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1 Departments of Endocrinology
2 Molecular and Developmental Biology, Children’s Hospital Research Foundation and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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decidual fibroblast differentiation; gene regulation; pregnancy; microarray
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Most knowledge about the regulation of human decidualization has come from studies using in vitro model systems. Decidualization can be induced in primary cultures of endometrial stromal cells by incubation of the cells with progesterone in combination with estradiol or relaxin or with high levels of cAMP in the absence of exogenous hormone (22, 27, 41). The treated endometrial cells acquire the characteristic morphologic phenotype of decidual cells and express decidual cell-specific markers such as prolactin and insulin-like growth factor binding protein-1 (IGFBP-1). Decidualization can also be induced in primary cultures of human decidual fibroblasts (36) and in a permanent cell line of human endometrial fibroblasts (St-2 cells) (8). Treatment of primary cultures of decidual fibroblasts and St-2 cells with cAMP induces prolactin gene expression and decidualization, but treatment with progesterone, alone or in combination with estradiol, is without effect. Treatment of the cells with progesterone, however, potentiates the induction of decidualization in response to cAMP. Another model system, the N5 endometrial cell line, the cells of which have phenotypic features of primary cultures of decidualized human endometrial stromal cells and secrete low levels of prolactin and IGFBP-1 constitutively, is also decidualized further in response to cAMP (6).
Studies using these model systems have identified several genes induced during decidualization but have so far provided little information about those that are repressed or activated with differing kinetics during decidualization. To identify new genes that are dynamically regulated during decidualization and their expression patterns, we performed sequential DNA microarray analyses of human decidual fibroblasts decidualized in vitro by treatment with progesterone, estradiol, and cAMP using the Incyte human GEM-V microarray that contains 6,918 genes. In addition, we compared the expression profiles of the dynamically regulated genes during decidualization to those regulated during differentiation of cytotrophoblast cells. Our findings suggest that decidualization, like cytotrophoblast differentiation, is characterized by "categorical reprogramming" in which there is strongly diminished levels of genes within the same category as many of the major induced genes. However, differentiation of the two different lineages is highly divergent, with the same genes exhibiting nearly opposite regulation in the two lineages. The results show that decidualization and cytotrophoblast differentiation exhibit markedly different patterns of expression and demonstrate the extent to which differentiation programs can be intensely cell-type specific.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The cells were plated in six-well tissue culture plates (2.5 x 106 cells/well; Falcon Plastics, Becton-Dickinson, Franklin Lakes, NJ) in FBS-supplemented medium. After allowing the cells to attach to the plates overnight, decidualization was induced by treatment with medroxyprogesterone acetate (1 µM), estradiol (10 nM) and dibutyryl-cAMP (50 µM). The medium was changed at 2, 4, 6, 9 and 12 days, and the experiment was terminated at 15 days. Cells from triplicate wells were collected at the time of each medium change, pooled, and stored at -70°C until the RNA was isolated.
RNA preparation.
Poly(A)+ RNA from cultured decidual cells was obtained using the Oligotex mRNA isolation kit (Qiagen, Valencia, CA) according to manufacturer’s instructions following initial total RNA isolation (11). The mRNA was purified by two passes through oligo d(T) columns.
RT-PCR analysis.
The relative amounts of prolactin and IGFBP-1 mRNA levels during decidualization of the decidual fibroblasts were determined by semiquantitative RT-PCR as described previously (39). For each assay sample, the amounts of prolactin and IGFBP-1 mRNAs were normalized to the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA content of the sample.
Northern blot analysis.
