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15 pages, 2734 KiB

Open AccessArticle

Controlling Trophoblast Cell Fusion in the Human Placenta—Transcriptional Regulation of Suppressyn, an Endogenous Inhibitor of Syncytin-1

by Jun Sugimoto, Danny J. Schust, Makiko Sugimoto, Yoshihiro Jinno and Yoshiki Kudo

Biomolecules 2023, 13(11), 1627; https://doi.org/10.3390/biom13111627 - 7 Nov 2023

Cited by 2 | Viewed by 1854

Abstract

Cell fusion in the placenta is tightly regulated. Suppressyn is a human placental endogenous retroviral protein that inhibits the profusogenic activities of another well-described endogenous retroviral protein, syncytin-1. In this study, we aimed to elucidate the mechanisms underlying suppressyn’s placenta-specific expression. We identified [...] Read more.

Cell fusion in the placenta is tightly regulated. Suppressyn is a human placental endogenous retroviral protein that inhibits the profusogenic activities of another well-described endogenous retroviral protein, syncytin-1. In this study, we aimed to elucidate the mechanisms underlying suppressyn’s placenta-specific expression. We identified the promoter region and a novel enhancer region for the gene encoding suppressyn, ERVH48-1, and examined their regulation via DNA methylation and their responses to changes in the oxygen concentration. Like other endogenous retroviral genes, the ERVH48-1 promoter sequence is found within a characteristic retroviral 5′ LTR sequence. The novel enhancer sequence we describe here is downstream of this LTR sequence (designated EIEs: ERV internal enhancer sequence) and governs placental expression. The placenta-specific expression of ERVH48-1 is tightly controlled by DNA methylation and further regulated by oxygen concentration-dependent, hypoxia-induced transcription factors (HIF1α and HIF2α). Our findings highlight the involvement of (1) tissue specificity through DNA methylation, (2) expression specificity through placenta-specific enhancer regions, and (3) the regulation of suppressyn expression in differing oxygen conditions by HIF1α and HIF2α. We suggest that these regulatory mechanisms are central to normal and abnormal placental development, including the development of disorders of pregnancy involving altered oxygenation, such as preeclampsia, pregnancy-induced hypertension, and fetal growth restriction. Full article

(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond)

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17 pages, 4401 KiB

Open AccessArticle

In Vitro Expression Analysis Reveals HML6-c14 to Be an Attractive Research Target

by Takaya Oda

Biomolecules 2023, 13(9), 1378; https://doi.org/10.3390/biom13091378 - 12 Sep 2023

Viewed by 1378

Abstract

HML6-c14, a long terminal repeat (LTR)-type retrotransposon identified by expressed sequence tag (EST) database screening, was found to undergo RNA processing resembling that of placental tissue by in vitro expression analysis. Previous in situ hybridization studies using normal placental tissue showed that the [...] Read more.

HML6-c14, a long terminal repeat (LTR)-type retrotransposon identified by expressed sequence tag (EST) database screening, was found to undergo RNA processing resembling that of placental tissue by in vitro expression analysis. Previous in situ hybridization studies using normal placental tissue showed that the transcript remained in the nucleus. However, among the transcripts forcedly expressed in cultured cells, the transcript that retained the 3.3 kb intron was observed in the nucleus, and a part of the spliced transcript was observed outside the nucleus. To verify whether this cytoplasmic transcript could be translated, we examined the coding potential of the open reading frame (ORF), consisting of 109 codons on the spliced transcript, along with two other putative ORFs detected in the intronic region. As a result, none of the ORF-derived products could be detected by Western blotting as fusion proteins tagged with the FLAG epitope, suggesting that HML6-c14 belongs to a group of long non-coding RNA (lncRNA) genes. Promoter analysis of the upstream 6.4 kb genomic region also suggested that the 5′-LTR itself potentially retains high promoter activity. Despite losing the ability to produce functional proteins, HML6-c14 continues to retain its transcriptional ability while converting to an lncRNA gene, which is an interesting subject for future research. Full article

(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond)

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Review

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26 pages, 1018 KiB

Open AccessReview

Species-Specific Transcription Factors Associated with Long Terminal Repeat Promoters of Endogenous Retroviruses: A Comprehensive Review

by Md Jakir Hossain, Perpetual Nyame and Kazuaki Monde

Biomolecules 2024, 14(3), 280; https://doi.org/10.3390/biom14030280 - 26 Feb 2024

Cited by 2 | Viewed by 2054

Abstract

Endogenous retroviruses (ERVs) became a part of the eukaryotic genome through endogenization millions of years ago. Moreover, they have lost their innate capability of virulence or replication. Nevertheless, in eukaryotic cells, they actively engage in various activities that may be advantageous or disadvantageous [...] Read more.

