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Endogenous Retroviruses and Placental Diversity: History
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In mammals, although size differences exist, most of organs consists of the same cells and exhibits the same structures. However, placentas are quite diverse in cell components, structures and the association between fetal membranes and maternal uteri. These differences have not been well characterized. Recently, endogenous retroviruses (ERVs) have been thought to have caused such diversity, which require both PEG type genes and syncytins. 

  • placenta
  • structural diversity
  • endogenous retroviruses (ERVs)
  • mammals

1. Introduction

Placentas are most diverse organs across mammalian species. Although the mammals obtained several new genes specific to pregnancy recognition and/or maintenance, the diversity of placental structures cannot be explained through the expression and functions of functional genes. It has long been thought that viral/transposon components exist in organism’ genomes. In 2000, Mi et al. found that endogenous retrovirus (ERV, Syncytin-1) exists in the human placenta. Since then, syncytin-like structures and their functions have been reported in many animal species [1][2][3], but none of them contain the same nucleotide structures, strongly suggesting that these ERVs are independently captured and integrated into mammalian genomes [4].

2. Involvement of PEG10/PEG11/RTL1 in the Initial Formation of Mammalian Placentas

Imprinting genes such as those of paternally expressed genes PEG10 [5] and PEG11/RTL1 [6] have been extensively studied and through gene ablation studies, these genes are found necessary for the formation of placental structures [7][8]. Because PEG10 is acquired more than 146 million years ago, PEG10 gene could explain the initial formation of placentas in mammals. However, placental diversity cannot be explained. The researchers have presented recent and related findings that explain how syncytin genes are involved in placental diversity. The researchers presented recent observations on ERVs and how these ERVs control gene expression of both functional genes as well as ERV themselves [9][10]. Based on the recent information, the researchers have presented the baton-pass hypothesis, successive integration of ERVs [11] and new models explaining placental diversity.

3. New Model Explaining Placental Diversity

Fusogenic activity in the mammalian trophectoderm exhibits a great deal of similarity across species, notwithstanding the huge diversity in placental structures and type of placentation such as invasive (humans and murine) or non-invasive (ruminants). Based on actual experimentation and typical amino acid sequences, their functions are generally limited to fusogenic activity and immunotolerance, which on their own are not sufficient to fully explain the structural diversity of placentas.

Dunn-Fletcher and colleagues (2018) have demonstrated that retroviral THE1B sequence serves as a cis-element for the regulation of corticotropin-releasing hormone (CRH) gene expression. Recently, progress has been made on research into ERV sequences serving as transcriptional and translational regulators [9][10]. These sequences could be co-opted for newly integrated retroviral gene regulation.

Nevertheless, solid confirmation of a retrovirus integration into sperm or egg has not been obtained, and the mechanism of integration remains unclear. The rarity of such events owes in no small part to the narrow windows of possibility for infection, but conversion to active ERVs is also contingent on the perfect confluence of criteria as follows:

  1. The insertion of ERVs can make functional genes of the host placenta-specific. i.e., Fematirn-1 integration into the intron 18 of pregnancy specific FAT2
  2. Its own LTR is sufficient to transcribe its own gene segments, which serves as the cis-acting element(s), resulting in the activation of a host gene. i.e., IFNG, THE1B on CRH.
  3. It can make use of transcription factors utilized by the pre-existing gene, as per the baton-pass hypothesis. i.e., A transcription factor GCM1 for syncytin-1 and syncytin-2.
  4. The ERV is co-opted along with its promoter/enhancer in the integrated genome; i.e., SPRE (syncytin post-transcriptional regulatory element).
  5. There is cooperation with miRNAs and/or lncRNAs, yet not definitely characterized under placental/trophectodermal conditions, either alone or together with ERV

In general, the placentas have lower DNA methylation levels than embryos, allowing freer expression of ERVs and transposons during gestation, thereby facilitating selection of advantageous genes from a wider market. Such extraembryonic circumstances might have allowed for not only domestication of ERVs to establish novel endogenous genes via multiple of selections but also the dissemination of ERVs and transposons throughout genomes as transcriptional regulators. Moreover, ERVs could serve as cis- and/or trans-acting factors for functional genes of the host. Similarly, various degrees of maternal-fetal cell interactions in the uterine compartment may have led to change in kinds and degree of gene usage [12], possibly resulting in cellular and morphological changes in placentas. It is interesting to speculate that the placentas themselves might have served as an evolutionary laboratory to promote mammalian evolution [13].

