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Expression and function of endogenous retroviruses in the placenta

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Abstract

Although the expression of endogenous retroviruses in the placenta of numerous species was observed a long time ago, their physiological function during gestation was demonstrated only very recently. Expression of retroviral envelope proteins, also called syncytins, in the placenta allows generation of the multinuclear syncytiotrophoblast as an outer cellular layer of the placenta by fusion of the trophoblast cells. This fusion process is crucial for the development of the placenta and for successful pregnancy. It is still unclear whether the immunosuppressive properties of the transmembrane envelope protein of the endogenous retroviruses expressed in the placenta contribute to immunosuppression to prevent the rejection of the semiallotransplant embryo. The presence of placenta cells expressing retroviral envelope proteins surrounded by immune cells deep in the maternal tissue supports an immunosuppressive function. It is important to emphasize that during evolution different species utilized (‘enslaved’) different endogenous retroviruses and that two or more endogenous retroviruses are involved in placentogenesis in each species.

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... In a noteworthy example of convergent evolution, endogenous retrovirus-derived proteins with apparent analogous function but different retroviral origins to those of the human syncytin proteins have been found expressed in almost all mammalian placental types so far studied. The pig, which has a non-invasive, epitheliochorial placenta, may be one exception [43]. However, taxa that have a minimally invasive placenta, such as the pecoran ruminants that include cattle, sheep, and deer do express placental syncytins, which are believed to promote fusion between mononucleated TB cells to give rise to large binucleated cells that comprise around 20% of total TB, and erode the integrity of local maternal uterine epithelium [44]. ...
... However, most, if not all, of the assorted retroviral insertions that have given rise to present day ERV genes, occurred well after the eutherian-marsupial divergence. ERVW-1, for example arose 20-30 MYA and is absent in new world monkeys, whereas ERVFRD-1, which integrated approximately 20 million years earlier, is present in all primates except prosimians [43]. One possibility is that new retroviral insertions provided additional envelope genes, which were then "enslaved" and subsequently selected to replace already functioning ones existing at the time [48]. ...
... Cell fusion is certainly an essential feature of placentation, but, additionally, there is some evidence in eutherians, at least, that sequences associated with ERV regulatory elements might control expression of multiple genes that, in combination, are hallmarks of the TB cell state [51]. In addition, many human syncytins carry an immunosuppressive domain that might assist in protecting the TB from maternal immune scrutiny [43]. In short, syncytin expression is intimately tied to the development, function, and evolution of the eutherian placenta, but it is far from clear whether or not the acquisition of one or more of these genes played a role in initiating the split that permitted eutherian mammals to diverge from their common ancestor with contemporary marsupials. ...
Article
Three versions of syncytiotrophoblast exist in the human placenta: an invasive type associated with the implanting conceptus, non-invasive villous type of definitive placenta, and placental bed giant cells. Syncytins are encoded by modified env genes of endogenous retroviruses (ERV), but how they contribute functionally to placental syncytial structures is unclear. A minimum of eight genes (ERVW1, ERVFRD-1, ERVV-1, ERVV-2, ERVH48-1, ERVMER34-1, ERV3-1, & ERVK13-1) encoding syncytin family members are expressed in human trophoblast, the majority from implantation to term. ERVW1 (Syncytin 1) and ERVFRD-1 (Syncytin 2) are considered the major fusogens, but, when the expression of their genes is analyzed by single cell RNAseq in first trimester placenta, their transcripts are distinctly patterned and also differ from those of their proposed binding partners, SLC1A5 and MFSD2A, respectively. ERVRH48-1 (suppressyn or SUPYN) and ERVMER34-1 are probable negative regulators of fusion and co-expressed, primarily in cytotrophoblast. The remaining genes and their products have been little studied. Syncytin expression is a feature of placental development in almost all eutherian mammals studied, in at least one marsupial, and in viviparous lizards, which lack the trophoblast lineage. Their expression has been inferred to be essential for pregnancy success in the mouse. All the main human ERV genes arose following independent retroviral insertion events, none of which trace back to the divergence of eutherians and metatherians (marsupials). While syncytins may be crucial for placental development, it seems unlikely that they helped orchestrate the divergence of eutherians and marsupials.
... Of particular interest for this review was the findings of some authors showing that infectious retroviruses have ribonucleic acid (RNA) genomes that can be reverse transcribed into double-stranded deoxyribonucleic acid (DNA) (Küry et al. 2018;Mager and Stoye 2015;Göke et al. 2015;Malik 2012). These viruses insert themselves into the host genome in the form of a provirus (Denner 2016;Furukawa et al. 2014), and once within the host genome, the retrovirus can replicate rapidly by transcribing new RNAs. ...
... These retroviruses have directly infected the genome in germline tissue in a manner that facilitates the creation of imprints to be passed to genomes in other cells and subsequent generations. The majority of insertions into the host genome usually occur instantly or slowly through the accumulation of mutations (Malik 2012;Denner 2016;Vernochet et al. 2014). Although a significant portion of retroviral imprints degenerate as a result of evolution, some are preserved and can be activated through mutations. ...
... Interestingly, there are some lineages of retroviruses with both endogenous and exogenous capabilities (Küry et al. 2018;Mager and Stoye 2015). In such instances, exogenous viruses may evolve into endogenous viruses by changing their properties and sequences once they enter germ cells (Göke et al. 2015;Malik 2012;Denner 2016). Nonetheless, in both exogenous and endogenous subpopulations, successful insertion into the host germline will result in the selection of elements that can replicate and move to other sites within the host (Furukawa et al. 2014). ...
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Significant advances have been observed in the field of cell biology, with numerous studies exploring the molecular genetic pathways that have contributed to species evolution and disease development. The current study adds to the existing body of research evidence by reviewing information related to the role of leftover viruses and/or viral remnants in human physiology. To explore leftover viruses, their incorporation, and their roles in human physiology. The study entailed conducting a systematic search in the PsycINFO, PubMed, Web of Science, and CINAHL databases to locate articles related to the topic of investigation. The search terms included “leftovers,” “viruses,” “genome sequences,” “transposable elements,” “immune response,” and “evolution.” Additional articles were selected from the references of the studies identified in the electronic databases. Evidence showed that both retroviruses and nonretroviruses can be integrated into the human germline via various mechanisms. The role of leftover viruses in human physiology has been explored by studying the activation of human retroviral genes in the human placenta, RNA transfer between neurons through virus-like particles, and RNA transfer through extracellular vesicles. Research evidence suggested that leftover viruses play key roles in human physiology. A more complete understanding of the underlying pathways may provide an avenue for studying human evolution and allow researchers to determine the pathogenesis of some viral infections. Evidence obtained in this review shows that leftover viruses may be incorporated into the human genome. Retroviral genes are critical for the development of different parts of the body, such as the placenta in mammals.
... 3 There are only a few genes that encode functional proteins such as HERV-K and HERV-W. 3,4 HERV-W encodes Syncytin proteins, which are essential for placental syncytiotrophoblast cell development. 4 Inactivation of HERVs can also be attributed to solo-LTRs, which are generated by non-allelic homologous recombination between the 5ʹ and 3ʹ LTRs. ...
... 3,4 HERV-W encodes Syncytin proteins, which are essential for placental syncytiotrophoblast cell development. 4 Inactivation of HERVs can also be attributed to solo-LTRs, which are generated by non-allelic homologous recombination between the 5ʹ and 3ʹ LTRs. 5,6 LTRs make great contributions to the complexity of the genome in providing promoters, enhancers, repressors, poly A signals and alternative splicing sites for human genes. ...
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Wenjun Cao,1 Ran Kang,2 Yining Xiang,1 Jidong Hong1 1Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Urology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, People’s Republic of ChinaCorrespondence: Jidong Hong Department of OncologyXiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, People’s Republic of ChinaEmail hongjidong1966@126.comAbstract: Human endogenous retroviruses (HERVs) form an important part of the human genome, commonly losing their coding ability and exhibiting only rare expression in healthy tissues to promote the stability of the genome. However, overexpression of HERVs has been observed in various malignant tumors, including clear cell renal cell carcinoma (ccRCC), and may be closely correlated with tumorigenesis and progression. HERVs may activate the interferon (IFN) signaling pathway by a viral mimicry process to enhance antitumor immune responses. There is increasing interest in the diagnostic and prognostic value of HERVs in cancers, and they may be candidate targets for tumor immunotherapy. The review will introduce the biological functions of HERVs in ccRCC and their clinical value, especially in regard to immunotherapy.Keywords: clear cell renal cell carcinoma, human endogenous retroviruses, immunotherapy, long terminal repeat, biomarker
... During early gestation, a high level of HERV expression has been noted, which decreases with increased gestational age, and increased DNA methylation levels [127,128]. Most HERVs are replication incompetent as a result of having sustained numerous mutations and losing relevant genes during evolution [129,130]. Nevertheless, HERVs express high levels of retroviral envelope proteins, supporting the survival of placental cells within an immunosuppressive environment in the presence of maternal immune cells [129]. HERV LTRs are active within the mammalian placenta, as well as the developing embryo, germ cells, and erythroid cells [131]. ...
... Most HERVs are replication incompetent as a result of having sustained numerous mutations and losing relevant genes during evolution [129,130]. Nevertheless, HERVs express high levels of retroviral envelope proteins, supporting the survival of placental cells within an immunosuppressive environment in the presence of maternal immune cells [129]. HERV LTRs are active within the mammalian placenta, as well as the developing embryo, germ cells, and erythroid cells [131]. ...
