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  • 1. Biochimica et Biophysica Acta 1822 (2012) 19311942Contents lists available at SciVerse ScienceDirectBiochimica et Biophysica Actajournal homepage: www.elsevier .com/locate/bbadisThe genomics of the human endometrium,Maria Ruiz-Alonso a, David Blesa b, Carlos Simn c,a IVIOMICS, Parc Cientific Universitat de Valencia, Calle Catedrtico Agustn Escardino, 9, 46980 Paterna, Valencia, Spainb IVI Foundation, Parc Cientific Universitat de Valencia, Calle Catedrtico Agustn Escardino, 9, 46980 Paterna, Valencia Spainc University of Valencia, Department of Paediatrics, Obstetrics and Gynaecology, Faculty of Medicine, Avenida Blasco Ibaez, 15, 46010, Valencia, Spaina r t i c l e i n f o a b s t r a c tArticle history:Received 14 December 2011Received in revised form 4 April 2012Accepted 6 May 2012Available online 24 May 2012Keywords:EndometriumTranscriptomicMenstrual cycleReceptivityInfertilityThe endometrium is a complex tissue that lines the inside of the endometrial cavity. The gene expression ofthe different endometrial cell types is regulated by ovarian steroids and paracrine-secreted molecules fromneighbouring cells. Due to this regulation, the endometrium goes through cyclic modifications which canbe divided simply into the proliferative phase, the secretory phase and the menstrual phase. Successful em-bryoimplantation depends on three factors: embryo quality, the endometrium's state of receptivity, and asynchronised dialogue between the maternal tissue and the blastocyst. There is a need to characterise theendometrium's state of receptivity in order to prevent reproductive failure. No single molecular or histolog-icalmarker for this status has yet been found. Here, we review the global transcriptomic analyses performedin the last decade on a normal human endometrium. These studies provide us with a clue about what globalgene expression can be expected for a non-pathological endometrium. These studies have shown endometri-alphase-specific transcriptomic profiles and common temporal gene expression patterns. We summarise thebiological processes and genes regulated in the different phases of natural cycles and present other works ondifferent conditions as well as a receptivity diagnostic tool based on a specific gene set profile. This article ispart of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure. 2012 Elsevier B.V. All rights reserved.1. IntroductionThe endometrium is a complex tissue that lines the inside of the en-dometrialcavity. It is morphologically divided into functional and basallayers. The functional layer occupies two thirds of the endometrialthickness and it presents different cellular compartments: the luminalepithelium, the glandular epithelium, stroma and the vascular compart-ments.The epitheliumis composed of epithelial cells that may be on thesurface or coat epithelial glands, and the stroma consists of an extracel-lularmatrix (ECM) and fibroblasts that differentiate during thedecidualization process. In the stroma, blood vessels (spiral arteries)are also present, alongwith immune resident cells such asmacrophagesand NK cells [13]. Regarding their function, the functional layer is re-sponsiblefor proliferation, secretion and tissue degeneration, whilethe regenerative capacity of this organ lies in the basal layer [24].The gene expression of the different endometrial cell types is reg-ulatedby ovarian steroids and paracrine-secreted molecules fromneighbouring cells. Due to this endocrine/paracrine regulation, theendometrium goes through cyclic modifications which compose theendometrial cycle. An endometrial cycle can be divided simply intothe proliferative phase, corresponding to the follicular phase in theovary, the secretory phase, corresponding to the luteal phase in theovary, and the menstrual phase. The first day of the endometrialcycle corresponds to the beginning of the menstrual phase (the firstday of menstrual bleeding) and desquamation of the functionallayer takes place during this phase. From the menstrual phase to ovu-lation,the proliferative phase takes place and, at this time, oestrogenlevels begin to rise, leading to not only a proliferation of stromal cellsand glands, but to the elongation of spiral arteries. Finally, the secre-toryphase is defined as the time between ovulation and menstrua-tion.The beginning of this phase is characterised by a rise inprogesterone levels [4]. The secretory phase has been the most stud-iedbecause, in this phase, the endometrium acquires a receptive phe-notypewhich allows the implantation of the blastocyst. This period ofreceptivity is known as the Window of implantation (WOI). TheWOI opens on day 19 or 20 of the cycle, and lasts 45 days [5]. If im-plantationdoes not occur, the progesterone and oestrogen levels de-crease,accompanying a vasoconstriction of the spiral arteries andleading to involution of the endometrium; then the cycle startsagain [4].It is generally accepted that successful implantation depends onthree