4. Conclusion

It is now clear that the emergence of mammalian placentas was made possible with the acquisition of therian PEG10 and eutherian PEG11/RTL1 genes, followed by independent, yet successive integrations of syncytin-type genes for structural variations. A question still arises as to whether the placental structures that we know now are the ultimate forms or are still evolving. If the latter is the case, placental structures may still be diversifying and new variations could be awaiting discovery

References

  1. Baba, K.; Nakaya, Y.; Shojima, T.; Muroi, Y.; Kizaki, K.; Hashizume, K.; Imakawa, K.; Miyazawa, T. Identification of novel endogenous betaretroviruses which are transcribed in the bovine placenta. J. Virol. 2011, 85, 1237–1245.
  2. Dewannieux, M.; Heidmann, T. Endogenous retroviruses: Acquisition, amplification and taming of genome invaders. Curr. Opin. Virol. 2013, 3, 646–656.
  3. Cornelis, G.; Heidmann, O.; Degrelle, S.A.; Vernochet, C.; Lavialle, C.; Letzelter, C.; Bernard-Stoecklin, S.; Hassanin, A.; Mulot, B.; Guillomot, M.; et al. Captured retroviral envelope syncytin gene associated with the unique placental structure of higher ruminants. Proc. Natl. Acad. Sci. USA 2013, 110, E828–E837.
  4. Nakagawa, S.; Bai, H.; Sakurai, T.; Nakaya, Y.; Konno, T.; Miyazawa, T.; Gojobori, T.; Imakawa, K. Dynamic evolution of endogenous retrovirus-derived genes expressed in bovine conceptuses during the period of placentation. Genome Biol. Evol. 2013, 5, 296–306.
  5. Ono, R.; Kobayashi, S.; Wagatsuma, H.; Aisaka, K.; Kohda, T.; Kaneko-Ishino, T.; Ishino, F. A retrotransposon-derived gene, PEG10, is a novel imprinted gene located on human chromosome 7q21. Genomics 2001, 73, 232–237.
  6. Charlier, C.; Segers, K.; Wagenaar, D.; Karim, L.; Berghmans, S.; Jaillon, O.; Shay, T.; Weissenbach, J.; Cockett, N.; Gyapay, G.; et al. Human-ovine comparative sequencing of a 250-kb imprinted domain encompassing the callipyge (clpg) locus and identification of six imprinted transcripts: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8. Genome. Res. 2001, 11, 850–862.
  7. Ono, R.; Nakamura, K.; Inoue, K.; Naruse, M.; Usami, T.; Wakisaka-Saito, N.; Hino, T.; Suzuki-Migishima, R.; Ogonuki, N.; Miki, H.; et al. Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality. Nat. Genet. 2006, 38, 101–106.
  8. Sekita, Y.; Wagatsuma, H.; Nakamura, K.; Ono, R.; Kagami, M.; Wakisaka, N.; Hino, T.; Suzuki-Migishima, R.; Kohda, T.; Ogura, A.; et al. Role of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placenta. Nat. Genet. 2008, 40, 243–248.
  9. Chuong, E.B. The placenta goes viral: Retroviruses control gene expression in pregnancy. PLoS Biol. 2018, 16, e3000028.
  10. Kitao, K.; Nakagawa, S.; Miyazawa, T. An ancient retroviral RNA element hidden in mammalian genomes and its involvement in co-opted retroviral gene regulation. Retrovirology 2021, 18, 36.
  11. Imakawa, K.; Nakagawa, S.; Miyazawa, T. Baton pass hypothesis: Successive incorporation of unconserved endogenous retroviral genes for placentation during mammalian evolution. Genes Cells 2015, 20, 771–788.
  12. Haig, D. Retroviruses and the placenta. Curr Biol 2012, 22, R609-613.
  13. Kaneko-Ishino, T.; Ishino, F. Mammalian-specific genomic functions: Newly acquired traits generated by genomic imprinting and LTR retrotransposon-derived genes in mammals. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 2015, 91, 511-538.
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