormone, calcitonin gene related peptide, K+-channels, etc) that mediate uterine relaxation act through G-protein coupled receptors (GPCR) (Brenninkmeijr et al., 1999). The present GPCR in the cDNA array blot employed here belongs to the chemokine family of orphan receptors whose ligand is unknown (Nomura et al., 1993). Given the general role of GPCR in the maintenance of smooth muscle tone, it could be suggested that this orphan GPCR may mediate uterine relaxation (during pregnancy) through an, as yet, unknown ligand. Smooth muscle contraction is initiated by an increase in intracellular Ca2+ concentration while relaxation is associated with the reduction of intracellular Ca2+ (Rashatwar et al., 1987). Owing to their ability to bind Ca2+ (Kelley et al., 1991; Dell'Angelica et al., 1996), the calcium binding proteins A and B (calgranulin A and B), could reduce excess intracellular Ca2+. Hence, its decreased expression in the labouring myometrium and comparatively increased expression in non-labouring pregnant myometrium could aid in the maintenance of uterine relaxation during pregnancy.
It has been reported that angiotensin converting enzyme and epidermal growth factor (EGF) receptor ligand are involved in uterine contraction, and decreased in the myometrium during pregnancy (Gardner et al., 1987; Svane et al., 1995). We extend these observations noting increased expression of these genes in the pregnant labouring myometrium compared with non-labouring myometrium. These findings exemplify the feasibility of the functional genomics approach, which assumes that a gene is expressed in a given tissue to contribute to the ongoing physiological process under specific conditions (Brown and Botstein, 1999). Other pregnancy-related genes, e.g. oxytocin, oxytocin receptors, CRH, CGRP, and PTHr-P, were not spotted in these cDNA arrays and it is beyond the scope of the present work to comment on their relative expression status in labouring and non-labouring pregnant myometrium.
We have also noted that in labouring myometrium, there is enhanced expression of several genes [Ca2+/CaM binding PKC substrate, guanine nucleotide binding protein (GS-), glutathione S-transferase M4, etc] which have been previously reported to participate in smooth muscle contraction but have not been reported in the context of myometrial contraction (Laneuville et al., 1991; Throckmorton et al., 1998; Kitazawa et al., 2000). Further research on these genes may contribute to our knowledge regarding their roles in myometrial contraction/quiescence during pregnancy.
Finally, we observed altered expression of several genes whose immediate role in smooth muscle contraction/relaxation, if any, is as yet unknown. For example, we observed that the expression of Y-box binding protein, DNA polymerase , replication protein A1 and integrin v were increased in the labouring myometrium (compared to non-labouring pregnant myometrium). Interestingly, the Y-box binding protein is a transcription factor that activates pro-collagenase gene transcription (Dhalla et al., 1998). An increased collagenase activity is required for degradation of collagen during cervical ripening and postpartum uterine involution. Generally, pro-collagenase activity is decreased in the non-labouring myometrium during pregnancy but increased during labour (Milwidsky et al., 1993). Hence our finding of increased expression of Y-box binding protein, an up-stream regulatory gene, in the labouring myometrium is a novel addition in the understanding of the molecular determinants of labour. As far as roles for replication protein A and DNA polymerase are concerned, they may be necessary for the increased demand of vascular remodelling during labour. These findings further illustrate the advantage of a functional genomics approach over a single gene approach in identifying novel genes in the human uterus that may play a role in the mechanisms of uterine contraction/relaxation during pregnancy.
In summary, this is the first reported application of gene array technology using a functional genomics approach to seek out candidate genes involved in the regulation of uterine quiescence and contractility. We envision that the application of gene array technology will be a powerful tool in several ways: (i) in identifying novel genes regulating myometrial quiescence; (ii) in delineating the various signal transduction pathways (e.g. those for nitric oxide, carbon monoxide, prostacyclin, parathyroid hormone) involved in uterine physiology; and (iii) in understanding of the pathological process of uterine dysfunction.
Acknowledgments
Theses studies were supported by the National Institutes of Health Grants HL-49999 (L.P.Thompson) and HL-49041 and HD 22294 (C.P.Weiner).
Notes
2 To whom correspondence should be addressed. E-mail: kaguan{at}ummc001.ummc.umaryland.edu 
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