Article
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Cancer is the second leading cause of mortality and morbidity in the developed world. Cancer progression involves genetic and epigenetic alterations, accompanied by aggressive changes, such as increased immune evasion, onset of metastasis, and drug resistance. Similar to cancer, DNA hypomethylation, immune suppression, and invasive cell behaviours are also observed in the human placenta. Mechanisms that lead to the acquisition of invasive behaviour, immune evasion, and drug and immunotherapy resistance are presently under intense investigations to improve patient outcomes. Here, we review current knowledge regarding the similarities between immune suppression and epigenome regulation, including the expression of repetitive elements (REs), endogenous retroviruses (ERVs) and transposable elements (TEs) in cells of the placenta and in cancer, which are associated with changes in immune regulation and invasiveness. We explore whether immune suppression and epigenome regulation in placenta offers novel insights into immunotherapy resistance in cancer, and we also discuss the implications and the knowledge gaps relevant to these findings, which are rapidly being accrued in these quite disparate research fields. Finally, we discuss potential linkages between TE, ERV and RE activation and expression, regarding mechanisms of immune regulation in placenta and cancer. A greater understanding of the role of immune suppression and associated epigenome regulation in placenta could help to elucidate some comparable mechanisms operating in cancer, and identify potential new therapeutic targets for treating cancer.
... In mammals, endogenous retroviral RNAs and proteins are present within the 820 endometrial epithelium and trophectoderm and have important functions during establishment 821 of pregnancy including cell proliferation, immunosuppression, and cell-cell fusion or syncytia 822 formation [107][108][109][110]. In sheep, expression of endogenous jaagsiekte retrovirus (enJSRV) and 823 syncytin-Rum1 retroviral RNAs occur within the trophectoderm and uterine epithelium [107, 824 111, 112]. ...
... Similar 828 to sheep, bovine trophectoderm and endometrial epithelium express bovine endogenous 829 retrovirus (BERVs) and syncytin-Rum1 during early pregnancy [109,114,115]. The BERVs and 830 syncytin-Rum1 are expressed within bovine conceptus binucleate cells (BNC) and have 831 fusogenic activity, likely contributing to the formation of fetal-maternal trinucleate cells (TNC) 832 in formation of the synepitheliochorial placenta [109,110,114]. 833 Importantly, it is not understood how ovine or bovine retroviral particles are produced 834 within the trophectoderm and endometrial epithelium in the presence of IFNT, an abundantly 835 secreted type I IFN that induces a number of anti-retroviral genes and processes within these 836 tissues. ...
Article
Bovine endometrium consists of epithelial and stromal cells that respond to conceptus interferon tau (IFNT), the maternal recognition of pregnancy (MRP) signal, by increasing expression of IFN-stimulated genes (ISGs). Endometrial epithelial and stromal cell specific ISGs are largely unknown but hypothesized to have essential functions during pregnancy establishment. Bovine endometrial epithelial cells were cultured in inserts above stromal fibroblast (SF) cells for 6 h in medium alone or with IFNT. The epithelial and SF transcriptomic response was analyzed separately using RNA sequencing and compared to a list of 369 DEGs recently identified in intact bovine endometrium in response to elongating bovine conceptuses and IFNT. Bovine endometrial epithelial and SF shared 223 and 70 DEGs in common with the list of 369 endometrial DEGs. Well known ISGs identified in the epithelial and SF were ISG15, MX1, MX2, and OAS2. DEGs identified in the epithelial but not SF included a number of IRF molecules (IRF1, IRF2, IRF3 and IRF8), mitochondria SLC transporters (SLC25A19, SLC25A28 and SLC25A30), and a ghrelin receptor (GHSR). Expression of ZC3HAV1, an anti-retroviral gene, increased specifically within the SF. Gene ontology analysis identified the type I IFN signaling pathway and activation of nuclear factor kappa B transcription factors as biological processes associated with the epithelial cell DEGs. This study has identified biologically relevant IFNT stimulated genes within specific endometrial cell types. The findings provide critical information regarding the effects of conceptus IFNT on specific endometrial compartments during early developmental processes in cattle.
... The human ERVs (HERVs), which accounts for about 8% of the human genome, is mostly nonfunctional. However, some envelope proteins of ERVs have been found to be essential for the development, and the formation of the placenta in human and in other primates (Blaise et al., 2003;Zhang et al., 2015;Muir et al., 2004;Denner, 2016). The 3.8 kb transcript of the retroviral genes was detected in the cytotrophoblastic cells, and compared to other tissues, the highest expression in human has been shown in the placenta . ...
... In recent years, HERVs has been also prominent in placental morphogenesis and trophoblast differentiation (Malassine et al., 2008). Although they are mostly nonfunctional, it is known that the HERV-W (syncytin-1) and HERV-FRD (syncytin-2) envelope proteins can expressed in cells with appropriate receptors, and can induce and contribute to the maintenance of cell-cell fusion Malassine et al., 2008;Denner, 2016). Syncytin-1 which is expressed in both normal and pathological placentas may also contribute towards immune tolerance of the developing embryo with abundant syncytin expression in placental syncytiotrophoblasts (Blaise et al., 2005;Ruebner et al., 2013;Gerbaud and Pidoux, 2015;Bolze et al., 2017). ...
Article
Background Syncytin-1 and syncytin-2 which are endogenous retroviral genes products play a great role in syncytialization during trophoblast differentiation in normal placental tissues. In aneuploidic placentas due to the low level of pregnancy-induced hormones an alteration was occurred in the syncytialization process, while in the presence of cytogenetically abnormal karyotype the effect of syncytin gene expression levels on syncytialization process and in occured to spontaneous abortions is not clear. To reveal this, we investigated in syncytin-1 and syncytin-2 genes expression levels of chromosomally abnormal and normal trophophoblastic tissues and we also discussed the effect of the syncytin gene expression levels to the occurense of the spontaneous abortion. Material and Methods To each one of the trophoblastic cells; cultivation, harvesting, banding, and analysis were performed and the chromosomes were classified according to the presence of abnormality and normal XY constitution. To exclude the maternal decidual cell contamination, female karyotyped abortion materials were omitted in control group. The patient group consisted of thirty six placental tissues including trisomy 16 (n=10), triploidy (n=9), monosomy X (n=9), trisomy 21 (n=5) and trisomy 7 (n=3). The control group was consisting twenty placental tissues with XY karyotypes. The some part of the dissected frozen trophoblastic cells were used for RNA isolation and were proceeded to the determination of the expression levels of syncytin-1 and syncytin-2 genes by single-step Real Time PCR. The cDNAs were obtained by probes used in the same PCR stages. The sequence analysis of the syncytin-1 and syncytin-2 genes were performed, and read by the usage of the FinchTV 1.4.0 program. Results Between the expression levels of syncytin-1 and syncytin-2 genes were statistically difference in the patients and controls. There was a difference (p <0.0001) between trisomy 7 and other patient groups and controls, regarding to the expression of syncytin-1 gene. Numerous mutations in the syncytin-1 and syncytin-2 genes (on the expression sites) were detected, and the mutation rate was higher in the syncytin-1 gene compared to the syncytin-2 gene in the patient and in the control groups (p<0.001). Conclusion The results of the study indicate that the expression of the syncytin-2 genes could be altered in the presence of chromosomally abnormal trophoblastic tissues, and these could lead to the loss of pregnancy due to the insufficient syncytialization. In sum, the current research has value for the further studies covering the mechanisms of trophoblast cell fusion, and syncytiotrophoblast regeneration, and thus the pathophysiology of human placental development in the presence of genomic anomaly.
... Retroviral env genes are known to have been co-opted many times by various vertebrate hosts for a wide range of functions. The most well-known one is perhaps the syncytin genes, which was captured for a function in placental formation numerous times by various mammals (see [31,32] for reviews). A recent study identified (for the first time) a functionally active syncytin gene outside mammals, namely syncytin-Mab1, in a lizard Mabuya [33,34]. ...
... One could thus imagine that the two genetic elements might be co-expressed and are in turn functionally associated, as has been repeatedly shown in several organisms [36][37][38]. Although geckos lay eggs and do not possess true placenta tissues such as Mabuya lizards, the physical association of EMC1 with co-opted retroviral env sequences suggests their possible involvement in the reproductive system of geckos, analogous to the syncytin gene in mammals [31,32] and viviparous placental lizards [33,34]. Furthermore, the EMC1 protein influences virus cross-membrane transportation and infectivity via direct physical contact with viral particles [39]. ...
Article
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A recent study reported the discovery of an endogenous reptilian foamy virus (FV), termed ERV-Spuma-Spu, found in the genome of tuatara. Here, we report two novel reptilian foamy viruses also identified as endogenous FVs (EFVs) in the genomes of panther gecko (ERV-Spuma-Ppi) and Schlegel’s Japanese gecko (ERV-Spuma-Gja). Their presence indicates that FVs are capable of infecting reptiles in addition to mammals, amphibians, and fish. Numerous copies of full length ERV-Spuma-Spu elements were found in the tuatara genome littered with in-frame stop codons and transposable elements, suggesting that they are indeed endogenous and are not functional. ERV-Spuma-Ppi and ERV-Spuma-Gja, on the other hand, consist solely of a foamy virus-like env gene. Examination of host flanking sequences revealed that they are orthologous, and despite being more than 96 million years old, their env reading frames are fully coding competent with evidence for strong purifying selection to maintain expression and for them likely being transcriptionally active. These make them the oldest EFVs discovered thus far and the first documented EFVs that may have been co-opted for potential cellular functions. Phylogenetic analyses revealed a complex virus–host co-evolutionary history and cross-species transmission routes of ancient FVs.
