Available online at www.sciencedirect.com Theriogenology 76 (2011) 589–597 0 d Review Gene expression in placentation of farm animals: An overview of gene function during development R.S.N. Barretoa,b,1, F.F. Bressana,1, L.J. Oliveiraa,1, F.T.V. Pereirac, F. Perecina, C.E. Ambrósioa, F.V. Meirellesa, M.A. Miglinob,* a Department of Basic Sciences, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, SP, Brazil b Sector of Animal Anatomy, Department of Surgery, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo, SP, Brazil c Faculty of Animal Sciences, Paulista State University, Dracena, SP, Brazil Received 22 June 2010; received in revised form 28 February 2011; accepted 1 March 2011 Abstract Eutherian mammals share a common ancestor that evolved into two main placental types, i.e., hemotrophic (e.g., human and mouse) and histiotrophic (e.g., farm animals), which differ in invasiveness. Pregnancies initiated with assisted reproductive techniques (ART) in farm animals are at increased risk of failure; these losses were associated with placental defects, perhaps due to altered gene expression. Developmentally regulated genes in the placenta seem highly phylogenetically conserved, whereas those expressed later in pregnancy are more species-specific. To elucidate differences between hemotrophic and epitheliochorial placentae, gene expression data were compiled from microarray studies of bovine placental tissues at various stages of pregnancy. Moreover, an in silico subtractive library was constructed based on homology of bovine genes to the database of zebrafish — a nonplacental vertebrate. In addition, the list of placental preferentially expressed genes for the human and mouse were collected using bioinformatics tools (Tissue-specific Gene Expression and Regulation [TiGER] — for humans, and tissue-specific genes database (TiSGeD) — for mice and humans). Humans, mice, and cattle shared 93 genes expressed in their placentae. Most of these were related to immune function (based on analysis of gene ontology). Cattle and women shared expression of 23 genes, mostly related to hormonal activity, whereas mice and women shared 16 genes (primarily sexual differentiation and glycoprotein biology). Because the number of genes expressed by the placentae of both cattle and mice were similar (based on cluster analysis), we concluded that both cattle and mice were suitable models to study the biology of the human placenta. © 2011 Elsevier Inc. All rights reserved. Keywords: Epitheliochorial placenta; Gene expression; Transcription factors; Placenta-specific genes; Farm animals Contents 1. Introduction .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590 2. Genes and early development: from pluripotency to established pregnancy ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591 3. Gene expression on placentation and embryonic development .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593 3.1. Gene expression and trophoblast invasion .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594 1 Contributed equally as first author. * Corresponding author. Tel.: �55 11 3091 7690; fax: �55 11 3091 7805. www.theriojournal.com E-mail address: miglino@usp.br (M.A. Miglino). 093-691X/$ – see front matter © 2011 Elsevier Inc. All rights reserved. oi:10.1016/j.theriogenology.2011.03.001 mailto:miglino@usp.br f t ( [ p b t t c p v i l t t c n w t s o t w c s c p f i c c u ( 590 R.S.N. Barreto et al. / Theriogenology 76 (2011) 589–597 3.2. Imprinted genes .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595 4. Conclusions .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595 References .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595 a i c t c c e f o d p b e n c s p 1. Introduction Adequate placentation is crucial for maintenance of pregnancy. Communication between the chorionic epithe- lium and endometrium promotes fetal development and survival by providing nutrition, gas transport, immunolog- ical and physical protection, and waste product removal [1,2]. Furthermore, the placenta secretes a wide range of molecules important to support pregnancy, e.g., hormones (estrogens, progesterone, placental lactogens, etc.) [1–4]. Epitheliochorial placentation occurred as a specialization rom an ancestral hemotrophic placenta [5]. During evolu- ion, a common ancestor with a bipotential placenta type hemotrophic and histiotrophic) evolved into four branches 5]. The two low branches of eutherian evolution are com- osed only of a hemotrophic placenta type, and the other two y a miscellaneous category (between hemotrophic and his- iotrophic placental types [5]; Fig. 1). Furthermore, evolu- ionary pressure for development of the epitheliochorial pla- enta could be a consequence of the need for more efficient lacental transport [6], increased maternal control over the ascular supply to the conceptus [7], or as a strategy for mmunological defense [8]. In epitheliochorial placentation, the maternal epithe- ium is preserved, whereas in the hemotrophic placenta, rophoblast