Verification of microarray results was accomplished by Northern blot analyses of RNA samples from an independent experiment in which decidual fibroblast cells were decidualized by a protocol identical to that used in the microarray experiment. The RNA samples from this experiment were analyzed for mRNA levels by Northern blot analyses using cDNA or DNA probes obtained from Incyte Genomics (St. Louis, MO): IGFBP-1 (Incyte clone 1448718), decorin (Incyte clone 3820761), epidermal growth factor (EGF)-containing fibulin-like extracellular protein-1 (Incyte clone 1798209), somatostatin (Incyte clone 2494617), tissue inhibitor of metalloproteinase 3 (TIMP3, Incyte clone 1998369), and endometrial bleeding associated factor (EBAF, Incyte clone 1865634). Equal loading and membrane transfer of RNA was verified by methylene blue staining of ribosomal bands. Quantitation of the signal on membranes was performed using a PhosphorImager screen (Molecular Dynamics, Sunnyvale, CA). The relative induction of the mRNAs determined by Northern blot analyses were then compared with that determined by microarray analyses.
DNA microarray.
DNA microarray analyses were performed using Cy3- and Cy5-labeled probes prepared from poly(A)+ mRNA from the fibroblast cells after 2, 4, 6, 9, 12 and 15 days of treatment. Microarray hybridizations were performed by Incyte Genomics (Palo Alto, CA) using the human GEM-V microarray. The reference "time 0" mRNA (Cy3) was prepared from untreated cells.
Primary data were examined using Incyte GEMTools software and GeneSpring software (Silicon Genetics, Redwood City, CA). Defective cDNA spots (irregular geometry, scratched, or <40% area compared with average) were eliminated from the data set. Data sets were subjected to normalization within each microarray experiment such that individual Cy5 spot intensities were multiplied by the ratio of the median intensity of the Cy3 channel to that of the Cy5 channel for all genes over the entire microarray (R = K x Cy5/Cy3). Each microarray contained 192 control genes present as nonmammalian single gene "spikes" or "complex targets." The complex targets consisted of probe sets that contain a pool of cellular genes expressed in most cell types. In addition, each experimental mRNA sample was augmented with incremental amounts of nonmammalian gene RNA (2x, 4x, 16x, etc.) to permit assessment of the dynamic range attained within each microarray. Little variation was observed across the microarray series with respect to the 192 control genes (not shown), providing support for interarray comparisons of temporally regulated genes.
We assembled a pool of genes that exhibited significant expression change during the cell culture period using a multistep procedure. Regulated genes were selected that exhibited a twofold increase or 50% decrease in their expression relative to the time 0 reference sample based upon the average gene expression value observed between any two adjacent time points. This maneuver filters out a significant noise component in the individual arrays but reduces the sensitivity to moderately regulated genes that are unique to a single time point. The dynamically regulated genes were clustered according to expression pattern dynamics by subjecting log2-transformed data series to K-means (17) and hierarchical tree clustering algorithms (13) as implemented in the GeneSpring program (Silicon Genetics). The hierarchical tree analysis was performed using a minimum distance value of 0.001, separation ratio of 0.5, and the standard correlation distance definition algorithm. The hierarchical tree structure was used to suggest approximate numbers of behavior sets for K-means clusters, and this was empirically confirmed by observing relatively consistent behaviors within the resulting sets. Too few groups resulted in sets composed of heterogeneously behaving genes, and too many groups led to adjacent sets that exhibited indistinguishable behavior.
Time-averaged microarray series.
Initial K-means analysis revealed that unique sets were formed on the basis of small behavior differences between subsequent time points that may have been attributable to technical variation or noise that was unrelated to biologic variation. For example, a gene that had a saw-tooth induction kinetic over the 0, 2, 4, 6, 9, 12, and 15 day time points would be grouped into a different set than one which had less of a saw-tooth component to its induction. We opted to decrease the noise contribution of the single microarray data point by using a time-averaged approach in which the average fold change of each gene at days 3, 5, 7.5, 10.5, and 13.5 was interpolated by averaging the two data points on either side. Although this decreases noise, it also decreases the ability to discern kinetic patterns that are confined to just one of the time points. However, based on the patterns of the vast majority of genes, the advantages of this approach appeared to greatly outweigh this potential disadvantage. A similar treatment was applied to the data set obtained from differentiating cytotrophoblast cells (2) to generate time-averaged values. This allowed for a comparison of regulatory behavior of genes between the decidual and trophoblast cells during differentiation.
