Volume 7 Supplement 1
Functional genomics of the pregnant uterus: from expectations to reality, a compilation of studies in the myometrium
© Breuiller-Fouche et al; licensee BioMed Central Ltd. 2007
Published: 1 June 2007
Studies on the human myometrium have reported on different microarrays containing different sets of genes or ESTs. However each study profiled only a small number of patients due to various constraints. More profiling information would be an addition to our knowledge base of parturition.
We compiled from five human studies, transcriptional differences between the non pregnant myometrium (NP), preterm myometrium (PTNIL), term myometrium not in labor (TNIL) and term myometrium in labor (TIL). Software modules developed by the Draghici's group at Wayne State University (Detroit, MI, USA) were used to propose a hierarchical list of several KEGG pathways most likely adjusted to changes observed in microarray experiments.
The differential expression of 118 genes could be dispatched in 14 main KEGG pathways that were the most representative of the changes seen in NP and PTNIL, versus TNIL or TIL. Despite the potential of multiple pitfalls inherent to the use of the microarray technology, gene module analysis of the myometrial transcriptome reveals the activation of precise signaling pathways, some of which may have been under evaluated.
The remodelling and maturation processes that the uterus undergoes in pregnancy appear clearly as phenomena which last during the full course of gestation. It is attested by the nature of the main signaling pathways represented, in the comparison of the PTNIL versus TNIL uterus. Comparatively, the onset of labor is a phenomenon which remains less well characterized by these methods of analysis, possibly because it is a phenomenon occurring in too short a window to have been grasped by the studies carried out up to now.
The common hallmark of recently published papers referring to functional genomics is their enthusiastic tone on expectations. The near-entire genomic sequence of the human and several model animals has given the opportunity to flesh out the relationships between genes, phenotypes and global transcriptional status at unprecedented speed and scale . The microarray technology allows the examination of the function of thousands of genes at once and in parallel, thereby providing an "assay" of the transcriptional status of cells or tissues in a wide variety of physiological or pathophysiological situations . Computational methods allow the identification of genes differentially expressed across cell types, developmental stages or pathological conditions; genes expressed in a coordinated manner across a set of conditions and to delineate clusters of genes sharing coherent expression features . These techniques open up new areas of unrecognized molecular networks and yet unidentified players in the anabolic-catabolic balance in intracellular signaling cascades which have been so far hardly investigated in the context of preterm labor.
From past studies in domestic animals, it has amply been demonstrated that during pregnancy the production/withdrawal of sex steroids, notably that of progesterone which is thought to actively block the transformation of the myometrium to a contractile phenotype, govern the precise timing of labor onset . Steroids modulate transcription by interacting with specific response elements in the promoter regions of target genes to recruit the basic transcriptional complex. Although it is not yet definitively established whether functional progesterone withdrawal is indeed a pivotal event in the human parturition cascade , all the preceding elements point to the fact that transcriptome studies of the myometrium, fetal membranes or placenta, should be a valuable approach to decipher the mechanisms involved in human parturition. In the course of the last 6 years, a number of transcriptomic studies on the preterm versus term pregnant human uterus [6–12] or fetal membranes [13–17] have been published.
Studies on the human myometrium have reported on different microarrays containing different sets of genes or ESTs. However each study profiled only a small number of patients due to various constraints. More gene expression profiling information would be an addition to our knowledge base of parturition. We compiled from human studies [7–9, 12, 18], transcriptional differences between the preterm myometrium (PTNIL), term myometrium not in labor (TNIL) and term myometrium in labor (TIL).
Studies used to compile the differential expression of the genes in the myometrium
Number of genes on chip
Supplemental data, where?