cells invade maternal tissue up to the endo- helial layer [2]. Therefore, the epitheliochorial placenta is onsidered a less invasive placenta, because fetal cells do ot bypass the endometrial basal membrane [9,10]. Not- ithstanding, there is migration of fetal cells toward ma- ernal tissues, i.e., binucleate trophoblast cells in cattle and heep, with synepitheliochorial placentae [2]. Migration f these cells facilitated the exchange of hormones be- ween maternal and fetal tissues [9–15]. Moffett and Loke [8] raised the question regarding hether the ability of invasion of trophoblast cells was ontrolled by specific gene expression in those cells, pecifically expression of major histocompatibility omplex (MHC) class I classical and nonclassical. Tro- hoblast cells downregulated expression of the classic orm of MHC class I and upregulated nonclassical soforms [16]. In humans and mice, expression of non- lassical molecules was widely reported and the spe- ific biological role of these nonclassical MHC is still nder investigation. The human leukocyte antigen HLA) G was heavily expressed by the human placenta; it was also expressed in two main isoforms (membrane bound and soluble [17]). The HLAG can interact with inhibitory receptors of natural killer (NK) cells, e.g., im- munoglobulin-like transcript (ILT) -2 and -4 [18]; these receptors were also present on other immune cells (i.e., macrophages and dendritic cells [19]). Furthermore, HLAG was detected systemically in pregnant women [20] and probably had a role in pregnancy-related immune changes in human. Local and systemic effects of HLAG expression during pregnancy are not yet fully understood, but the lower expression of HLAG can activate uterine natural killer cells against trophoblast cells, and thereby induce trophoblast invasion [21]. Although maternal fetal interactions vary broadly among species, some characteristics of placentae are maintained, e.g., occurrence of imprinted genes [2,22]. Allelic expression of specific genes may explain the pa- rental conflict theory, i.e., that paternal genes will maxi- mize fetal development to increase nutrient supply to the fetus, even to the detriment of the dam’s life, for example insulin growth factor 2 (IGF2) [23]. Conversely, the dam will protect herself by suppressing expression of growth- induced genes by the maternal allele [23]. The imprinting status of certain genes would confer to the dam greater control over fetal development, without deleterious effects on fetal development or the life of the dam [5]. Recent activities, especially the increased use of ssisted reproductive techniques (ARTs) in livestock, .e., in vitro fertilization (IVF) or cloning by somatic ell nuclear transfer (SCNT), highlighted the impor- ance of adequate placental function to pregnancy suc- ess (at all stages of pregnancy). There is a clear asso- iation between ARTs and placental defects [24–26], mphasizing the need to elucidate similarities and dif- erences of placental anatomy and function for species ther than just humans and mice [24,26]. One consequence of producing embryos by SCNT was eregulation of gene expression, especially during the reimplantation period, compared with producing em- ryos by IVF, AI, or natural service [26]. Disrupted gene xpression in SCNT embryos may occur due to failures of uclear reprogramming and/or suboptimal in vitro embryo ulture conditions [27,28]. For example, abnormal expres- ion of imprinted genes, e.g., imprinted maternally ex- ressed transcript (non-protein coding) gene H19 and in- sulin growth factor 2 receptor (IGF2R) by SCNT embryos, H H M � N e 591R.S.N. Barreto et al. / Theriogenology 76 (2011) 589–597 caused pregnancy losses from preimplantation to neonatal life in sheep, cattle, and mice [25,29]. The purpose of this review is to compile current data regarding gene expression of placenta among livestock (represented mainly by cattle) and to compare that with humans and mice, highlighting similarities and differ- ences with regards to placental type. Fig. 1. Phylogenetic tree of therian mammals. Eutherians are the u Afrotheria clades, Marsupials are an out-group. Blue subscriptions a model according to Vogel [5]. Table 1 Expression of transcription factors at four-cell, eight-cell, and blasto Species Four-cell stage POU5F1 NANOG SOX2 POU5F Cattle N/A N/A N/A N/A Pigs � � � � orses N/A N/A N/A N/A umans � � � � ice N/A N/A N/A N/A , gene expressed but spatial expression unknown; –, gene not expre ANOG, Nanog homeobox; POU5F1, POU domain, class 5, transc xpressed by epithelial trophectoderm cells. 