Application of functional genomics to primate endometrium: Insights into biological processes

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, 505 Parnassus, M1496, Box 0132, San Francisco, CA 94143-0132, USA.
Reproductive Biology and Endocrinology (Impact Factor: 2.23). 02/2006; 4 Suppl 1(Suppl 1):S4. DOI: 10.1186/1477-7827-4-S1-S4
Source: PubMed


Endometrium is a dynamic tissue that responds on a cyclic basis to circulating levels of the ovarian-derived steroid hormones, estradiol and progesterone. Functional genomics has enabled a global approach to understanding gene regulation in whole endometrial tissue in the setting of a changing hormonal milieu. The proliferative phase of the cycle, under the influence of estradiol, has a preponderance of genes involved in DNA synthesis and cell cycle regulation. Interestingly, genes encoding ion channels and cell adhesion, as well as angiogenic factors, are also highly regulated in this phase of the cycle. After the LH surge, different gene expression profiles are uniquely observed in the early secretory, mid-secretory (window of implantation), and late secretory phases. The early secretory phase is notable for up-regulation of multiple genes and gene families involved in cellular metabolism, steroid hormone metabolism, as well as some secreted glycoproteins. The mid-secretory phase is characterized by multiple biological processes, including up-regulation of genes encoding secreted glycoproteins, immune response genes with a focus on innate immunity, and genes involved in detoxification mechanisms. In the late secretory phase, as the tissue prepares for desquamation, there is a marked up-regulation of an inflammatory response, along with matrix degrading enzymes, and genes involved in hemostasis, among others. This monograph reviews hormonal regulation of gene expression in this tissue and the molecular events occurring therein throughout the cycle derived from functional genomics analysis. It also highlights challenges encountered in using human endometrial tissue in translational research in this context.