... In particular, two HERV-derived Env-proteins, Syncytin-1, the Env protein of HERV-W, and Syncytin-2, which is encoded by HERV-FRD, have been implicated in the process of proper placentation and cell-cell fusion (161). Both Syncytin-1 and Syncytin-2 contribute to syncytialization by their expression during placentation, leading to the fusion of the villous trophoblast to the syncytiotrophoblast (162). Syncytin-1 is expressed in the extravillous trophoblast and the villous trophoblast, while Syncytin-2 is expressed solely in the villous trophoblast (161). ...
... Syncytin-1 is expressed in the extravillous trophoblast and the villous trophoblast, while Syncytin-2 is expressed solely in the villous trophoblast (161). Syncytin-1 and Syncytin-2 function after their ligation to their cognate receptors Na-dependent neutral amino acid transporter 2 (ASCT2) and Major Facilitator Superfamily Domain Containing 2 (MFSD2) (161,162). The importance of these HERV-derived proteins in the normal placental formation is pointed out by the observed deregulation of Syncytin-1 expression in the setting of placental syndromes, such as pre-eclampsia, probably offering smaller advantages to those fetuses (163) and of Syncytin-2 in chromosomally abnormal trophoblastic tissues, which leads to insufficient syncytialization and subsequent spontaneous pregnancy loss (164). ...
Article
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Being responsible for almost 12% of cancers worldwide, viruses are among the oldest known and most prevalent oncogenic agents. The quality of the evidence for the in vivo tumorigenic potential of microorganisms varies, thus accordingly, viruses were classified in 4 evidence-based categories by the International Agency for Research on Cancer in 2009. Since then, our understanding of the role of viruses in cancer has significantly improved, firstly due to the emergence of high throughput sequencing technologies that allowed the “brute-force” recovery of unknown viral genomes. At the same time, multi-omics approaches unravelled novel virus-host interactions in stem-cell biology. We now know that viral elements, either exogenous or endogenous, have multiple sometimes conflicting roles in human pathophysiology and the development of cancer. Here we integrate emerging evidence on viral causality in human cancer from basic mechanisms to clinical studies. We analyze viral tumorigenesis under the scope of deep-in-time human-virus evolutionary relationships and critically comment on the evidence through the eyes of clinical epidemiology, firstly by reviewing recognized oncoviruses and their mechanisms of inducing tumorigenesis, and then by examining the potential role of integrated viruses in our genome in the process of carcinogenesis.
... protection from viral infection, preimplantation conceptus development and placental morphogenesis 459 (Denner, 2016;Dunlap et al., 2005Dunlap et al., , 2006bDunlap et al., , 2006a). We speculate that the upregulation of ERVs in 460 ...
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The majority of pregnancy loss in ruminants occurs during the preimplantation stage, which is thus the most critical period determining reproductive success. While ovulation rate is the major determinant of litter size in sheep, interactions among the conceptus, corpus luteum and endometrium are essential for pregnancy success. Here, we performed a comparative transcriptome study by sequencing total mRNA from corpus luteum (CL) collected during the preimplantation stage of pregnancy in Finnsheep, Texel and F1 crosses, and mapping the RNA-Seq reads to the latest Rambouillet reference genome. A total of 21,287 genes were expressed in our dataset. Highly expressed autosomal genes in the CL were associated with biological processes such as progesterone formation ( STAR, CYP11A1 , and HSD3B1 ) and embryo implantation (eg. TIMP1, TIMP2 and TCTP ). Among the list of differentially expressed genes, a group of sialic acid-binding immunoglobulin (Ig)-like lectins (Siglecs), solute carriers ( SLC13A5, SLC15A2, SLC44A5 ) and chemokines ( CCL5, CXCL13, CXCL9 ) were upregulated in Finnsheep, while four multidrug resistance-associated proteins (MRPs) were upregulated in Texel ewes. A total of 17 genes and two non-coding RNAs (ncRNA) were differentially expressed in breed-wise comparisons owing to flushing diet effect. Moreover, we report, for the first time in any species, several genes that are active in the CL during early pregnancy (including SIGLEC13, SIGLEC14, SIGLEC6, MRP4 , and CA5A ). Importantly, functional analysis of differentially expressed genes suggested that Finnsheep have a better immune system than Texel and that high prolificacy in Finnsheep might be governed by immune system regulation.
... cats, dogs) (Cornelis et al., 2014;Leiser and Koob, 1993) and hemochorial placentation (e.g. humans, mice, rabbits, rats) (Blaise et al., 2003;Denner, 2016;Dupressoir et al., 2005;Heidmann et al., 2009). ...
Article
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Bats are the primary reservoirs and carriers of a wide range of viruses of unknown infectivity and unknown pathogenic potential. Some of those if transmitted to other species can cause enormous economic losses in agriculture, and mortality in humans. Bats can be persistently infected with viruses while not showing any symptoms of disease, despite having high virus titre levels in their tissues and shedding virions for months or years after primary infection. It has been suggested that the lack of symptoms of viral infections and low mortality rate in bats might be due to immune adaptations that result from their long-term co-evolution with viruses. In this study, we screened all publicly available bat genomes from six bat families within which we have identified several envelope sequences of retroviral origin (gammaretroviruses). We analysed found sequences with Bayesian methods and maximum-likelihood inference to generate a phylogenetic tree with additional reference sequences of known endogenous and exogenous viral envelope genes. We also identified groups of orthologous viral envelopes and analysed them to detect if any of them might be an EVE (endogenous virus element) with an EDI (EVE- derived immunity) function or a candidate for a bat syncytin gene, which is an endogenized viral envelope, mostly known from its function in placentation in animals. Our study shows that bat genomes contain a substantial number of large, intact envelopes in open reading frames, which were found clustering closely on a phylogenetic tree reconstruction with syncytin sequences of other species. That might indicate that such sequences are good candidates for further bat-syncytin/EDI search.
... Among critically involved factors, some human endogenous retroviral (HERV) proteins deserve a particular attention since their expression is unique to human placenta. HERVs derive from exogenous retroviruses infections occurred in primates millions of years ago, which integrated into our genome and progressively lost their infection potential; however, along the evolution, the capability to express specific proteins was preserved to fulfil fundamental functions in placenta development [15,16]. Three endogenous retroviral envelope (Env) glycoproteins are specifically expressed in human placenta, exerting different roles during syncytiotrophoblast differentiation: ERVW-1 Env, known as syncytin-1, is mainly implicated in cytotrophoblasts cell-cell fusion [17,18], ERV3-1 Env is mostly involved in cytotrophoblasts differentiation [19] and ERVFRD-1 Env, known as syncytin-2, has both fusogenic and immunosuppressive properties [20][21][22]. ...
Article
Placenta is a target organ of Bisphenol A (BPA). To investigate possible effects on syncytiotrophoblast, the exchanging surface between mother and fetus, we exposed a trophoblast model (BeWo) to BPA concentrations occurring in humans (1 and 50 nM). We assessed the gene and protein expression of three human endogenous retroviral envelopes, specifically expressed in placenta (ERVW-1, ERVFRD-1 and ERV3-1), the secretion of β-hCG, the extent of trophoblast fusion and the activity of apoptosis markers (caspases 8, 3, 9 and PARP); additionally, the gene expression of transcription factors regulating HERV expression (i.e. GCM1, PPARγ, ERα and ERβ) was evaluated. At 50 nM, BPA induced ERVW-1, ERVFRD-1 and the corresponding syncytin proteins, ERV3-1, PPARγ, ERα and ERβ expression, increased β-hCG secretion and BeWo cells fusion, thus promoting the syncytiotrophoblast phenotype. The results support placenta as a target organ of BPA. Possible implications on fetal and pregnancy health should be carefully considered.
... The genome of sheep contains at least 32 ERVs related to JSRV (Sistiaga-Poveda and Jugo 2014), and these ERVs are essential during pregnancy, including during placental morphogenesis and conceptus elongation (Palmarini et al. 2001, Dunlap et al. 2006a, Spencer and Palmarini 2012. A number of earlier studies have suggested critical roles of ERVs in uterine protection from viral infection, preimplantation conceptus development and placental morphogenesis (Dunlap et al. 2005, Dunlap et al. 2006a, Dunlap et al. 2006b, Denner 2016. Interestingly, one of the novel genes (ENSOARG00000009959) predicted to be an ERV was part of reduced FecL locus which is linked to prolificacy in French Lacaune breed (Drouilhet et al. 2013). ...
Article
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Carefully coordinated interaction between the endometrium and embryo is critical for the establishment and maintenance of pregnancy in mammals. By exploring the gene expression dynamics of this tissue during preimplantation development, we may be able to get insight into the genetic mechanisms of reproduction during early pregnancy. Here, we have performed comparative transcriptome profiling of the endometrium in response to spherical (Day 7 to Day 12) and elongated (Day 13 to Day 17) embryos in Finnsheep, Texel and their F1 crosses using RNA sequencing (RNA-seq) approach. A total of 21125 genes were expressed in our dataset of which 554 were significantly (absolute log2 fold change > 2.5; adjusted p-value < 0.01) upregulated in the endometrium with elongated embryos. Highly abundant autosomal genes in the endometrium were associated with biological processes such as facilitation of maternal recognition of pregnancy, trophoblast elongation and implantation (LGALS15, CST3, CST6, and EEF1A1). Several endogenous retroviruses (ERVs) including a novel ERV gene located in a reduced FecL locus potentially associated with sheep prolificacy were expressed in our dataset. Comparative transcriptome profiling of the endometrium having spherical and elongated embryos revealed distinct gene expression patterns. Genes that were upregulated in response to elongated embryos indicated the importance of immune system at the maternal-embryo interface prior to implantation.
