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Critical Reviews in Microbiology Nov 2018The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these... (Review)
Review
The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these are defective or silenced through epigenetic changes, they were historically considered "junk DNA" and their potential role in human physiology or pathological circumstances have been poorly studied. The most recently acquired, human endogenous retrovirus-K (HERV-K), has multiple copies in the human genome and some of them have complete open reading frames that are transcribed and translated, especially in early embryogenesis. Phylogenetically, HERV-K is considered a supergroup of viruses. One of the subtypes, termed HML-2, seems to be the most active and hence, it is the best studied. Aberrant expression of HML-2 in adult tissues has been associated with certain types of cancer and with neurodegenerative diseases. This review discusses the discovery of these viruses, their classification, structure, regulation and potential for replication, physiological roles, and their involvement in disease pathogenesis. Finally, it presents different therapeutic approaches being considered to target these viruses.
Topics: Animals; Endogenous Retroviruses; Genome, Human; Humans; Retroviridae; Retroviridae Infections; Virus Replication
PubMed: 30318978
DOI: 10.1080/1040841X.2018.1501345 -
Cell Stem Cell Feb 2020Mouse embryonic stem cells (ESCs) sporadically express preimplantation two-cell-stage (2C) transcripts, including MERVL endogenous retrovirus and Zscan4 cluster genes....
Mouse embryonic stem cells (ESCs) sporadically express preimplantation two-cell-stage (2C) transcripts, including MERVL endogenous retrovirus and Zscan4 cluster genes. Such 2C-like cells (2CLCs) can contribute to both embryonic and extraembryonic tissues when reintroduced into early embryos, although the molecular mechanism underlying such an expanded 2CLC potency remains elusive. We examine global nucleosome occupancy and gene expression in 2CLCs and identified miR-344 as the noncoding molecule that positively controls 2CLC potency. We find that activation of endogenous MERVL or miR-344-2 alone is sufficient to induce 2CLCs with activation of 2C genes and an expanded potency. Mechanistically, miR-344 is activated by DUX and post-transcriptionally represses ZMYM2 and its partner LSD1, and ZMYM2 recruits LSD1/HDAC corepressor complex to MERVL LTR for transcriptional repression. Consistently, zygotic depletion of Zmym2 compromises the totipotency-to-pluripotency transition during early development. Our studies establish the previously unappreciated DUX-miR-344-Zmym2/Lsd1 axis that controls MERVL for expanded stem cell potency.
Topics: Animals; Endogenous Retroviruses; Mice; MicroRNAs; Mouse Embryonic Stem Cells; Zygote
PubMed: 32032525
DOI: 10.1016/j.stem.2020.01.004 -
Nucleic Acids Research Jun 2023Endogenous retroviruses (ERVs) have been proposed as a driving force for the evolution of the mammalian placenta, however, the contribution of ERVs to placental...
Endogenous retroviruses (ERVs) have been proposed as a driving force for the evolution of the mammalian placenta, however, the contribution of ERVs to placental development and the underlying regulatory mechanism remain largely elusive. A key process of placental development is the formation of multinucleated syncytiotrophoblasts (STBs) in direct contact with maternal blood, through which constitutes the maternal-fetal interface critical for nutrient allocation, hormone production and immunological modulation during pregnancy. We delineate that ERVs profoundly rewire the transcriptional program of trophoblast syncytialization. Here, we first determined the dynamic landscape of bivalent ERV-derived enhancers with dual occupancy of H3K27ac and H3K9me3 in human trophoblast stem cells (hTSCs). We further demonstrated that enhancers overlapping several ERV families tend to exhibit increased H3K27ac and reduced H3K9me3 occupancy in STBs relative to hTSCs. Particularly, bivalent enhancers derived from the Simiiformes-specific MER50 transposons were linked to a cluster of genes important for STB formation. Importantly, deletions of MER50 elements adjacent to several STB genes, including MFSD2A and TNFAIP2, significantly attenuated their expression concomitant to compromised syncytium formation. Together, we propose that ERV-derived enhancers, MER50 specifically, fine-tune the transcriptional networks accounting for human trophoblast syncytialization, which sheds light on a novel ERV-mediated regulatory mechanism underlying placental development.
Topics: Animals; Female; Humans; Pregnancy; Endogenous Retroviruses; Gene Expression Regulation; Mammals; Placenta; Trophoblasts; Enhancer Elements, Genetic
PubMed: 36864754
DOI: 10.1093/nar/gkad109 -
The Journal of Clinical Investigation Jul 2023Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated...
Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated provirus HERV-K (HML-2) can be reactivated in certain cancers. Here, we report pathological expression of HML-2 in malignant gliomas in both cerebrospinal fluid and tumor tissue that was associated with a cancer stem cell phenotype and poor outcomes. Using single-cell RNA-Seq, we identified glioblastoma cellular populations with elevated HML-2 transcripts in neural progenitor-like cells (NPC-like) that drive cellular plasticity. Using CRISPR interference, we demonstrate that HML-2 critically maintained glioblastoma stemness and tumorigenesis in both glioblastoma neurospheres and intracranial orthotopic murine models. Additionally, we demonstrate that HML-2 critically regulated embryonic stem cell programs in NPC-derived astroglia and altered their 3D cellular morphology by activating the nuclear transcription factor OCT4, which binds to an HML-2-specific long-terminal repeat (LTR5Hs). Moreover, we discovered that some glioblastoma cells formed immature retroviral virions, and inhibiting HML-2 expression with antiretroviral drugs reduced reverse transcriptase activity in the extracellular compartment, tumor viability, and pluripotency. Our results suggest that HML-2 fundamentally contributes to the glioblastoma stem cell niche. Because persistence of glioblastoma stem cells is considered responsible for treatment resistance and recurrence, HML-2 may serve as a unique therapeutic target.
Topics: Humans; Animals; Mice; Endogenous Retroviruses; Glioblastoma; Stem Cell Niche; Proviruses
PubMed: 37395282
DOI: 10.1172/JCI167929 -
Nature Communications Aug 2023The human endogenous retrovirus K (HERV-K) is the most recently acquired endogenous retrovirus in the human genome and is activated and expressed in many cancers and...
The human endogenous retrovirus K (HERV-K) is the most recently acquired endogenous retrovirus in the human genome and is activated and expressed in many cancers and amyotrophic lateral sclerosis. We present the immature HERV-K capsid structure at 3.2 Å resolution determined from native virus-like particles using cryo-electron tomography and subtomogram averaging. The structure shows a hexamer unit oligomerized through a 6-helix bundle, which is stabilized by a small molecule analogous to IP6 in immature HIV-1 capsid. The HERV-K immature lattice is assembled via highly conserved dimer and trimer interfaces, as detailed through all-atom molecular dynamics simulations and supported by mutational studies. A large conformational change mediated by the linker between the N-terminal and the C-terminal domains of CA occurs during HERV-K maturation. Comparison between HERV-K and other retroviral immature capsid structures reveals a highly conserved mechanism for the assembly and maturation of retroviruses across genera and evolutionary time.
Topics: Humans; Endogenous Retroviruses; Amyotrophic Lateral Sclerosis; Biological Evolution; Capsid; Capsid Proteins
PubMed: 37620323
DOI: 10.1038/s41467-023-40786-w -
EBioMedicine Nov 2022Gallbladder cancer (GBC), the most common malignancy of the biliary tract, shows late diagnosis and low survival rate and requires continued search for new diagnostic...
BACKGROUND
Gallbladder cancer (GBC), the most common malignancy of the biliary tract, shows late diagnosis and low survival rate and requires continued search for new diagnostic biomarkers and therapeutic targets. Human endogenous retroviruses (HERVs) are specifically prone to be reactivated in diverse cancers and are implicated in cancer progression and immunotherapy.
METHODS
Single-cell RNA sequencing was performed on tumor tissues and paired adjacent tissues from 4 GBC patients. Dual-luciferase reporter assay was applied to measure enhancer activity of HERV sequences.
FINDINGS
We dissected the cellular diversity and described the HERV transcriptomic landscape for GBC. We found that HERVs were transcribed in a cell type-specific manner and different HERV families were associated with diverse biological effects. HERVs could function as enhancers, presumably causing altered expression of neighboring genes. The transcription level of HERVH was gradually elevated with the malignant transformation of epithelial cells, suggesting HERVH may be a potential early diagnostic biomarker of GBC. HHLA2, a newly emerging immune checkpoint, was derived by HERVH, exhibited an expressional correlation with HERVH, and was identified as a promising target for immunotherapy.
INTERPRETATION
Exploring the transcriptional landscape and potential functional impact of HERVs highlights the important role of HERVs in GBC and provides a fresh perspective on managing GBC.
FUNDING
This study was supported by the National Natural Science Foundation of China (31970176, 81972256) and the research grants from the Innovation Capacity Building Project of Jiangsu province (BM2020019).