Endogenous retroviruses (ERVs) became a part of the eukaryotic genome through endogenization millions of years ago. Moreover, they have lost their innate capability of virulence or replication. Nevertheless, in eukaryotic cells, they actively engage in various activities that may be advantageous or disadvantageous to the cells. The mechanisms by which transcription is triggered and implicated in cellular processes are complex. Owing to the diversity in the expression of transcription factors (TFs) in cells and the TF-binding motifs of viruses, the comprehensibility of ERV initiation and its impact on cellular functions are unclear. Currently, several factors are known to be related to their initiation. TFs that bind to the viral long-terminal repeat (LTR) are critical initiators. This review discusses the TFs shown to actively associate with ERV stimulation across species such as humans, mice, pigs, monkeys, zebrafish, Drosophila, and yeast. A comprehensive summary of the expression of previously reported TFs may aid in identifying similarities between animal species and endogenous viruses. Moreover, an in-depth understanding of ERV expression will assist in elucidating their physiological roles in eukaryotic cell development and in clarifying their relationship with endogenous retrovirus-associated diseases. Full article

(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond)

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17 pages, 1696 KiB

Open AccessReview

Roles of Human Endogenous Retroviruses and Endogenous Virus-Like Elements in Cancer Development and Innate Immunity

by Hirokazu Katoh and Tomoyuki Honda

Biomolecules 2023, 13(12), 1706; https://doi.org/10.3390/biom13121706 - 24 Nov 2023

Cited by 5 | Viewed by 2461

Abstract

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the host genome. Although mutations and silencing mechanisms impair their original role in viral replication, HERVs are believed to play roles in various biological processes. Long interspersed nuclear elements (LINEs) are non-LTR [...] Read more.

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the host genome. Although mutations and silencing mechanisms impair their original role in viral replication, HERVs are believed to play roles in various biological processes. Long interspersed nuclear elements (LINEs) are non-LTR retrotransposons that have a lifecycle resembling that of retroviruses. Although LINE expression is typically silenced in somatic cells, it also contributes to various biological processes. The aberrant expression of HERVs and LINEs is closely associated with the development of cancer and/or immunological diseases, suggesting that they are integrated into various pathways related to the diseases. HERVs/LINEs control gene expression depending on the context as promoter/enhancer elements. Some RNAs and proteins derived from HERVs/LINEs have oncogenic potential, whereas others stimulate innate immunity. Non-retroviral endogenous viral elements (nrEVEs) are a novel type of virus-like element in the genome. nrEVEs may also be involved in host immunity. This article provides a current understanding of how these elements impact cellular physiology in cancer development and innate immunity, and provides perspectives for future studies. Full article

(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond)

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15 pages, 1432 KiB

Open AccessReview

Progressive Exaptation of Endogenous Retroviruses in Placental Evolution in Cattle

by Toshihiro Sakurai, Kazuya Kusama and Kazuhiko Imakawa

Biomolecules 2023, 13(12), 1680; https://doi.org/10.3390/biom13121680 - 21 Nov 2023

Viewed by 1585

Abstract

Viviparity is made possible by the placenta, a structure acquired relatively recently in the evolutionary history of eutherian mammals. Compared to oviparity, it increases the survival rate of the fetus, owing to the eutherian placenta. Questions such as “How was the placenta acquired?” [...] Read more.

Viviparity is made possible by the placenta, a structure acquired relatively recently in the evolutionary history of eutherian mammals. Compared to oviparity, it increases the survival rate of the fetus, owing to the eutherian placenta. Questions such as “How was the placenta acquired?” and “Why is there diversity in placental morphology among mammalian species?” remain largely unsolved. Our present understanding of the molecules regulating placental development remains unclear, owing in no small part to the persistent obscurity surrounding the molecular mechanisms underlying placental acquisition. Numerous genes associated with the development of eutherian placental morphology likely evolved to function at the fetal–maternal interface in conjunction with those participating in embryogenesis. Therefore, identifying these genes, how they were acquired, and how they came to be expressed specifically at the fetal–maternal interface will shed light on some crucial molecular mechanisms underlying placental evolution. Exhaustive studies support the hypothesis that endogenous retroviruses (ERVs) could be evolutional driving forces for trophoblast cell fusion and placental structure in mammalian placentas including those of the bovine species. This review focuses on bovine ERVs (BERVs) and their expression and function in the placenta. Full article

(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond)

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14 pages, 969 KiB

Open AccessFeature PaperReview

Understanding the Immunopathology of HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma: A Comprehensive Review

by Shingo Nakahata, Daniel Enriquez-Vera, M. Ishrat Jahan, Kenji Sugata and Yorifumi Satou

Biomolecules 2023, 13(10), 1543; https://doi.org/10.3390/biom13101543 - 19 Oct 2023

Cited by 3 | Viewed by 3317

Abstract

Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 carriers have a lifelong asymptomatic balance between infected cells and host antiviral immunity; however, 5–10% of carriers lose this balance and develop ATL. Coinfection with Strongyloides promotes ATL development, suggesting that [...] Read more.

Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 carriers have a lifelong asymptomatic balance between infected cells and host antiviral immunity; however, 5–10% of carriers lose this balance and develop ATL. Coinfection with Strongyloides promotes ATL development, suggesting that the immunological status of infected individuals is a determinant of HTLV-1 pathogenicity. As CD4+ T cells play a central role in host immunity, the deregulation of their function and differentiation via HTLV-1 promotes the immune evasion of infected T cells. During ATL development, the accumulation of genetic and epigenetic alterations in key host immunity-related genes further disturbs the immunological balance. Various approaches are available for treating these abnormalities; however, hematopoietic stem cell transplantation is currently the only treatment with the potential to cure ATL. The patient’s immune state may contribute to the treatment outcome. Additionally, the activity of the anti-CC chemokine receptor 4 antibody, mogamulizumab, depends on immune function, including antibody-dependent cytotoxicity. In this comprehensive review, we summarize the immunopathogenesis of HTLV-1 infection in ATL and discuss the clinical findings that should be considered when developing treatment strategies for ATL. Full article

(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond)

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15 pages, 1741 KiB

Open AccessReview

Acquisition and Exaptation of Endogenous Retroviruses in Mammalian Placenta

by Sayumi Shimode

Biomolecules 2023, 13(10), 1482; https://doi.org/10.3390/biom13101482 - 4 Oct 2023

Cited by 2 | Viewed by 3753

Abstract

Endogenous retroviruses (ERVs) are retrovirus-like sequences that were previously integrated into the host genome. Although most ERVs are inactivated by mutations, deletions, or epigenetic regulation, some remain transcriptionally active and impact host physiology. Several ERV-encoded proteins, such as Syncytins and Suppressyn, contribute to [...] Read more.

Endogenous retroviruses (ERVs) are retrovirus-like sequences that were previously integrated into the host genome. Although most ERVs are inactivated by mutations, deletions, or epigenetic regulation, some remain transcriptionally active and impact host physiology. Several ERV-encoded proteins, such as Syncytins and Suppressyn, contribute to placenta acquisition, a crucial adaptation in mammals that protects the fetus from external threats and other risks while enabling the maternal supply of oxygen, nutrients, and antibodies. In primates, Syncytin-1 and Syncytin-2 facilitate cell–cell fusion for placental formation. Suppressyn is the first ERV-derived protein that inhibits cell fusion by binding to ASCT2, the receptor for Syncytin-1. Furthermore, Syncytin-2 likely inserted into the genome of the common ancestor of Anthropoidea, whereas Syncytin-1 and Suppressyn likely inserted into the ancestor of catarrhines; however, they were inactivated in some lineages, suggesting that multiple exaptation events had occurred. This review discusses the role of ERV-encoded proteins, particularly Syncytins and Suppressyn, in placental development and function, focusing on the integration of ERVs into the host genome and their contribution to the genetic mechanisms underlying placentogenesis. This review provides valuable insights into the molecular and genetic aspects of placentation, potentially shedding light on broader evolutionary and physiological processes in mammals. Full article

(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond)

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20 pages, 2646 KiB

Open AccessReview

Retrovirus-Derived RTL/SIRH: Their Diverse Roles in the Current Eutherian Developmental System and Contribution to Eutherian Evolution

by Tomoko Kaneko-Ishino and Fumitoshi Ishino

Biomolecules 2023, 13(10), 1436; https://doi.org/10.3390/biom13101436 - 22 Sep 2023

Cited by 5 | Viewed by 2573

Abstract

Eutherians have 11 retrotransposon Gag-like (RTL)/sushi-ichi retrotransposon homolog (SIRH) genes presumably derived from a certain retrovirus. Accumulating evidence indicates that the RTL/SIRH genes play a variety of roles in the current mammalian developmental system, such as in the placenta, brain, and innate immune [...] Read more.

Eutherians have 11 retrotransposon Gag-like (RTL)/sushi-ichi retrotransposon homolog (SIRH) genes presumably derived from a certain retrovirus. Accumulating evidence indicates that the RTL/SIRH genes play a variety of roles in the current mammalian developmental system, such as in the placenta, brain, and innate immune system, in a eutherian-specific manner. It has been shown that the functional role of Paternally Expressed 10 (PEG10) in placental formation is unique to the therian mammals, as are the eutherian-specific roles of PEG10 and PEG11/RTL1 in maintaining the fetal capillary network and the endocrine regulation of RTL7/SIRH7 (aka Leucine Zipper Down-Regulated in Cancer 1 (LDOCK1)) in the placenta. In the brain, PEG11/RTL1 is expressed in the corticospinal tract and hippocampal commissure, mammalian-specific structures, and in the corpus callosum, a eutherian-specific structure. Unexpectedly, at least three RTL/SIRH genes, RTL5/SIRH8, RTL6/SIRH3, and RTL9/SIRH10, play important roles in combating a variety of pathogens, namely viruses, bacteria, and fungi, respectively, suggesting that the innate immunity system of the brain in eutherians has been enhanced by the emergence of these new components. In this review, we will summarize the function of 10 out of the 11 RTL/SIRH genes and discuss their roles in eutherian development and evolution. Full article

(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond)

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