... This is achieved through epigenetic regulation via DNA methylation in normal tissues [52,53], indicating that CpG methylation is an important mechanism of silencing and turning off expression of HERV [53][54][55]. The regulation of HERVs by selective hypomethylation at HERV LTR is critical during embryonic development, such as in the placenta during the course of pregnancy [51,55,56]. The ability for host cells to manage HERV expression through epigenetic regulation suggests that this acquired neutralization strategy could be exploited for current efforts to combat latent HIV. ...
Article
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Latent HIV reservoir is the main obstacle that prevents a cure for HIV-1 (HIV). While antiretroviral therapy is effective in controlling viral replication, it cannot eliminate latent HIV reservoirs in patients. Several strategies have been proposed to combat HIV latency, including bone marrow transplantation to replace blood cells with CCR5-mutated stem cells, gene editing to disrupt the HIV genome, and "Shock and Kill" to reactivate latent HIV followed by an immune clearance. However, high risks and limitations to scale-up in clinics, off-target effects in human genomes or failure to reduce reservoir sizes in patients hampered our current efforts to achieve an HIV cure. This necessitates alternative strategies to control the latent HIV reservoirs. This review will discuss an emerging strategy aimed to deeply silence HIV reservoirs, the development of this concept, its potential and caveats for HIV remission/cure, and prospective directions for silencing the latent HIV, thereby preventing viruses from rebound.
... Likewise, all mammals have two or more ERVencoded Env expressed as syncytins in their placentas, but the identity of the ERVs encoding them is different for each order of mammals. 120 In the human case, one of these proteins, HERV-W env (syncytin-1), comes from an ERV which integrated into the genome after divergence from other primates. Humans, other primates, guinea pigs, cattle, sheep, rodents, carnivores, and marsupials each has its own characteristic syncytins encoded by different Env sequences from different ERVs. ...
Article
Conventional 20th century evolution thinking was based on the idea of isolated genomes for each species. Any possibility of life‐history inputs to the germ line was strictly excluded by Weismann's doctrine, and genome change was attributed to random copying errors. Today, we know that many life‐history events lead to rapid and nonrandom evolutionary change mediated by specific cellular functions. There are many ways that genomes, viruses, cells, and organisms interact to generate evolutionary variation. These include cell mergers and activation of natural genetic engineering by stress, infection, and interspecific hybridization. In addition, we know molecular mechanisms for transmitting life‐history information across generations through gametes. These discoveries require a new agenda for evolutionary theory and novel experimental designs to investigate the genomic impacts of stresses, biotic interactions, and sensory inputs coming from the environment. The review will offer some generic recommendations for enriching evolution experiments to incorporate new knowledge and find answers to previously excluded questions.
... Unlike extravillous cytotrophoblasts, VCTs are noninvasive but fuse to form and maintain the structure of the peripheral syncytiotrophoblast (STB) layer through a well-regulated process. A number of studies have demonstrated that envelope (Env) genes from human endogenous retrovirus (HERV), remnant of former ancestral retroviral infectious events, are implicated in this fusion through their fusogenic domain [6,7]. Convincing data have clearly suggested that Env Syncytin-1 and Syncytin-2 indeed participate in the formation of the STB layer by mediating fusion with underlying cytotrophoblast cells through interaction with their specific receptors [8]. ...
Article
Modulation of the activation status of immune cell populations during pregnancy depends on placental villous cytotrophoblast (VCT) cells and the syncytiotrophoblast (STB) layer. Failure in the establishment of this immunoregulatory function leads to pregnancy complications. Our laboratory has been studying Syncytin-2 (Syn-2), an endogenous retroviral protein expressed in placenta and on the surface of placental exosomes. This protein plays an important role in STB formation through its fusogenic properties, but also possesses an active immunosuppressive domain (ISD). Considering that Syn-2 expression is importantly reduced in preeclamptic placentas, we were interested in addressing its possible immunoregulatory effects on T cells. Activated Jurkat T cells and peripheral blood mononuclear cells (PBMCs) were treated with monomeric or dimerized version of a control or a Syn-2 ISD peptide. Change in phosphorylation levels of ERK1/2 MAP kinases was selectively noted in Jurkat cells treated with the dimerized ISD peptide. Upon incubation with the dimerized Syn-2 ISD peptide, significant reduction in Th1 cytokine production was further demonstrated by ELISA and Human Th1/Th2 Panel Multi-Analyte Flow Assay. To determine if exosome-associated Syn-2 could also have an immunosuppressive effect, placental exosomes were incubated with activated Jurkat T cells and PBMCs. Upon quantification of Th1 cytokines in the supernatants, T cell activation was severely reduced. Interestingly, exosomes from Syn-2-silenced VCT incubated with PBMCS were less suppressive when compared to exosome derived from VCT transfected with control siRNA. Our results suggest that Syn-2 could be an important immune regulator both locally and at the systemic level, via its association with placental exosomes.
... The trophoblastic cells of the placenta resemble cancer in their ability to divide rapidly, migrate, induce vascularization, suppress maternal immune rejection and, by these abilities, to effectively invade maternal tissues (Soundararajan & Rao, 2004). Remarkably, these properties rely heavily on genes of retroviral origin: on syncytins to enable cell fusion and immune suppression (reviewed in Denner, 2016), and possibly also on gene regulatory networks (Chuong, 2013). While now these genes benefit the host and can be considered to be 'domesticated', their expression in the placenta probably evolved originally to facilitate retroviral transmission between the mother and the foetus (Haig, 2012). ...
Article
The aetiology of cancer involves intricate cellular and molecular mechanisms that apparently emerge on the short timescale of a single lifetime. Some of these traits are remarkable not only for their complexity, but also because it is hard to conceive selection pressures that would favour their evolution within the local competitive microenvironment of the tumour. Examples include ‘niche construction’ (re‐programming of tumour‐specific target sites) to create permissive conditions for distant metastases; long‐range feedback loops of tumour growth; and remarkably ‘plastic’ phenotypes (e.g. density‐dependent dispersal) associated with metastatic cancer. These traits, which we term ‘paradoxical tumour traits’, facilitate the long‐range spread or long‐term persistence of the tumours, but offer no apparent benefit, and might even incur costs in the competition of clones within the tumour. We discuss three possible scenarios for the origin of these characters: somatic selection driven by specific selection regimes; non‐adaptive emergence due to inherent vulnerabilities in the organism; and manipulation by putative transmissible agents that contribute to and benefit from these traits. Our work highlights a lack of understanding of some aspects of tumour development, and offers alternative hypotheses that might guide further research.
... This shared property between exogenous and endogenous retroviruses led to the identification of an immunosuppressive domain (ISD) in the transmembrane unit of the Env protein (reviewed in [51]). Exposure of human PBMCs to ISD-derived peptides from different retroviruses, including HIV and HERV-K, increases the expression of different cytokines, including IL-10, IL-6, IL-8, RANTES, MCP-1, MCP-2, TNF-α, MIP-1α, MIP-1β, MIP-3, IL-1β and Gro(α,β,γ), and decreases the expression of IL-2 and CXCL9 [52,53]. Although all studies converge so far to a direct effect on cellular immune effectors, the exact impact of ISD remains unclear, and no interaction with the innate immune response has been clearly highlighted. ...
Article
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Human Endogenous Retroviruses (HERVs) are accounting for 8% of the human genome. These sequences are remnants from ancient germline infections by exogenous retroviruses. After million years of evolution and multiple integrations, HERVs have acquired many damages rendering them defective. At steady state, HERVs are mostly localized in the heterochromatin and silenced by methylation. Multiple conditions have been described to induce their reactivation, including auto-immune diseases and cancers. HERVs re-expression leads to RNA (simple and double-stranded) and DNA production (by reverse transcription), modulating the innate immune response. Some studies also argue for a role of HERVs in shaping the evolution of innate immunity, notably in the development of the interferon response. However, their exact role in the innate immune response, particularly in cancer, remains to be defined. In this review, we see how HERVs could be key-players in mounting an antitumor immune response. After a brief introduction on HERVs characteristics and biology, we review the different mechanisms by which HERVs can interact with the immune system, with a focus on the innate response. We then discuss the potential impact of HERVs expression on the innate immune response in cancer.
... ERVWE1, a locus on chromosome 7q, contains a member of the HERV-W family with a single complete ORF that putatively encodes an envelope protein (HERV-W env, also known as Syncytin-1) (Kury et al. 2018). HERV-W env performs vital functions in the fusogenic (Frendo et al. 2003) and immunosuppressive activity in placental morphogenesis (Denner 2016). Recent studies show that aberrant expression of HERV-W env has been associated with human diseases, such as cancer (Yu et al. 2014), multiple sclerosis (Antony et al. 2007;Emmer et al. 2018;Morandi et al. 2017;Perron et al. 2013;Perron et al. 1997), and schizophrenia (Huang et al. 2011;Qin et al. 2016;Tu et al. 2017;Wang et al. 2018;Xiao et al. 2017). ...