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    • "Our literature search (see Supplementary data, Table S1 and Figure S1) resulted in over 160 relevant manuscripts (61% of all identified 'omics' studies) (Figure 1). Endometrial transcriptomics has been applied to many aspects of endometrial physiology and pathophysiology, including the normal menstrual cycle (see reviews Horcajadas et al., 2004; White and Salamonsen, 2005; Giudice, 2006; Sherwin et al., 2006; Horcajadas et al., 2007; Aghajanova et al., 2008a, b; Bellver et al., 2012; Haouzi et al., 2012; Ruiz-Alonso et al., 2012), implantation and implantation failure (see reviews Toth et al., 2011; Koot et al., 2012), infertility including treatment protocols (see reviews Martinez-Conejero et al., 2007; Ruiz-Alonso et al., 2012), the impact of endometriosis (see reviews Matsuzaki, 2011; Fassbender et al., 2012a, b), endometrial cancer (see reviews Sherwin et al., 2006; Doll et al., 2008) and others (see reviews Horcajadas et al., 2007; Ruiz-Alonso et al., 2012; Garrido-Gomez et al., 2013). While any given study yields numerous candidate genes to explore, the number of genes, which have been identified in more than one study as potential biomarkers in endometrial physiology and pathophysiology, has remained somewhat small. "
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    ABSTRACT: BACKGROUND'Omics' high-throughput analyses, including genomics, epigenomics, transcriptomics, proteomics and metabolomics, are widely applied in human endometrial studies. Analysis of endometrial transcriptome patterns in physiological and pathophysiological conditions has been to date the most commonly applied 'omics' technique in human endometrium. As the technologies improve, proteomics holds the next big promise for this field. The 'omics' technologies have undoubtedly advanced our knowledge of human endometrium in relation to fertility and different diseases. Nevertheless, the challenges arising from the vast amount of data generated and the broad variation of 'omics' profiling according to different environments and stimuli make it difficult to assess the validity, reproducibility and interpretation of such 'omics' data. With the expansion of 'omics' analyses in the study of the endometrium, there is a growing need to develop guidelines for the design of studies, and the analysis and interpretation of 'omics' data.METHODS Systematic review of the literature in PubMed, and references from relevant articles were investigated up to March 2013.RESULTSThe current review aims to provide guidelines for future 'omics' studies on human endometrium, together with a summary of the status and trends, promise and shortcomings in the high-throughput technologies. In addition, the approaches presented here can be adapted to other areas of high-throughput 'omics' studies.CONCLUSIONA highly rigorous approach to future studies, based on the guidelines provided here, is a prerequisite for obtaining data on biological systems which can be shared among researchers worldwide and will ultimately be of clinical benefit.
    Full-text · Article · Sep 2013 · Human Reproduction Update
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    • "GATHER was unable to identify any significant pathway for the 27 mRNAs that were differentially expressed by both cell types. Further, there was an up-regulation of secreted glycoprotein mRNAs in the glands in the potentially receptive samples as reported previously (Giudice, 2006). The glycoproteins that were increased in expression were the mucins MUC 6 and MUC 20 as well as ceruloplasmin (CP). "
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    ABSTRACT: To use contemporary biochemical markers to characterize mRNA/gene expression in the potentially fertile secretory endometrium to confirm its identification based on histological characteristics in order to develop a clinically applicable test. Nine, fertile, cycling Caucasian women were sampled from one IVF clinic. Endometrial samples were collected from them in two to four menstrual cycles at 2 and 7 days post first significant rise in blood LH. Separate endometrial glands and stroma populations were obtained by laser microdissection. Linear polymerase chain reaction amplified mRNAs which were hybridized to both Affymetrix U133 Plus2 and Agilent 4 × 44K microarrays followed by gene set analysis. Four histopathologists reviewed the sample set using the same histological criteria to date and characterize the non-receptive and potentially receptive samples. mRNA expression of microdissected glands and stroma provided molecular signatures that characterized the two specific phases of the cycle with distinct clustering patterns. Cell proliferation and five other associated biological pathways were significantly down-regulated when the endometrium is considered potentially receptive accompanied by an increase in secreted glycoproteins mRNAs in the potentially receptive glands. Reported histological findings identified the presence of one histological feature characteristic of each phase: glandular mitoses indicated a non-receptive endometrium, whereas a potentially receptive endometrium was distinguished by supranuclear vacuolation. This study defined a transcriptome characteristic of active cell proliferation in the non-receptive samples with a marked overall down-regulation of this pathway in potentially receptive samples-suggesting a transitional state associated with receptivity but not implantation. However, microarrays involve expensive, specialized testing and require significant post-data analysis. Sampling according to endocrinological and molecular prediction improved the consistency of histological assessment and allowed reliable histological markers of glandular mitosis in the non-receptive phase and supranuclear vacuolation of the potentially receptive endometrium to be identified. Thus, histology can provide an affordable, clinically applicable test in the context of reproduction.
    Full-text · Article · Jun 2012 · Human Reproduction
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    • "The cited studies conclude that it is possible to accurately catalogue endometria at different stages based on their transcriptomic profiles, thus facilitating the transition from the anatomical to the molecular medicine of the human endometrium [16] "
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    ABSTRACT: The endometrium is a complex tissue that lines the inside of the endometrial cavity. The gene expression of the different endometrial cell types is regulated by ovarian steroids and paracrine-secreted molecules from neighbouring cells. Due to this regulation, the endometrium goes through cyclic modifications which can be divided simply into the proliferative phase, the secretory phase and the menstrual phase. Successful embryo implantation depends on three factors: embryo quality, the endometrium's state of receptivity, and a synchronised dialogue between the maternal tissue and the blastocyst. There is a need to characterise the endometrium's state of receptivity in order to prevent reproductive failure. No single molecular or histological marker for this status has yet been found. Here, we review the global transcriptomic analyses performed in the last decade on a normal human endometrium. These studies provide us with a clue about what global gene expression can be expected for a non-pathological endometrium. These studies have shown endometrial phase-specific transcriptomic profiles and common temporal gene expression patterns. We summarise the biological processes and genes regulated in the different phases of natural cycles and present other works on different conditions as well as a receptivity diagnostic tool based on a specific gene set profile. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.
    Preview · Article · May 2012 · Biochimica et Biophysica Acta
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