Genes were classified into biological function groups by adaptation of the gene ontology classification we used previously in a study of human cytotrophoblast differentiation (2). To view all gene expression data, cluster groups, and the functional categories of the dynamically regulated genes, please refer to the Supplementary Material1 for this article, published online at the Physiological Genomics web site.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1; transgelin; regulator of G protein signaling 4; fibronectin 1; hexabrachion (tenascin C, cytotactin); and IGFBP-5. A complete list of the 100 most regulated genes, along with the accession numbers and fold change from day 0 level of expression is shown in Table 1.
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Divergent behaviors not only occurred in the same functional class but also in members of the same gene family. As shown in Fig. 6, family members of the integrin, collagen, and laminin gene families varied widely in their regulation during decidualization. In each gene family, one or two members were strongly induced while several others were strongly downregulated. Taken together, these findings support the hypothesis that efficient execution of some biologic processes, such as the modification of adhesion or tissue structure, is best accomplished by both induction and repression of individual genes within the category. Other gene categories illustrated the same theme of coordinate induction and repression, including metabolism and transcriptional and translational regulation.
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In an earlier study (2), we investigated the expression profiles of genes dynamically regulated during the differentiation of human cytotrophoblast cells to syncytiotrophoblast cells using the same microarrays used in the present study. We observed 397 genes that were regulated using the same criteria as applied to this study. To better appreciate those aspects of the decidual fibroblast differentiation program that were specific vs. those that might be related to in vitro cell culture per se or are representative of general differentiation processes that were independent of the cell type of origin, we sought to compare the relative behavior of the genes identified in each model. To make these comparisons, we combined the two experiments into a single series and compared the relative behavior of the pooled 569 genes dynamically regulated in either experiment to hierarchical tree cluster analysis. Most of the strongly upregulated and downregulated genes were unique to a single model (Fig. 7), with only 81 genes meeting selection criteria for both. Using the K-means algorithm, we were able to divide these 81 commonly regulated genes into 7 clusters that consisted of genes that exhibited a variety of induction and repression kinetics across the two cell types, with 52 of these exhibiting similar regulation and 29 completely opposite (data can be found in the Supplementary Material published online at the Physiological Genomics web site). Most of the induced genes that were in common to both cell types were related to metabolism, whereas most of the repressed genes were related to cytoskeletal organization and cell adhesion.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In an earlier report on genes changed during decidualization, Popovici and coworkers (34) performed DNA microarray analyses on human endometrial stromal cells after 10 days of exposure to progesterone or 2 days of exposure to cAMP. Of 588 genes screened, marked regulation was noted for cytokines, growth factors, nuclear transcription factors, members of the cyclin family, and mediators of the cAMP signal transduction pathway. Changes were also noted for the insulin receptor, some neurotransmitter receptors, neuromodulators, follicle-stimulating hormone receptor, inhibin/activin-ßA subunit, inhibin-, and tumor necrosis growth factor-related apoptosis-inducing ligand (TRAIL). The total number of regulated genes was not indicated, and only two downregulated genes were identified (monocyte chemotactic protein-1 receptor and Ca2+ calmodulin-dependent kinase type IV catalytic subunit). Unfortunately, the genes represented on Clontech human Atlas cDNA expression array used by these investigators do not overlap extensively with those on the Incyte human GEM-V microarray used in the present study, thus precluding a useful cross-comparison.
A major difference between our study and earlier investigations, including that of Popovici et al. (34), is that we examined gene expression at multiple intervals during the decidualization process. We observed several different inductive and repressive kinetic patterns associated with decidualization, and we were able to correlate the functions of genes to their expression patterns during decidualization. The patterns consisted of variable delays prior to induction or repression as well as several patterns with biphasic kinetics.