2. Genes and early development: from pluripotency to established pregnancy Expression of a triad of transcription factors, namely POU domain, class 5, transcription factor 1 (POU5F1), Nanog homeobox (NANOG), and SRY (sex determin- ing region Y)-box 2 (SOX2), was essential for mainte- Laurasiatheria (green), Euarchontoglires (yellow), Xenarthra, and ns with histiotrophic placenta and black hemotrophic. Phylogenetic ges of cattle, pigs, horses, humans, and mice [30,32,34–38]. t-cell stage Blastocyst stage NANOG SOX2 POU5F1 NANOG SOX2 N/A N/A ICM/TE ICM � � � ICM/TE ICM � N/A N/A ICM/TE ICM/TE TE � � � � � N/A N/A ICM ICM � M, gene expressed by cells of inner cell mass; N/A, not applicable; factor 1; SOX2, SRY (sex determining region Y)-box 2; TE, gene nion of re theria cyst sta Eigh 1 ssed; IC ription 592 R.S.N. Barreto et al. / Theriogenology 76 (2011) 589–597 Fig. 2. Ontology of placental genes of humans, mice, and cattle, compared with a zebrafish orthologous database. (a) Ontology of genes in a mouse cluster. (b) Ontology of genes in cattle cluster. (c) Ontology of genes in human cluster. (d) Venn diagram of placenta preferential expressed genes in humans and mice, bovine placental genes from array studies, and zebrafish orthologous. (e) Ontology of common genes among human and mouse clusters. (f) Ontology of common genes among human and cattle clusters. (g) Ontology of common genes among human, mouse, and 593R.S.N. Barreto et al. / Theriogenology 76 (2011) 589–597 nance of self-renewal and pluripotency of embryonic stem (ES) cells and inner cell mass (ICM) cells [30]. Transcription of POU5F1, NANOG, and SOX2 were tightly regulated by each other, in a regulatory loop manner [30–32]. According to Adachi [32], downregu- lation of POU5F1 in human ES cells led to SOX2 and NANOG downregulation. In addition, lower expression of NANOG caused downregulation of POU5F1, but not SOX2. However, downregulation of SOX2 induced signif- icant decreases in NANOG expression. Furthermore, upregulation of SOX2 resulted in de- creased expression of POU5F1 and NANOG. Synergis- tically, POU5F1, NANOG, and SOX2 regulated tran- scription of their target genes. It was noteworthy that these three factors interacted with 3%, 9%, and 7%, respectively, of the promoter regions of approximately 18 000 genes in human ES cells [33]. However, ex- pression of these transcription factors did not happen in the same manner in all mammals. For example, porcine embryos expressed POU5F1 at both the four and eight cell stages of embryonic development, whereas expres- sion of NANOG and SOX2 started at eight cell to blastocyst stages [30,34]. To date, there are apparently no data regarding expression of POU5F1, NANOG, and SOX2 in bovine or equine embryos until the blastocyst stage, when POU5F1 and NANOG were expressed by both trophectoderm and the inner cell mass. Moreover, in mice, expression of POU5F1 was reported only at the eight cell stage [30], with no data for expression of NANOG or SOX2. At the blastocyst stage, all three transcription factors were expressed in bovine, porcine, equine, and murine embryos, albeit with some spatial differences (Table 1). Little is known about mechanisms underlying pluri- potency of embryonic stem cells (ES cells) in farm animal species. For example, the optimal time to initi- ate a blastocyst-derived cell culture for establishing ES cell lines is unknown [39]. A better understanding of how ES cells maintained their undifferentiated status could elucidate core mechanisms to establish ES cell lines in species of interest, e.g., cattle and pigs [30]. Protocols to establish ES cell lines in farm animals could be used to develop animal models, other than those involving primates or mice, for example, to study human genetic disorders and cellular therapy. More- over, ES cell lines could be used to produce transgenic cattle clusters. (h) Distance analysis of developmental status of pla graphics are represented by number of daughters in each mother fu human; M, mouse; C, cattle; Z, zebrafish; �, intersection among groups. animals (to improve specific traits and to use them as bioreactors for the biopharmacy industry [39]). Characterization of the bovine genome [40] revealed that humans and cattle shared 1791 genes, whereas humans and rodents shared 1481 orthologous genes, making cattle 21% more similar to humans than mice. Based on genetic similarities between cattle and hu- mans, the former were a suitable model for human genetic research, such as gene therapy [41]. 3. Gene expression on placentation and embryonic development In general, developmentally regulated genes were largely conserved phylogenetically across placental types. Nevertheless, genomic mechanisms that lead to emergence and diversification of the eutherian placenta remain unknown [42]. In mice, during early pregnancy, the decidua and the placenta mainly express genes that have eukaryote an- cient origins [42]. Later in pregnancy, gene expression is more based on rodent-specific genes that appeared later in evolution. Similarly, in humans, ancient genes are mainly expressed in early stages of gestation, whereas the expression of primate-specific genes arise during later stages of pregnancy [42]. Consequently, it is not surpris- ing that genes expressed during mouse development are expected to be present in other mammals. To understand similarities and differences among placental types, we searched for published data on placental gene