Topics: Humans; Endogenous Retroviruses; Gallbladder Neoplasms; Immunotherapy; Exome Sequencing; Sequence Analysis, RNA; Immunoglobulins
PubMed: 36374772
DOI: 10.1016/j.ebiom.2022.104319 -
Cells Aug 2022The main roles of placentas include physical protection, nutrient and oxygen import, export of gasses and fetal waste products, and endocrinological regulation. In... (Review)
Review
The main roles of placentas include physical protection, nutrient and oxygen import, export of gasses and fetal waste products, and endocrinological regulation. In addition to physical protection of the fetus, the placentas must provide immune protection throughout gestation. These basic functions are well-conserved; however, placentas are undoubtedly recent evolving organs with structural and cellular diversities. These differences have been explained for the last two decades through co-opting genes and gene control elements derived from transposable elements, including endogenous retroviruses (ERVs). However, the differences in placental structures have not been explained or characterized. This manuscript addresses the sorting of ERVs and their integration into the mammalian genomes and provides new ways to explain why placental structures have diverged.
Topics: Animals; DNA Transposable Elements; Endogenous Retroviruses; Female; Mammals; Placenta; Pregnancy
PubMed: 35954303
DOI: 10.3390/cells11152458 -
Viruses Sep 2022Human endogenous retrovirus-K (HERV-K) is the most recently integrated retrovirus in the human genome, with implications for multiple disorders, including cancer.... (Review)
Review
Human endogenous retrovirus-K (HERV-K) is the most recently integrated retrovirus in the human genome, with implications for multiple disorders, including cancer. Although typically transcriptionally silenced in normal adult cells, dysregulation of HERV-K (HML-2) elements has been observed in cancer, including breast, germ cell tumors, pancreatic, melanoma, and brain cancer. While multiple methods of carcinogenesis have been proposed, here we discuss the role of HERV-K (HML-2) in the promotion and maintenance of the stem-cell in cancer. Aberrant expression of HERV-K has been shown to promote expression of stem cell markers and promote dedifferentiation. In this review, we discuss HERV-K (HML-2) as a potential therapeutic target based on evidence that some tumors depend on the expression of its proteins for survival.
Topics: Adult; Endogenous Retroviruses; Genome, Human; Humans; Melanoma
PubMed: 36146825
DOI: 10.3390/v14092019 -
Frontiers in Immunology 2022Human Endogenous Retroviruses (HERVs) are derived from ancient exogenous retroviral infections that have infected our ancestors' germline cells, underwent endogenization... (Review)
Review
Human Endogenous Retroviruses (HERVs) are derived from ancient exogenous retroviral infections that have infected our ancestors' germline cells, underwent endogenization process, and were passed throughout the generations by retrotransposition and hereditary transmission. HERVs comprise 8% of the human genome and are critical for several physiological activities. Yet, HERVs reactivation is involved in pathological process as cancer and autoimmune diseases. In this review, we summarize the multiple aspects of HERVs' role within the human genome, as well as virological and molecular aspects, and their fusogenic property. We also discuss possibilities of how the HERVs are possibly transactivated and participate in modulating the inflammatory response in health conditions. An update on their role in several autoimmune, inflammatory, and aging-related diseases is also presented.
Topics: Humans; Endogenous Retroviruses; Retroviridae Infections; Neoplasms; Genome, Human; Autoimmune Diseases
PubMed: 36518758
DOI: 10.3389/fimmu.2022.1057791 -
Retrovirology Aug 2018Retroviral integration into germline DNA can result in the formation of a vertically inherited proviral sequence called an endogenous retrovirus (ERV). Over the course... (Review)
Review
Retroviral integration into germline DNA can result in the formation of a vertically inherited proviral sequence called an endogenous retrovirus (ERV). Over the course of their evolution, vertebrate genomes have accumulated many thousands of ERV loci. These sequences provide useful retrospective information about ancient retroviruses, and have also played an important role in shaping the evolution of vertebrate genomes. There is an immediate need for a unified system of nomenclature for ERV loci, not only to assist genome annotation, but also to facilitate research on ERVs and their impact on genome biology and evolution. In this review, we examine how ERV nomenclatures have developed, and consider the possibilities for the implementation of a systematic approach for naming ERV loci. We propose that such a nomenclature should not only provide unique identifiers for individual loci, but also denote orthologous relationships between ERVs in different species. In addition, we propose that-where possible-mnemonic links to previous, well-established names for ERV loci and groups should be retained. We show how this approach can be applied and integrated into existing taxonomic and nomenclature schemes for retroviruses, ERVs and transposable elements.
Topics: Animals; Endogenous Retroviruses; Evolution, Molecular; Genetic Loci; Genetic Variation; Genomics; Humans; Terminology as Topic; Vertebrates
PubMed: 30153831
DOI: 10.1186/s12977-018-0442-1