Article
The activation and involvement of human endogenous retroviruses W family envelope gene (HERV-W env, also called ERVWE1) have been reported in several neuropsychiatric disorders, including schizophrenia, as well as in multiple sclerosis (MS). Dysregulation of intracellular calcium content is also involved in the pathogenesis of these diseases. Our previous studies showed that HERV-W env overexpression results in activation of small conductance Ca²⁺-activated K⁺ channel protein 3 (SK3), a potential risk factor for schizophrenia. In the present study, we aimed to elucidate the relationship between HERV-W env and calcium signaling in schizophrenia. Our results showed that HERV-W env could induce Ca²⁺ influx in two human neuroblastoma cell lines and upregulate the expression and activation of TRPC3 in cells. The abnormal increase in intracellular Ca²⁺ concentration was inhibited by addition of the TRPC3 channel blocker pyr3, demonstrating that the Ca²⁺ influx induced by HERV-W env was TRPC3-dependent. Further experiments showed that HERV-W env overexpression downregulated DISC1, while knockdown of DISC1 promoted activation of TRPC3 without affecting TRPC3 expression. In conclusion, HERV-W env induced Ca²⁺ influx in human neuroblastoma cells by activating the TRPC3 channel through directly regulating its expression or downregulating DISC1, which could also increase TRPC3 activation without affecting TRPC3 expression. These findings provide new insights into how HERV-W env affects neuronal activity and contributes to the pathogenesis of schizophrenia.
... Whereas in these species retroviruses are known to induce tumors, in pigs until now such an association was not reported [1,33]. In addition, in many mammalian species the role of endogenous retroviruses in placentogenesis is well studied, whereas in pigs an involvement of PERVs is still unknown [34]. ...
Article
Full-text available
Porcine endogenous retroviruses (PERVs) are integrated in the genome of pigs and are transmitted like cellular genes from parents to the offspring. Whereas PERV-A and PERV-B are present in all pigs, PERV-C was found to be in many, but not all pigs. When PERV-C is present, recombination with PERV-A may happen and the PERV-A/C recombinants are characterized by a high replication rate. Until now, nothing has been known about the copy number of PERVs in wild boars and little is known about the prevalence of the phylogenetically youngest PERV-C in ancient wild boars. Here we investigated for the first time the copy number of PERVs in different populations of wild boars in and around Berlin using droplet digital PCR. Copy numbers between 3 and 69 per genome have been measured. A lower number but a higher variability was found compared to domestic pigs, including minipigs reported earlier (Fiebig et al., Xenotransplantation, 2018). The wild boar populations differed genetically and had been isolated during the existence of the Berlin wall. Despite this, the variations in copy number were larger in a single population compared to the differences between the populations. PERV-C was found in all 92 analyzed animals. Differences in the copy number of PERV in different organs of a single wild boar indicate that PERVs are also active in wild boars, replicating and infecting new cells as has been shown in domestic pigs.
... Human endogenous retroviruses (HERVs) are an increasingly recognized part of the human genome that entered the germline in the course of evolution and today comprise more than eight percent of it (Makałowski, 2001;de Parseval and Heidmann, 2005). Most of these sequences are no longer protein coding due to mutations, but there are several exceptions such as syncytins, which exert a physiological function in placenta development (Denner, 2016). ...
Article
Full-text available
More than eight percent of the human genome consists of human endogenous retroviruses (HERVs). Typically, the expression of HERVs is repressed, but varying activities of HERVs have been observed in diseases ranging from cancer to neuro-degeneration. Such activities can include the transcription of HERV-derived open reading frames, which can be translated into proteins. However, as a consequence of mutations that disrupt open reading frames, most HERV-like sequences have lost their protein-coding capacity. Nevertheless, these loci can still influence the expression of adjacent genes and, hence, mediate biological effects. Here, we present WebHERV (http://calypso.informatik.uni-halle.de/WebHERV/), a web server that enables the computational prediction of active HERV-like sequences in the human genome based on a comparison of genome coordinates of expressed sequences uploaded by the user and genome coordinates of HERV-like sequences stored in the specialized key-value store DRUMS. Using WebHERV, we predicted putative candidates of active HERV-like sequences in Hodgkin lymphoma (HL) cell lines, validated one of them by a modified SMART (switching mechanism at 5′ end of RNA template) technique, and identified a new alternative transcription start site for cytochrome P450, family 4, subfamily Z, polypeptide 1 (CYP4Z1).
... cats, dogs) (Cornelis et al., 2014;Leiser and Koob, 1993) and hemochorial placentation (e.g. humans, mice, rabbits, rats) (Blaise et al., 2003;Denner, 2016;Dupressoir et al., 2005;Esnault et al., 2013;Heidmann et al., 2009). ...
Article
Despite a small genome size, bats have comparable diversity of retroviral and non-retroviral endogenous sequences to other mammals. These include Class I and Class II retroviral sequences, foamy viruses, and deltaretroviruses, as well as filovirus, bornavirus, and parvovirus endogenous viral elements. Some of these endogenous viruses are sufficiently preserved in bat genomes to be expressed, with potential effects for host biology. It is clear that the bat immune system differs when compared with other mammals, yet the role that virus-derived endogenous elements may have played in the evolution of bat immunity is poorly understood. In this review, we discuss some of the bat-specific immune mechanisms that may have resulted in a virus-tolerant phenotype and link these to the long-standing virus-host coevolution that may have allowed a large diversity of endogenous retroviruses and other endogenous viral elements to colonize bat genomes. We also consider the possible effects of endogenization in the evolution of the bat immune system. Expected final online publication date for the Annual Review of Virology, Volume 7 is September 29, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... was complete. Expression of env proteins in mammals, including human, mouse, cattle, sheep, cats, and dogs, allows for the generation of multinuclear syncytiotrophoblasts in the placenta as an outer cellular layer by the fusion of trophoblast cells (Denner, 2016a). The physiological function of PERV env remains unknown. ...
Article
Full-text available
In pig-to-human xenotransplantation, the transmission risk of porcine endogenous retroviruses (PERVs) is of great concern. However, the distribution of PERVs in pig genomes, their genetic variation among Eurasian pigs, and their evolutionary history remain unclear. We scanned PERVs in the current pig reference genome (assembly Build 11.1), and identified 36 long complete or near-complete PERVs (lcPERVs) and 23 short incomplete PERVs (siPERVs). Besides three known PERVs (PERV-A, -B, and -C), four novel types (PERV-JX1, -JX2, -JX3, and -JX4) were detected in this study. According to evolutionary analyses, the newly discovered PERVs were more ancient, and PERV-Bs probably experienced a bottleneck ~0.5 million years ago (Ma). By analyzing 63 high-quality porcine whole-genome resequencing data, we found that the PERV copy numbers in Chinese pigs were lower (32.0±4.0) than in Western pigs (49.1±6.5). Additionally, the PERV sequence diversity was lower in Chinese pigs than in Western pigs. Regarding the lcPERV copy numbers, PERV-A and -JX2 in Western pigs were higher than in Chinese pigs. Notably, Bama Xiang (BMX) pigs had the lowest PERV copy number (27.8±5.1), and a BMX individual had no PERV-C and the lowest PERV copy number (23), suggesting that BMX pigs were more suitable for screening and/or modification as xenograft donors. Furthermore, we identified 451 PERV transposon insertion polymorphisms (TIPs), of which 86 were shared by all 10 Chinese and Western pig breeds. Our findings provide systematic insights into the genomic distribution, variation, evolution, and possible biological function of PERVs.
... Evolution of mammals with viruses gave rise to syncytial capability. The endogenous retroviral gene sycytin allows for trophoblast fusion, and may contribute to viral suppression (44). Syncytiotrophoblast expresses immunoglobulin Fc receptors, facilitating transfer of passive humoral immunity to the fetus. ...
Article
The placenta functions as a shield against infection of the fetus. The innate and adaptive immune defenses of the developing fetus are poorly equipped to fight infections. Infection by bacteria, viruses, and protozoa may cause infertility, spontaneous abortion, stillbirth, growth retardation, anomalies of development, premature delivery, neonatal morbidity, and mortality. However, appreciation of the human microbiome and host cell–microbe interactions must be taken into consideration as we try to determine what interactions are pathologic. Infection is typically recognized histologically by the presence of inflammation. Yet, several factors make comparison of the placenta to other human organs difficult. The placenta comprises tissues from two persons, complicating the role of the immune system. The placenta is a temporary organ. It must be eventually expelled; the processes leading to partuition involve maternal inflammation. What is normal or pathologic may be a function of timing or extent of the process. We now must consider whether bacteria, and even some viruses, are useful commensals or pathogens. Still, recognizing infection of the placenta is one of the most important contributions placental pathologic examination can give to care of the mother and neonate. This review provides a brief overview of placental defense against infection, consideration of the placental microbiome, routes of infection, and the histopathology of amniotic fluid infection and TORCH infections.
... One striking example is the lineage-specific cooption of endogenous retroviral envelope genes as "syncytin" genes, which are essential for trophoblast cell fusion (Mi, et al. 2000) and probably related to maternofetal tolerance (Mangeney, et al. 2007). These exapted syncytin genes have been identified in lineages including humans, mice, cows, sheep and rabbits, but not in pigs and horses which do not form a multinucleated syncytiotrophoblast layer (Furukawa, et al. 2014;Denner 2016). Endogenous retroviruses (ERVs) are one class of Transposable elements (TEs) (that also include LINEs, SINEs, and DNA transposons) that make up more than half of human genome and have been documented as critical facilitators of genome evolution (Feschotte 2008;Chuong, et al. 2016a). ...