factors: embryo quality, the endometrium's state of receptivity,and a synchronised dialogue between the maternal tissue and the This article is part of a Special Issue entitled: Molecular Genetics of HumanReproductive Failure.Disclosures: The authors declare that they have competing interests. CS is theinventor of the patent application, AX090139WO, covering the Endometrial Recep-tivityArray (ERA). All the authors work full- or part-time for IVIOMICS, which com-mercialisesthe ERA. Corresponding author. Tel.: +34 963903305; fax: +34 963902522.E-mail addresses: maria.ruiz@iviomics.com (M. Ruiz-Alonso), David.Blesa@ivi.es(D. Blesa), Carlos.Simon@ivi.es (C. Simn).0925-4439/$ see front matter 2012 Elsevier B.V. All rights reserved.doi:10.1016/j.bbadis.2012.05.004

2. 1932 M. Ruiz-Alonso et al. / Biochimica et Biophysica Acta 1822 (2012) 19311942blastocyst (as cited in [6]). This dialogue is the result of a series ofcomplex autocrine, paracrine and/or juxtacrine interactions of differ-entmolecules and their receptors, which are expressed in a coordi-natedmanner in the endometrium and/or the embryo [7,8]. Theembryo implantation process can be summarised as follows: the em-bryo,in the morula stage, enters the uterine cavity where it continuesto divide to form the blastocyst. This happens in a defined time periodof between 72 and 96 h after fertilisation. Once inside the uterine cav-ity,a dialogue is established between the blastocyst and the receptiveendometrium, mediated by hormones and growth factors (reviewedin [9]), and the blastocyst is oriented correctly (apposition). The blas-tocystthen comes into contact with the endometrial epithelium andadheres to its surface (adhesion). Following this, penetration of theendometrium by the blastocyst occurs (invasion) (reviewed in[2,10]). This process is mediated by immune cells, cytokines, growthfactors, chemokines and adhesion molecules (reviewed in [9]). Toreach this point, the endometrium needs to display a proper, coordi-natedgene expression regulation during the whole endometrialcycle.1.1. Transcriptomics of the human endometriumDuring the endometrial cycle, there are morphological and func-tionalchanges that are specific to each menstrual cycle phase andwhich are caused by the response of the different endometrial celltypes to steroid hormones and paracrine molecules. Since 1950, thehistological point of view has been used for endometrial dating [11].Afterwards, the need to understand the genetic mechanism underly-ingthe histological changes emerged. Before the genomic era, re-searcherswere limited to studying gene by gene to determine themolecular changes responsible for the alterations observed. Howeverin the genomic era, the general trend is a global screening of all thegenes transcribed and their interactions [12]. So in the last decade,the transcriptional mechanisms underlying endometrial biologyhave been broadly investigated.For global transcriptomic analyses, the preferred technique hasbeen microarray-based gene expression (for a review see: [1221]).Table 1 summarises some of the most representative reviews on en-dometrialtranscriptomics in natural cycles analysed by microarraytechnology. Nevertheless despite its obvious advantages, this tech-nologyis not without its limitations [12,14]. Ponnampalam et al.[22] were the first authors to propose the transcriptomic characteri-sationof the human endometrium throughout the menstrual cycleby using this technology as an alternative to histological dating. How-ever,other groups had previously used this tool to search for a molec-ularsignature of receptivity [2326].Endometrial transcriptomics studies could be classified accordingto their main objective: firstly, identification of the transcriptomicphysiological profile in each endometrial cycle phase (with emphasisplaced on endometrial receptivity) [2238]; secondly, a comparisonbetween the endometrial profiles of fertile patients and those withrecurrent implantation failure [3941]; thirdly, comparisons of pro-filesbetween healthy women and women with endometrial pathol-ogies[42,43]; and finally, studies on the altered transcriptomicprofiles following different ovarian stimulation protocols [44,45].Table 2 lists some of the most representative original papers on en-dometrialtranscriptomics in natural cycles analysed by microarraytechnology.There is some disagreement among transcriptomic studies, whichmay be attributed to differences in experimental designs, in the typeof array used (distinct probes in different arrays), sampling conditions,sample selection criteria, sample size, day of the cycle when the sampleTable 1Reviews on endometrial transcriptomics.Authors Date ReferenceGiudice, L.C. 2003 [19]Horcajadas et al. 2004 [13]White and Salamonsen 2005 [14]Sherwin et al. 2006 [12]Giudice, L.C. 2006 [16]Simmen and Simmen 2006 [15]Horcajadas et al. 2007 [20]Aghajanova et al. 2008 [17]Aghajanova et al. 2008 [21]Haouzi et al. 2011 [18]Table 2Origina

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