Earlier studies of endometrial stromal cell differentiation, usually performed by immunochemical analyses of tissue samples, showed marked changes in proteins involved in extracellular organization, cytoskeletal organization, and cell adhesion. Cadherin-11 (10), laminin (21), integrin-4 (fibronectin receptor), integrin-ß1, and integrin-5ß3 (28), and desmin and vimentin intermediate elements (9) were shown to increase during decidualization. Furthermore, the ratio of type III to type I collagen decreased, and the ratio of type V to type I collagen significantly increased (23) during the decidualization process. Our microarray studies also indicate striking changes in extracellular matrix protein genes during decidualization of decidual fibroblasts. There was early induction of the extracellular matrix proteins decorin and fibromodulin and early repression of collagen type X 1, collagen type XI 1, collagen type I 1, collagen type XVI 1, collagen type IV 1, laminin-4, integrin-4, vimentin, glypican-1, and fibronectin-1. There was also induction of the proteolytic enzymes matrix metalloproteinases-2 and -11 and TIMP3 and repression of plasminogen activator inhibitor type I. Taken together, these findings indicate that striking reprogramming of genes that determine extracellular matrix and tissue strength and integrity occurs during decidualization and suggest that these changes are a prominent feature of decidualization. Interestingly, previous studies using in vitro models showed no changes in integrin expression by immunofluorescence and flow cytometry in cultured endometrial stromal cells decidualized by treatment with progesterone and estrogen (18). In contrast, the microarray data presented here demonstrated changes in integrin expression during decidual fibroblast cell differentiation in vitro. Of note was the induction of integrin-4 (fibronectin receptor) expression, which is known to peak during mid-luteal phase and is downregulated in the endometrium of infertile women during implantation (35).
One of the earliest induced genes was the transcription factor forkhead O1A, which was originally isolated from a human alveolar rhabdomyosarcoma (38). The function of this member of the forkhead family member is unknown, but other members of the family have been implicated in the development of the lung and other tissues (19, 42). ID-3, a member of the inhibitors of DNA binding family, was also markedly induced. This binding protein acts as a negative helix-loop-helix protein that modifies the action of other HLX transcription factors (37). Changes in the expression of ID family members have been noted in several cell types during differentiation (3, 24), including placenta, but the role of the protein in decidualization is unknown.
Dramatic changes were observed in many members of the IGFBP family. IGFBP-1, which is widely recognized as a marker of decidualization in endometrial stromal cells (27), was the most induced gene in the decidual fibroblast cells undergoing differentiation, whereas IGFBP-5 was the most repressed gene. IGFBP-3 and IGFBP-4 were also induced. Decidual IGFBP-1 has been demonstrated to exert several different actions at the maternal-fetal interface and within the endometrium (15). IGFBP-1, which usually exists as a phosphorylated, high-affinity species, sequesters IGFs, thereby inhibiting their local action (15).
Our results support the hypothesis that there is a highly specific control network affecting IGF action at the maternal-fetal interface. Paracrine modulation of phosphorylated IGFBP-1, involving dephosphorylation and proteolysis by placental alkaline phosphatase and proteases that results in increased IGF bioavailability has been proposed (15). IGFBP-1 stimulates human extravillous trophoblast cell migration by signaling through integrin-5ß1 and the mitogen-activated protein kinase pathway (16). This supports a role for decidual IGFBP-1 in trophoblast invasion as well as during the menstrual cycle since secretory endometrium has significantly more IGFBP-1 than proliferative endometrium (12). IGFBP-5, the major binding protein in bone tissue, inhibits IGF binding to its receptor (25). The binding of IGFBP-5 to extracellular matrix leads to a decrease in its affinity for IGF-I and an increase in IGF-I bioavailability (32). Taken together, these findings strongly suggest that the differential expression of the IGFBPs during decidualization markedly affect the biological actions of IGFs.
There was also early induction of genes involved in the mitogen-activated protein (MAP) kinase signaling pathway (MAP kinase kinase kinase 5 and SH3-domain binding protein 5) as well as the TGF-ß1 family member genes EBAF and inhibin-ßA. Induced later were several other genes involved in the phosphoinositide signal transduction pathway (phosphatidic acid phosphatase 2b and phospholipase D1). At present, the roles of these signaling pathways in human decidualization are unknown.