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In mammals, the placenta mediates maternal-fetal nutrient and waste exchange and provides immunomodulatory actions that facilitate maternal-fetal tolerance. The placenta is highly diversified among mammalian species, yet the molecular mechanisms that distinguish the placenta of human from other mammals are not fully understood. Using an interspecies transcriptomic comparison of human, macaque, and mouse term placentae, we identified hundreds of genes with lineage-specific expression – including dozens that are placentally-enriched and potentially related to pregnancy. We further annotated the enhancers for different human tissues using epigenomic data and demonstrate that the placenta and chorion are unique in that their enhancers display the least conservation. We identified numerous lineage-specific human placental enhancers, and found they are highly overlapped with specific families of endogenous retroviruses (ERVs), including MER21A, MER4A/B and MER39B that were previously linked to immune response and placental function. Among these ERV families, we further demonstrate that MER41 insertions create dozens of lineage-specific Serum Response Factor (SRF) binding loci in human, including one adjacent to FBN2 , a placenta-specific gene with increased expression in humans that produces the peptide hormone placensin to stimulate glucose secretion and trophoblast invasion. Our results demonstrate the prevalence of lineage-specific human placental enhancers which are frequently associated with ERV insertions and likely facilitated the lineage-specific evolution of the mammalian placenta.
... In each case, the retroviral env gene has been repurposed from its normal function of producing surface and transmembrane proteins for retroviral and host cell membrane fusion (Lavialle et al. 2013). About ten non-orthologous ERVs in eight host lineages have been repurposed to contribute cell-cell fusion activities (Denner 2016;Lavialle et al. 2013 and that these domestications were facilitated by mammalian-specific qualities that promoted cooption of certain ERVs with specific features distinguishing them from the vast pool of non-coopted ERVs in mammalian genomes. ...
Article
Full-text available
Retroviruses have infiltrated vertebrate germlines for millions of years as inherited endogenous retroviruses (ERVs). Mammalian genomes host large numbers of ERVs and transposable elements (TEs), including retrotransposons and DNA transposons, that contribute to genomic innovation and evolution as coopted genes and regulators of diverse functions. To explore features distinguishing coopted ERVs and TEs from other integrations, we focus on the potential role of ZBED6 and repeated ERV domestication as repurposed Syncytin genes. The placental mammal-specific ZBED6 is a DNA transposon-derived transcription regulator and we demonstrate that its binding motifs are associated with distinct Syncytins, and that ZBED6 binding motifs are 2-to-3 fold more frequent in ERVs than in flanking DNA. Our observations suggest that ZBED6 could contribute an extended regulatory role of genomic expression, utilizing ERVs as platforms for genomic innovation and evolution.
... Porcine cells and organs have been shown to produce PERV particles, which presents a risk of zoonotic transmission if left to circulate in humans (12). Additionally, PERVs are considered to be a source of envelope GPs that may be leveraged in porcine placentogenesis (13). Although PERVs have received significant attention for their prospective role in xenotransplantation, there is little biochemical data regarding PERV envelope GPs. ...
Article
Full-text available
Retroviral elements from endogenous retroviruses have functions in mam-malian physiology. The best-known examples are the envelope proteins that function in placenta development and immune suppression. Porcine endogenous retroviruses (PERVs) are an understudied class of endogenous retroviruses that infect cultured human cells, raising concern regarding porcine xenografts. The PERV envelope glycopro-tein has also been proposed as a possible swine syncytin with a role in placental development. Despite the growing interest in PERVs, their envelope glycoproteins remain poorly characterized. Here, we successfully determined the postfusion crystal structure of the PERV core fusion ectodomain. The PERV fusion protein structure reveals a conserved class I viral fusion protein six-helix bundle. Biophysical experiments demonstrated that the thermodynamic stability of the PERV fusion protein secondary structure was the same at physiological and acidic pHs. A conserved surface analysis highlights the high degree of sequence conservation among retroviral fusogens in the chain reversal region that facilitates the large-scale conformational change required for membrane fusion. Further structural alignment of class I viral fusogens revealed a phylogenetic clustering that shows evolution into various lineages that correlate with virus mechanisms of cell entry. Our work indicates that structural dendrograms can be used to qualitatively infer insights into the fusion mechanisms of newly discovered class I viral fusogen structures. IMPORTANCE Class I viral fusion proteins represent a diverse group of fusogens that cat-alyze membrane fusion. Although structural studies have focused on those from exoge-nous viruses, ancient retroviral infections of germ line cells have immortalized ancient fusogens in eukaryotic genomes. These "fossilized" glycoproteins are poorly defined compared to modern fusogens. In this study, we characterized and determined the structure of the porcine endogenous retrovirus fusogen, an ancient retroviral element captured by swine. This fusion protein revealed remarkable alignment to exogenous ret-roviral fusion proteins, suggesting that fossil fusogens utilize similar structural determinants to perform membrane fusion. Moreover, structural phylogenetic analysis demonstrates that class I viral fusogens cluster into distinct lineages defined by mechanism of membrane fusion. Our results suggest that structural dendrograms can be used to infer mechanistic insights for uncharacterized fusion proteins.
... Summing up these facts, it is tempting to speculate that the horizontal transfer of viral fusion genes has contributed to the development of sexual reproduction [52], thereby allowing the formation of complex multicellular organisms [53]. ERV genes exert many functions in the development, including gene activation in a zygote after fertilization [54], promotion of placenta development, protection of the host from infection, and regulation of genome plasticity [55]. The syncytin-2 protein (HERV-FRD) is an immunosuppressant, whose immunosuppressive domain helps the fetus to escape the mother's immune system [56]. ...
Article
Full-text available
The advancement of precision medicine critically depends on the robustness and specificity of the carriers used for the targeted delivery of effector molecules in the human body. Numerous nanocarriers have been explored in vivo, to ensure the precise delivery of molecular cargos via tissue-specific targeting, including the endocrine part of the pancreas, thyroid, and adrenal glands. However, even after reaching the target organ, the cargo-carrying vehicle needs to enter the cell and then escape lysosomal destruction. Most artificial nanocarriers suffer from intrinsic limitations that prevent them from completing the specific delivery of the cargo. In this respect, extracellular vesicles (EVs) seem to be the natural tool for payload delivery due to their versatility and low toxicity. However, EV-mediated delivery is not selective and is usually short-ranged. By inserting the viral membrane fusion proteins into exosomes, it is possible to increase the efficiency of membrane recognition and also ease the process of membrane fusion. This review describes the molecular details of the viral-assisted interaction between the target cell and EVs. We also discuss the question of the usability of viral fusion proteins in developing extracellular vesicle-based nanocarriers with a higher efficacy of payload delivery. Finally, this review specifically highlights the role of Gag and RNA binding proteins in RNA sorting into EVs.
... Antibodies against HERV-K have been found in tumor patients and pregnant women, indicating that virus proteins are expressed [25,26]. It is well known now that the envelope proteins of endogenous retroviruses of numerous species are functioning as syncytins in the placenta development (for review, see [27,28]). ...
Article
Full-text available
Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs, and some of them are able to infect human cells. Therefore, PERVs pose a risk for xenotransplantation, the transplantation of pig cells, tissues, or organ to humans in order to alleviate the shortage of human donor organs. Up to 2021, a huge body of knowledge about PERVs has been accumulated regarding their biology, including replication, recombination, origin, host range, and immunosuppressive properties. Until now, no PERV transmission has been observed in clinical trials transplanting pig islet cells into diabetic humans, in preclinical trials transplanting pig cells and organs into nonhuman primates with remarkable long survival times of the transplant, and in infection experiments with several animal species. Nevertheless, in order to prevent virus transmission to the recipient, numerous strategies have been developed, including selection of PERV-C-free animals, RNA interference, antiviral drugs, vaccination, and genome editing. Furthermore, at present there are no more experimental approaches to evaluate the full risk until we move to the clinic.
... For example, over 300 transcriptional signals used for placental development in mice come from a superfamily of mouse-specific ERVs, most of which are not even found in rats [228]. Similarly, each mammalian order has its own distinct set of Syncytin proteins [231,232]. This is not the pattern we would expect to find if these ERV-derived functions arose early in mammalian evolution and were retained as different orders of mammals radiated over time. ...
Chapter
Eibi Nevo’s research highlights the complexity of evolutionary responses to ecological parameters. This important work pioneered a growing awareness of the multiple levels of biological activity and organismal interactions that contribute to evolutionary change. In large measure, our current understanding of adaptive innovation is based on the newly acquired ability to track the details of evolutionary processes through genome analysis. Genomics has unambiguously demonstrated the importance of cell fusion, symbiosis, interspecific hybridization, genome restructuring involving mobile DNA elements, and the many forms of infectious heredity all to be major contributors to the appearance of organisms with novel adaptive characteristics. In addition, genomics has confirmed interspecific hybridization as a major stimulus to the rapid emergence of new taxa among sexually reproducing organisms. The work of Eibi and many other scientists has shown that ecology can trigger and influence all these different modes of hereditary change. We must recognize that genomic analyses have provided 21st century evolutionary scientists with such a rich variety of documented paths to inherited novelty that it has become impossible to formulate a comprehensive theory of evolutionary change. Thus an important part of the future in evolution science will be to adapt Eibi’s wisdom by devising synthetic Evolution Canyons as complex experimental microcosms, where we can rigorously study the principles governing ecological and biological interactions in adaptive innovation. Hopefully those interactive principles will make it possible to integrate information from genomic analysis into a coherent picture of evolution as a biological response to ecological change.
... One striking example is the lineagespecific co-option of endogenous retroviral envelope genes as "syncytin" genes, which are essential for trophoblast cell fusion (Mi et al. 2000) and probably related to maternofetal tolerance (Mangeney et al. 2007). These exapted syncytin genes have been identified in lineages including humans, mice, cows, sheep, and rabbits, but not in pigs and horses which do not form a multinucleated syncytiotrophoblast layer (Furukawa et al. 2014;Denner 2016). Endogenous retroviruses (ERVs) are one class of Transposable elements (TEs) (that also include LINEs, SINEs, and DNA transposons) that make up more than half of human genome and have been documented as critical facilitators of genome evolution (Feschotte 2008;Chuong et al. 2016a). ...