Rehman et al., 
Incyte Genomics UniGEM V microarray Version 1.0
- Yes (raw data)
- # GSM 6791 NCBI GEO (from 2005)
Bethin et al., 
Affymetrix HG-U95A chips
U95 set, approx. 10,000 genes (oligo)
- PDF files
- no open access
Charpigny et al., 
Clontech Atlas Human 1.2 & 1.2II
- Yes (raw data)
- XLS files
- Lab., open access
Esplin et al., 
6,912 cDNA in duplicate
- Yes (raw data)
- XLS files
- Lab., open access
Havelock et al., 
Incyte Genomics UniGEM V microarray Version 2.0
The main KEGG metabolic pathways, regulatory pathways or molecular complexes expressed in the myometrium
The MAPK signaling pathway differentially expressed in the myometrium
MAPK signaling pathway
Drawbacks and limitations inherent to the use of Onto-Tools or of their cognate alternatives for ontological analysis have been discussed. These limitations remain to the present day, questions over the robustness of array data and the criteria under which their conclusions were drawn have been made . A recent review by Allison et al. , has the merit of proposing simple sound recommendations for future microarrays analysis methods.
Despite the potential of pitfalls inherent to the use of the microarray technology (review in ), gene module analysis of the myometrial transcriptome reveals the activation of precise signaling pathways, some of which may have been under evaluated. Thus, the remodelling and maturation processes that the uterus undergoes in pregnancy appear clearly as phenomena which last during the full course of gestation. It is attested by the nature of the main signaling pathways represented, in the comparison of the PTNIL versus TNIL uterus. Comparatively, the onset of labor is a phenomenon which remains less well described by these methods of analysis, possibly because it is a phenomenon occurring in too short a window to have been grasped by the few studies carried out up to now.
Also, although the myometrium is considered to be a relatively homogeneous tissue, some of its largest changes at term occurred in genes that were not normally associated with muscle. This is consistent with animal studies which better allow to explore the global pattern of gene expression and their co-regulation on the basis of their genomic location over the full time-course of myometrial transformation or following experimentally-controlled infection [28–31].
Today, a main handicap with high throughput methods is the capacity for each individual research group to handle samples and data. These methods indeed suggested a number of potentially new biochemical markers of preterm labor , some of which, for example, could be detected in circulating immune-cells. However, all studies, notably in the human, have suffered from several limitations, among which are the limited size of samples which hardly can be considered as representative of even a small population; the regular inconsistency in nomenclature usage or terminology in reference to the molecules studied; the lack of integrated databases to compile different studies and the underestimation of heterogeneity of the tissue exposed to the microarray analysis.
Genomic studies of the pregnant uterus, like in other domains, widen our comprehension of the structural and metabolic transformations which affect the myometrium from the beginning of pregnancy until parturition. Although the studies so far published remain a few numbers, they throw light on the urgent need to constitute a Working Group to standardize the techniques, terminology and experimental plans as well as to design new integrated databasing protocols. In this respect we have much to learn from those who anticipated the burst of genome biology . Access to dedicated databases by researchers and clinicians will be critical to progress in biomarker identification for the major obstetrical concern, namely the preterm birth.
List of abbreviations
cell adhesion molecules
expressed sequence tags
G-protein coupled membrane receptors
Janus kinases/Signal transducers and activators of transcription
Kyoto Encyclopedia of Genes and Genomes
mitogen-activated protein kinase
Online Mendelian Inheritance in Man
preterm not in labor
transforming growth factor
term myometrium in labor
term not in labor
- Wnt protein/signaling:
wingless-type protein/signaling. Gene names, see  for detailed names of genes listed in this article.
We wish to acknowledge the sponsorship of Ferring, PerkinElmer and Serono, who helped to cover publishing charges of the article. We are also indebted to the financial support and organization by the EU project SAFE (The Special Non-Invasive Advances in Fetal and Neonatal Evaluation Network, LSHB-CT-2004-503243) of the 2005 and 2006 PTL workshops, where data of this article were presented as oral communications.
This article has been published as part of BMC Pregnancy and Childbirth Volume 7, Supplement 1, 2007: Proceedings of the First and Second European Workshops on Preterm Labour of the Special Non-Invasive Advances in Fetal and Neonatal Evaluation (SAFE) Network of Excellence. The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2393/7?issue=S1.
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