expression, focusing on human, murine, and bovine models. In the present study, microarray data in gene expression of placenta were compiled into a list of genes expressed in placental tissues at various stages of pregnancy in cattle [4,43–50]. Microarray data alone highlighted genes involved in cell metabo- lism, the cell cycle, and other core cellular processes not specifically involved in placental function. Also, the wide variety of protocols for producing and analyzing data regarding global expression experiments did not make microarray data a tissue-specific gene expression database. To minimize this effect, we searched the expression of the listed genes on the database of ze- brafish as a strategy to generate in silico a subtractive library for placental genes in cattle. enes in human, mouse, and cattle. (a–c) and (e–f) Percentages in group of total daughter functional groups in each gene cluster. H, cental g nctional x a ( h e u o e m n i v 594 R.S.N. Barreto et al. / Theriogenology 76 (2011) 589–597 Likewise, using the Tissue-specific Gene Expression and Regulation (TiGER; http://bioinfo.wilmer.jhu.edu/ tiger/) database [51], we recovered a list of preferen- tially expressed genes in the human placenta, and using Tissue-Specific Genes Database (TiSGED; http://bioinf. mu.edu.cn/databases/TiSGeD/index.html) to human nd mouse [52]. In TiSGED a specific measure value SPM) varying from 0.0 to 1.0 (whereas genes with igher SPM values are more likely to be specifically xpressed in a given tissue than genes with lower val- es of SPM) is required before gene list acquisition; for ur analysis, the SPM was set at 0.8. This setting xcluded some genes commonly expressed in the ouse placenta, e.g., insulin growth factor 2 (IGF2) did ot appear in the mouse list. The SPM value for IGF2 s 0.6, compared with human which is 0.8. The SPM alues suggest that IGF2 may be not as specific to the placenta in mouse as it is in human. A comparison of placental gene expression among these four species was performed using the generated database (Fig. 2). Based on ontology analysis, genes commonly ex- pressed by more than one species (e.g., cattle, humans, mice, and zebrafish) participated in core cellular processes such a biosynthesis of hormones and cytokines, regulation of cell cycle and apoptosis, and organelle organization (Supplementary Files 1 and 2; online version only). Humans, mice, and cattle shared a total of 93 genes expressed by their placentae. Based on ontology anal- ysis, most of those genes were related to immune sys- tem modulation (“C-C chemokine receptor activity” and “negative regulation of T cell proliferation”). For example, V-set and immunoglobulin domain-contain- ing 4 (VSIG4) negatively regulated T-cell activation [53], and was highly expressed by endometrial macro- phages in the pregnant cow [54]. Another example was CD274 (also known as programmed cell death 1 ligand 1); it was suggested to promote and enhance induced regulatory T-cells (iTreg) through antagonism of AKT/ mTOR cascade in naive T-cells on nonhematopoietic tissues [55,56]. Moreover, blocked or absent expression of CD274 during pregnancy in mice led to increased maternal rejection in allogeneic, but not syngeneic, pregnancies [57]. Genes characteristic of the development of primary sexual characteristics and cellular pluripotency, e.g., zinc finger protein 42 homolog (ZFP42) [35], and T box gene 3 (TBX3) [58], were commonly expressed by humans and mice. Also, ontology highlighted genes related to protein glycosylation processes (mannosi- dase, alpha, class 1A, member 2 [MAN1A2], and man- nosidase, alpha, class 1C, member 1 [MAN1C1]). Re- cently, in vivo-derived blastocysts produced in cows with elevated circulating progesterone concentrations had decreased expression of mannosidase, alpha, class 1C, member 1 (MAN1C1) among downregulated genes, com- pared with blastocysts recovered from cows with physiologic blood progesterone concentrations [59], suggesting the embryonic protein glycosylation may be a maternal hormonally-controlled process in the cow. Finally, cows and women shared expression of 23 genes by their placentae (compared with 16 genes shared between mice and women). Of these 23 genes, 22 had hormone activity ontology, including insulin growth factor 2 (IGF2), insulin (INS), placental lacto- gens (chorionic somatotropin hormone 1 [CSH1] and StAR-related lipid transfer [START] domain contain- ing 8 [STARD8]). Using cluster analyses, the distance of bovine and murine placental gene expression were compared in relation to that of humans. Since both cattle and mice had a similar distance relative to humans in regards to placental gene expression (Fig. 2h), we inferred that cattle might be as appropriate as mice as a suitable model to study human placental biology and disorders. Therefore, the specific choice of a cow or mouse to test a given hypothesis should be made according to how target genes or cellular processes in humans are similar to the cow or mouse. 