Article
Full-text available
In mammals, the placenta mediates maternal-fetal nutrient and waste exchange and acts in an immunomodulatory way to facilitate maternal-fetal tolerance. The placenta is highly diverse across mammalian species, yet the molecular mechanisms that distinguish the placenta of human from other mammals are not fully understood. Using an interspecies transcriptomic comparison of human, macaque, and mouse late-gestation placentae, we identified hundreds of genes with lineage-specific expression—including dozens that are placentally-enriched and potentially related to pregnancy. We further annotated the enhancers for different human tissues using epigenomic data and demonstrate that the placenta and chorion are unique in that their enhancers display the least conservation. We identified numerous lineage-specific human placental enhancers and found they highly overlap with specific families of endogenous retroviruses (ERVs), including MER21A, MER41A/B and MER39B that were previously linked to immune response and placental function. Among these ERV families, we further demonstrate that MER41A/B insertions create dozens of lineage-specific Serum Response Factor (SRF) binding loci in human, including one adjacent to FBN2, a placenta-specific gene with increased expression in humans that produces the peptide hormone placensin to stimulate glucose secretion and trophoblast invasion. Overall, our results demonstrate the prevalence of lineage-specific placental enhancers which are frequently associated with ERV insertions and likely facilitate the lineage-specific evolution of the mammalian placenta.
... also known as ERVWE-1) can be mentioned. The encoded protein called syncytin-1 is expressed in the placenta, where it mediates cytotrophoblast fusion to the syncytiotrophoblast layer based on its fusogenic properties (7,8). On the other hand, activation of HERV-W ENV has been associated with neurological disorders like multiple sclerosis (MS) due to its localization in brain lesions and detection of anti-HERV-W antibodies in sera of MS patients (9)(10)(11). ...
Article
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Neuroblastoma (NB) is the commonest solid tumor outside the central nervous system in infancy and childhood with a unique biological heterogeneity. In patients with advanced, metastasizing neuroblastoma, treatment failure and poor prognosis is often marked by resistance to chemo- or immunotherapy. Thus, identification of robust biomarkers seems essential for understanding tumor progression and developing effective therapy. Here, we have studied the expression of human endogenous retroviruses (HERV) as potential targets in NB cell lines during stem-cell medium-induced microenvironmental change. Quantitative PCR revealed that relative expression of the HERV-K family and HERV-W1 ENV were increased in all three NB cell lines after incubation in stem-cell medium. Virus transcriptome analyses revealed the transcriptional activation of three endogenous retrovirus elements: HERV-R ENV (ERV3-1), HERV-E1 and HERV-Fc2 ENV (ERVFC1-1). Known malignancy markers in NB, e.g. proto-oncogenic MYC or MYCN were expressed highly heterogeneously in the three investigated NB cell lines with up-regulation of MYC and MYCN upon medium-induced microenvironmental change. In addition, SiMa cells exclusively showed a phenotype switching from loosely-adherent monolayers to low proliferating grape-like cellular aggregates, which was accompanied by an enhanced CD133 expression. Interestingly, the overexpression of HERV was associated with a significant elevation of immune checkpoint molecule CD200 in both quantitative PCR and RNA-seq analysis suggesting tumor escape mechanism in NB cell lines after incubation in serum-free stem cell medium.
... ERV remnants can attain vital functions essential to host biology, and endogenization has in fact been considered a mechanism for host evolution (12). This review does not discuss the role of endogenous retroviral syncytin proteins in placentation and mammalian evolution, normal biological processes, immune modulation, oncogenesis, and disease progression, and readers are referred to these topics elsewhere (10,(13)(14)(15)(16). We specifically examine reported impacts of endogenous virus on outcomes of exogenous retroviral infections. ...
Article
Endogenous retroviruses (ERVs) serve as markers of ancient viral infections and provide invaluable insight into host and viral evolution. ERVs have been exapted to assist in performing basic biological functions, including placentation, immune modulation, and oncogenesis. A subset of ERVs share high nucleotide similarity to circulating horizontally transmitted exogenous retrovirus (XRV) progenitors. In these cases, ERV–XRV interactions have been documented and include ( a) recombination to result in ERV–XRV chimeras, ( b) ERV induction of immune self-tolerance to XRV antigens, ( c) ERV antigen interference with XRV receptor binding, and ( d) interactions resulting in both enhancement and restriction of XRV infections. Whereas the mechanisms governing recombination and immune self-tolerance have been partially determined, enhancement and restriction of XRV infection are virus specific and only partially understood. This review summarizes interactions between six unique ERV–XRV pairs, highlighting important ERV biological functions and potential evolutionary histories in vertebrate hosts. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 9 is February 16, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... For instance, only about 20% of ERV are transcribed in chicken embryo fibroblasts, and a subset of these are also transcribed in vivo (Bolisetty et al., 2012). In addition, recent studies show that some silent ERV can be activated and expressed under certain conditions (Crichton et al., 2014), and their expression is affected by many factors, such as cell type or tissue type (especially placenta and germ cells), cell differentiation and aging process, cytokines, the factors that disrupt the normal function of cells, and nutritional factors (Taruscio and Mantovani, 2004;Denner, 2016;Elaheh et al., 2018). In recent decades, the biological functions of ERV have been gradually uncovered: 1) Transposition of ERV may destabilize host genomes, but ERV as an original genetic material allow host animals to increase diversity among and within species, enhance adaptability to environment, and maintain continuous evolution (Zhang et al., 2008); 2) Promoters and enhancers in the LTR regions of ERV can affect the transcription of their adjacent genes and alter the epigenetic status of adjacent regions (such as DNA methylation and histone modification) (Thompson et al., 2016); 3) By binding Env proteins to host receptors, ERV can block the binding of exogenous viruses to the same receptors, thus providing host cells with the ability to resist exogenous viruses (Nadeau et al., 2015); 4) ERV transcripts can activate the innate immune system and induce the production of cytokines such as IFN via the double-stranded RNA-dependent TLR3/MDA5 signaling pathway, thus inhibiting tumors (Chiappinelli et al., 2015); and 5) ERV are also involved in the occurrence and development of some diseases, such as aging, autoimmunity, and degenerative neurological diseases (Mager and Stoye, 2015;Nadeau et al., 2015). ...
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It is known that nutrition and immunity are connected, but the mechanism is not very clear. Endogenous retroviruses (ERVs) account for 8-10% of the human and mouse genomes and play an important role in some biological processes of animals. Recent studies indicate that the activation of ERVs can affect the expression of the immunity- or inflammation-related genes, and the activities of ERVs are subjected to regulation of many factors including nutritional factors. Therefore, we hypothesize that nutritional status can affect the expression of the immunity- or inflammation-related genes via ERVs. To verify this hypothesis, the nutritional status of animals was altered by fasting or overfeeding, and the expression of intact ERV (ERVK18P, ERVK25P) and immunity or inflammation-related genes (DDX41, IFIH1, IFNG, IRF7, STAT3) in the liver was determined by quantitative PCR, followed by overexpressing ERVK25P in goose primary hepatocytes and determining the expression of the immunity or inflammation-related genes. The data showed that compared with the control group (no fasting), the expression of ERVs and the immunity- or inflammation-related genes was increased in the liver of the fasted chickens but decreased in the liver of the fasted geese. Moreover, compared with the control group (routinely fed), the expression of ERVs and the immunity- or inflammation-related genes was increased in the liver of the overfed geese. In addition, overexpression of ERVK25P in goose primary hepatocytes can induce the expression of the immunity or inflammation-related genes. In conclusion, these findings suggest that ERVs mediate the effects of fasting and overfeeding on the expression of the immunity- or inflammation-related genes, the mediation was varied with poultry species, and ERVs and the immunity- or inflammation-related genes may be involved in the development of goose fatty liver. This study provides a potential mechanism for the connection between nutrition and immunity.
... Transposable elements including endogenous retroviruses are a major driving force of evolution (Belyayev, 2014;Koonin, 2016;Ito et al., 2020). Endogenous retroviruses for example play a role in the evolution of the placenta by providing fusogenic envelope genes co-opted for the formation of the syncytiotrophoblasts and having immunosuppressive properties (for review see Denner, 2016a). Most important, retroviral regulatory sequences have also been co-opted for host needs, they specify the temporal control of cellular genes. ...
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This study reports and characterises two novel distinct lineages of foamy viruses (FVs) in the forms of endogenous retroviruses (ERVs). Several closely related elements were found in the genome of oriental stork (Ciconia boyciana) and other was found in the genome of spine-bellied sea snake (Hydrophis hardwickii), designated ERV-Spuma.N-Cbo (where 'N' runs from one to thirteen) and ERV-Spuma.1-Hha, respectively. This discovery of avian and serpentine endogenous FVs adds snakes, and perhaps more crucially, birds to the list of currently known hosts of FVs, in addition to mammals, reptiles, amphibians, and fish. This indicates that FVs are, or at least were, capable of infecting all major lineages of vertebrates. Moreover, together with other FVs, phylogenetic analyses showed that both of them are most closely related to mammalian FVs. Further examination revealed that reptilian FVs form a deep paraphyletic group that is basal to mammalian and avian FVs, suggesting that there were multiple ancient FV cross-class transmissions among their hosts. Evolutionary timescales of various FV lineages were estimated in this study, in particular, the timescales of reptilian FVs and that of the clade of mammalian, avian, and serpentine FVs. This was accomplished by using the recently established time-dependent rate phenomenon models, inferred using mainly the knowledge of the co-speciation history between FVs and mammals. It was found that the estimated timescales matched very well with those of reptiles. Combined with the observed phylogenetic patterns, these results suggested that FVs likely co-speciated with ancient reptilian animals, but later jumped to a protomammal and/or a bird, which ultimately gave rise to mammalian and avian FVs. These results contribute to our understanding of FV emergence, specifically the emergence of mammalian and avian FVs, and provide new insights into how FVs co-evolved with their non-mammalian vertebrate hosts in the distant past.