In addition to prolactin and IGFBP-1, other genes induced in endometrial stromal cells during decidualization include c-Src kinase (29), ubiquitin cross-reactive protein (4), superoxide dismutase (40), fatty acid synthase (33), 11ß-hydroxysteroid dehydrogenase (1), and endothelin B (26). In contrast, the mRNA expression of CD63 (a transmembrane 4 superfamily member), which has been reported to be downregulated during progesterone-induced decidualization of human endometrial stromal cells (31), was unchanged in our analysis of decidualization.
The mechanisms for gene activation or mRNA repression during decidualization remain to be identified. Mechanisms could include both transcriptional and posttranscriptional activation of gene expression systems already in place within the untreated decidual cell, or through the synthesis of new gene products that impact on gene expression. The different kinetic patterns may represent the occurrence of multiple regulatory mechanisms. Repression is particularly intriguing since specific machinery for selective mRNA decay or accelerated turnover has not been described in the decidual cell.
Comparison of genes activated and repressed in the differentiation of trophoblasts and decidual fibroblasts demonstrated only limited overlap in their identities, with only 81 out of the 569 in common. Of the overlapping genes, many were reciprocally regulated. However, the great majority of the 569 fell into gene function categories that were of vital importance to both cell types, with extensive representation of genes related to cell and tissue structure and cell-cell interaction. Of particular interest is the fact that in both models there was strong downregulation of key members of these categories simultaneous with the induction of other members of the same categories. This suggests that "categorical reprogramming" is fundamental for the differentiation of both cell types but that the two cells differ in the genes that are induced and degraded during differentiation and that the two different lineages are engaged in very distinct programs. We believe that cross-comparative analyses will be a powerful approach to identifying and distinguishing gene expression patterns that play general and specific roles in biologic processes.
In summary, we have shown that decidualization comprises a highly dynamic gene program that significantly affects the mRNA levels of 281 of 6,918 individual genes queried. The genes regulated during this process differ markedly from those observed in cytotrophoblast differentiation, demonstrating the specificity of the two programs. Several distinct kinetic patterns were observed involving both induction and strong repression. We hypothesize that decidualization, like trophoblast differentiation, requires both activation and repression of a substantial number of genes and that distinct classes of regulated genes are responsible for decidualization. The first is the induction of gene products responsible for cell functions that were not necessary prior to differentiation but that play a role for differentiated cell functions. Examples would include hormone production, unique metabolic processes, or mediators of differentiation per se. The other class represents genes induced that are to replace existing gene products with those that cause the cell to switch structure and function. To accomplish this, we envision that cells must eliminate mRNAs of gene products that compete or interfere with specific biochemical or cell biological functions of the induced genes. Thus our hypothesis is that the successful accomplishment of cellular differentiation requires both the induction of the effectors of the differentiated cell as well as dynamic reprogramming of genes within functional pathways that are critical for both precursor and product cell lineages. The fact that trophoblast cells and decidual fibroblast cells both manifest the phenomena of categorical reprogramming, but do so with largely nonoverlapping genes, suggests that this may represent a fundamental aspect of cellular differentiation.
It remains to be determined the extent to which these patterns and individual gene behaviors are polymorphic in human populations. Some variance may be of little consequence; however, regulatory variance or allelism within some of these decidualization-associated genes may be associated with decreased fertility, increased risk of endometriosis, or other pathological processes.
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ACKNOWLEDGMENTS |
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This work was supported by National Institutes of Health Grant HD-15201. This work was also supported by an infrastructure grant to the University of Cincinnati College of Medicine from the Howard Hughes Medical Institute.
Portions of this work were presented at the 83rd Annual Meeting of the Endocrine Society, in Denver, CO, July 2001.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. K. Brar, Dept. of Endocrinology, Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-2029 (E-mail: Anoop.Brar{at}).