3.1. Gene expression and trophoblast invasion Gene expression seemed to change according to placental morphology [60]. Perhaps marked differences between placental gene expression are needed to regu- late trophoblast invasion [42]. The level of invasiveness in the epitheliochorial placenta is lower than the hemo- chorial placenta [2]. Although trophoblastic cells do not invade beyond the maternal basal membrane in cattle, in humans and mice, trophoblast cells are bathed by maternal blood in the decidua [2]. Decades ago, Mossman [1] said that “chromosome- mediated fetal membrane defects” were responsible for fetal pathologies, abnormalities, or even death, and concluded that very little was known about the genetics of fetal membranes. Although much knowledge regard- ing genes expressed in human, mouse, and bovine pla- centae has been published, there are few comparative studies among these species [40,48,60–62]. For exam- ple, based on global gene expression analysis from human and bovine placental/endometrial macrophages, cells in both species were activated in a similar manner, despite differences in placental morphology [54,63]. http://bioinfo.wilmer.jhu.edu/tiger/ http://bioinfo.wilmer.jhu.edu/tiger/ http://bioinf.xmu.edu.cn/databases/TiSGeD/index.html http://bioinf.xmu.edu.cn/databases/TiSGeD/index.html p t 595R.S.N. Barreto et al. / Theriogenology 76 (2011) 589–597 Moffett and Loke [8] suggested that an epithechorial lacenta provided a better immunological barrier be- ween mother and fetus when compared with he- motrophic placenta. Based on the gene expression analy- sis [54,63] highlighted above, although the epithechorial placenta is not as invasive as hemochorial placenta, im- munological events, at least on the basis of gene ex- pression, were very similar between the two placental types. Therefore, this information should contribute to understanding some placental disorders, e.g., pre- eclampsia, which are closely associated with reduced cell infiltration into the uterus [8]. 3.2. Imprinted genes Approximately 200 genes in the mammalian ge- nome are imprinted. More than 70 imprinted genes in mice and at least 50 in humans have already been reported. For most genes, imprinting status is conserved between the mouse and human. Furthermore, for some genes, the imprinted status is also reported to be con- served in other species, e.g., cattle. Several genes had exclusively imprinted expression in placenta or early embryos in humans and rodents [62,64,65]. Many imprinted genes, e.g., IGF2 [66], are involved in the control of fetal growth and placental develop- ment. All imprinted genes have functional nonequiva- lence according to their allelic origin (maternal or pa- ternal); this is also true for placental imprinted genes. There is a pronounced difference between imprinted and methylated genes. The imprinting status relates to the monoallelic expression of a specific gene, whereas methylated genes are inactive in all cells, but can be made active or inactive by signals in differentiated cells [67]. Imprinted genes are differentially methylated in one region (DMR) of one allele. One evolutionary explanation for this hypothesis is that by restricting fetal growth, females have a longer reproductive lifespan, assuring their reproductive suc- cess. In contrast, having more numerous and stronger progeny is more advantageous for males [64]. This sexual antagonism was clearly evident in the large numbers of genes with imprinted expression in the placenta, i.e., H19, IGF2, INS and MAGE-like 2 (MAGEL2) [65], more than in any other tissue. Al- terations in expression of imprinted genes may lead to fetal and placenta growth abnormalities (e.g., in IVF and SCNT embryos), due to abnormal cellular nuclear reprogramming [64,68,69]. Genomic imprinting is well studied in mice and humans, both of which have invasive hemochorial pla- centation [22,66,69–71]. Regarding farm animal spe- cies (epitheliochorial placentation), studies have fo- cused on cattle, including comparisons between cloned and noncloned pregnancies [4,48,49]. Specific characteristics of large offspring syndrome (LOS) produced by ARTs in ruminants had similar clinical and experimental phenotypes as those in hu- mans. Furthermore, IFV/SCNT-derived animals also had disrupted expression and/or effects of H19 and IGF2, similar to the human [72]. It is noteworthy that large offspring syndrome (LOS) was a common syn- drome for SCNT outcomes, mostly associated with altered levels of IGF2-H19 genes [25,29]. 4. Conclusions Despite substantial diversification of placental mor- phology, gene expression was relatively similar among placental types. Although mice are the most widely used model to study the biology of placenta for human disorders, cattle also share a large number of genes preferentially expressed by the human placenta. There- fore, in addition to the mouse, cattle can be also a suitable model for placental studies, despite differences in morphology and cellular invasion. 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