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Syncytin genes are fusogenic envelope protein (env) genes of retroviral origin that have been captured for a function in placentation. Within rodents, two such genes have previously been identified in the mouse-related clade, allowing a demonstration of their essential role via knockout mice. Here, we searched for similar genes in a second major clade of the Rodentia order, the squirrel-related clade, taking advantage of the complete sequencing of the ground squirrel Ictidomys tridecemlineatus genome. In silico search for env genes with full coding capacity identified several candidate genes with one displaying placenta-specific expression, as revealed by quantitative reverse transcription-PCR analysis of a large panel of tissues. This gene belongs to a degenerate endogenous retroviral element, with recognizable hallmarks of an integrated provirus. Cloning of the gene in an expression vector for ex vivo cell-cell fusion and pseudotype assays demonstrated fusogenicity on a large panel of mammalian cells. In situ hybridization on placenta sections showed specific expression in domains where trophoblast cells fuse into a syncytiotrophoblast at the fetomaternal interface, consistent with a role in syncytium formation. Finally, we show that the gene is conserved among the tribe Marmotini, thus dating its capture back to about at least 25 million years ago, with evidence for purifying selection and conservation of fusogenic activity. This gene that we named syncytin-Mar1 is distinct from all seven syncytin genes identified to date in eutherian mammals and is likely to be a major effector of placentation in its related clade.
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Retroviruses have had a tremendous, recurring impact on animal genomes. At least eight percent of the human genome is comprised of retroviruses at various stages of “fossilization” (1). These elements represent retroviruses that have directly infected genomes of germline tissues such that their imprints can now be passed on with the rest of the genome. Most insertions into host genomes are likely to (i) be instantly so deleterious that they are never passed on, or alternatively (ii) have very little consequence to host biology and be expected to abrade away via the accumulation of mutations (2). Although the large fraction of retroviral imprints show expected signatures of mutational degeneration, some retroviral genes have been surprisingly preserved against mutational inactivation. These represent instances in which host genomes have usurped some retroviral genes for their own use. Particularly intriguing are host domestications of retroviral envelope (env) genes. The best-known classes of these genes are the syncytin genes, which have been coopted by the host to mediate nutrient transfer from the mother to the developing embryo in eutherian mammals. In PNAS, Dupressoir and coworkers describe the oldest known domestication of retroviral envelopes represented by the Syncytin-Car1 gene (3), which was domesticated at least 60 Mya, before the radiation of Carnivora. These results extend the range and age of syncytin domestications in mammals, but also raise intriguing questions about the biology underlying their recurrent invention.
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In most mammalian species, a critical step of placenta development is the fusion of trophoblast cells into a multinucleated syncytiotrophoblast layer fulfilling essential fetomaternal exchange functions. Key insights into this process came from the discovery of envelope genes of retroviral origin, the syncytins, independently acquired by the human (syncytin-1 and -2), mouse (syncytin-A and -B), and rabbit (syncytin-Ory1) genomes, with fusogenic properties and placenta-specific expression. We previously showed that mouse syncytin-A is essential for the formation of one of the two syncytiotrophoblast layers and for embryo survival. Here, we have generated syncytin-B KO mice and demonstrate that syncytin-B null placenta displays impaired formation of syncytiotrophoblast layer II (ST-II), with evidence of unfused apposed cells, and enlargement of maternal lacunae disrupting the placenta architecture. Unexpectedly, syncytin-B null embryos are viable, with only limited late-onset growth retardation and reduced neonate number. Microarray analyses identified up-regulation of the connexin 30 gene in mutant placentae, with the protein localized at the fetomaternal interface, suggesting gap junction-mediated compensatory mechanisms. Finally, double-KO mice demonstrate premature death of syncytin-A null embryos if syncytin-B is deleted, indicating cooperation between ST-I and ST-II. These findings establish that both endogenous retrovirus-derived syncytin genes contribute independently to the formation of the two syncytiotrophoblast layers during placenta formation, demonstrating a major role of retroviral gene capture, through convergent evolution, to generate multiple placental structures. Although some are absolutely required for completion of pregnancy, others are still amenable to "epigenetic" compensations, thus illustrating the complexity of the molecular machinery that developed during placental evolution.
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ERV-3 is an evolutionarily conserved single-copy human endogenous retrovirus with a coding envelope gene potentially involved in important placental functions. We have investigated the sequence variability of this gene among 150 unrelated Caucasian individuals and found eight polymorphic sites. One of them corresponds to the introduction of a stop codon resulting in the production of a severely truncated ERV-3 envelope protein lacking both the fusion peptide and the immunosuppressive domain of the protein. The stop codon is observed in a homozygous state in approximately 1% of Caucasian individuals without evidence for counterselection, thus precluding the involvement of any essential function of the gene in placental implantation and development. This natural knockout provides a mean to investigate other potential roles for this otherwise highly conserved gene.
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Endogenous retroviruses (ERVs) are the proviral phase of exogenous retroviruses that become integrated into a host germ line. They can play an important role in the host genome. Bioinformatic tools have been used to detect ERVs in several vertebrates, primarily primates and rodents. Less information is available regarding ERVs in other mammalian groups, and the source of this information is basically experimental. We analyzed the genome of the cow (Bos taurus) using three different methods. A BLAST-based method detected 928 possible ERVs, LTR_STRUC detected 4,487 elements flanked by long terminal repeats (LTRs), and Retrotector detected 9,698 ERVs. The ERVs were not homogeneously distributed across chromosomes; the number of ERVs was positively correlated with chromosomal size and negatively correlated with chromosomal GC content. The bovine ERVs (BoERVs) were classified into 24 putative families, with 20 of them not previously described. One of these new families, BoERV1, was the most abundant family and appeared to be specific to ruminants. An analysis of representatives of ERV families from rodents, primates, and ruminants showed a phylogenetic relationship following their hosts' relationships. This study demonstrates the importance of using multiple methods when trying to identify new ERVs and shows that the number of bovine ERV families is not as limited as previously thought.
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Syncytins are envelope genes of retroviral origin that have been co-opted by the host to mediate a specialized function in placentation. Two of these genes have already been identified in primates, as well as two distinct, non orthologous genes in rodents. Here we identified within the rabbit Oryctolagus cuniculus-which belongs to the lagomorpha order- an envelope (env) gene of retroviral origin with the characteristic features of a bona fide syncytin, that we named syncytin-Ory1. An in silico search for full-length env genes with an uninterrupted open reading frame within the rabbit genome first identified two candidate genes that were tested for their specific expression in the placenta by quantitative RT-PCR of RNA isolated from a large set of tissues. This resulted in the identification of an env gene with placenta-specific expression and belonging to a family of endogenous retroelements present at a limited copy number in the rabbit genome. Functional characterization of the identified placenta-expressed env gene after cloning in a CMV-driven expression vector and transient transfection experiments, demonstrated both fusogenic activity in an ex vivo cell-cell fusion assay and infectivity of pseudotypes. The receptor for the rabbit syncytin-Ory1 was found to be the same as that for human syncytin-1, i.e. the previously identified ASCT2 transporter. This was demonstrated by a co-culture fusion assay between hamster A23 cells transduced with an expression vector for ASCT2 and A23 cells transduced with syncytin-Ory1. Finally, in situ hybridization of rabbit placenta sections with a syncytin-Ory1 probe revealed specific expression at the level of the junctional zone between the placental lobe and the maternal decidua, where the invading syncytial fetal tissue contacts the maternal decidua to form the labyrinth, consistent with a role in the formation of the syncytiotrophoblast. The syncytin-Ory1 gene is found in Leporidae but not in Ochotonidae, and should therefore have entered the lagomorpha order 12-30 million years ago. The identification of a novel syncytin gene within a third order of mammals displaying syncytiotrophoblast formation during placentation strongly supports the notion that on several occasions retroviral infections have resulted in the independent capture of genes that have been positively selected for a convergent physiological role.
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In most mammalian species, a key process of placenta development is the fusion of trophoblast cells into a highly specialized, multinucleated syncytiotrophoblast layer, through which most of the maternofetal exchanges take place. Little is known about this process, despite the recent identification of 2 pairs of envelope genes of retroviral origin, independently acquired by the human (syncytin-1 and syncytin-2) and mouse (syncytin-A and syncytin-B) genomes, specifically expressed in the placenta, and with in vitro cell-cell fusion activity. By generating knockout mice, we show here that homozygous syncytin-A null mouse embryos die in utero between 11.5 and 13.5 days of gestation. Refined cellular and subcellular analyses of the syncytin-A-deficient placentae disclose specific disruption of the architecture of the syncytiotrophoblast-containing labyrinth, with the trophoblast cells failing to fuse into an interhemal syncytial layer. Lack of syncytin-A-mediated trophoblast cell fusion is associated with cell overexpansion at the expense of fetal blood vessel spaces and with apoptosis, adding to the observed maternofetal interface structural defects to provoke decreased vascularization, inhibition of placental transport, and fetal growth retardation, ultimately resulting in death of the embryo. These results demonstrate that syncytin-A is essential for trophoblast cell differentiation and syncytiotrophoblast morphogenesis during placenta development, and they provide evidence that genes captured from ancestral retroviruses have been pivotal in the acquisition of new, important functions in mammalian evolution.
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