1 Supplementary Material to this article is available online at http://physiolgenomics.physiology.org/cgi/content/full/7/2/ 135/DC1. 
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J.J. Kim, O.L. Buzzio, S. Li, and Z. Lu Role of FOXO1A in the Regulation of Insulin-Like Growth Factor-Binding Protein-1 in Human Endometrial Cells: Interaction with Progesterone Receptor Biol Reprod, October 1, 2005; 73(4): 833 - 839. [Abstract] [Full Text] [PDF]
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C.A. White, E. Dimitriadis, A.M. Sharkey, and L.A. Salamonsen Interleukin-11 inhibits expression of insulin-like growth factor binding protein-5 mRNA in decidualizing human endometrial stromal cells Mol. Hum. Reprod., September 1, 2005; 11(9): 649 - 658. [Abstract] [Full Text] [PDF]
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C. A White and L. A Salamonsen A guide to issues in microarray analysis: application to endometrial biology Reproduction, July 1, 2005; 130(1): 1 - 13. [Abstract] [Full Text] [PDF]
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 M. Tang, H. S. Taylor, and S. Tabibzadeh In vivo gene transfer of lefty leads to implantation failure in mice Hum. Reprod., July 1, 2005; 20(7): 1772 - 1778. [Abstract] [Full Text] [PDF]
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G. Nie, Y. Li, M. Wang, Y. X. Liu, J. K. Findlay, and L. A. Salamonsen Inhibiting Uterine PC6 Blocks Embryo Implantation: An Obligatory Role for a Proprotein Convertase in Fertility Biol Reprod, April 1, 2005; 72(4): 1029 - 1036. [Abstract] [Full Text] [PDF]
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H. Okada, G. Nie, and L. A. Salamonsen Requirement for Proprotein Convertase 5/6 during Decidualization of Human Endometrial Stromal Cells in Vitro J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1028 - 1034. [Abstract] [Full Text] [PDF]
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K. Shazand, S. Baban, C. Prive, B. Malette, P. Croteau, M. Lagace, J.-B. Racine, and P. Hugo FOXO1 and c-jun transcription factors mRNA are modulated in endometriosis Mol. Hum. Reprod., December 1, 2004; 10(12): 871 - 877. [Abstract] [Full Text] [PDF]
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J. Mazella, M. Tang, and L. Tseng Disparate effects of relaxin and TGF{beta}1: relaxin increases, but TGF{beta}1 inhibits, the relaxin receptor and the production of IGFBP-1 in human endometrial stromal/decidual cells Hum. Reprod., July 1, 2004; 19(7): 1513 - 1518. [Abstract] [Full Text] [PDF]
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S. K. Dey, H. Lim, S. K. Das, J. Reese, B. C. Paria, T. Daikoku, and H. Wang Molecular Cues to Implantation Endocr. Rev., June 1, 2004; 25(3): 341 - 373. [Abstract] [Full Text] [PDF]
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 N. Sakai, T. Maruyama, R. Sakurai, H. Masuda, Y. Yamamoto, A. Shimizu, I. Kishi, H. Asada, S. Yamagoe, and Y. Yoshimura Involvement of Histone Acetylation in Ovarian Steroid-induced Decidualization of Human Endometrial Stromal Cells J. Biol. Chem., May 2, 2003; 278(19): 16675 - 16682. [Abstract] [Full Text] [PDF]
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G.-Y. Nie, Y. Li, H. Minoura, J. K. Findlay, and L. A. Salamonsen Specific and Transient Up-Regulation of Proprotein Convertase 6 at the Site of Embryo Implantation and Identification of a Unique Transcript in Mouse Uterus During Early Pregnancy Biol Reprod, February 1, 2003; 68(2): 439 - 447. [Abstract] [Full Text] [PDF]
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 S. Handwerger and B. Aronow Dynamic Changes in Gene Expression During Human Trophoblast Differentiation Recent Prog. Horm. Res., January 1, 2003; 58(1): 263 - 281. [Abstract] [Full Text] [PDF]
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