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Endogenous Retroviruses in Development and Disease

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 83446

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Special Issue Editors

Dr. Molly Gale Hammell

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Guest Editor

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Interests: ERV biology; human genomics; neurodegenerative disease

Dr. Helen Mary Rowe

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Guest Editor

Centre for Immunobiology, Blizard Institute, Queen Mary University of London,4 Newark St, London E1 2AT, UK
Interests: epigenetic control of ERVs in development; ERVs as adjuvants

Special Issue Information

Dear Colleagues,

Endogenous retroviruses (ERVs) represent a large fraction of human genomes, and yet have frequently been ignored in genomic studies due to the difficulties in dealing with these highly repetitive sequences. New technological and computational tools have enabled the better inclusion of ERV sequences, which allows for the probing of contributions to human development and disease. While the transcription and mobility of ERVs is generally tightly regulated, certain developmental windows allow for elevated ERV activity, which can have both beneficial and detrimental consequences. Beyond these developmental windows, there appears to be variable activity in aging somatic cells that may accumulate over time. Specifically, evidence is mounting suggesting that ERV activity is a contributing factor in several age-associated human diseases ranging from cancer to neurodegeneration. However, many open questions remain. How is ERV silencing maintained in different somatic cell types? Does imperfect ERV regulation allow for their gradual accumulation in very long-lived cells? Are ERVs normally activated for the benefit of their hosts in certain contexts, for example to help to sustain an immune response upon pathogen challenge? What are the downstream molecular consequences of ERV activity for the cell, including in cancer or autoimmune disease?

This Special Issue is designed to provide a current survey of ERV biology, tools for ERV genomics, developmental regulation of ERV sequences, and links to human disease.

Dr. Molly Gale Hammell
Dr. Helen Mary Rowe
Guest Editors

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Keywords

endogenous retroviruses
ERVs
cancer
neurodegeneration
transposable elements
genetics
epigenetics and genomics

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Published Papers (13 papers)

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Editorial

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3 pages, 166 KiB

Open AccessEditorial

Editorial Overview: Endogenous Retroviruses in Development and Disease

by Molly Gale Hammell and Helen M. Rowe

Viruses 2020, 12(12), 1446; https://doi.org/10.3390/v12121446 - 16 Dec 2020

Viewed by 2161

Abstract

As guest editors, we are pleased to present this Special Issue on endogenous retroviruses (ERVs) and their impact on mammalian development and disease [...] Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

Research

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25 pages, 5276 KiB

Open AccessArticle

Human Endogenous Retrovirus K Rec Forms a Regulatory Loop with MITF that Opposes the Progression of Melanoma to an Invasive Stage

by Manvendra Singh, Huiqiang Cai, Mario Bunse, Cédric Feschotte and Zsuzsanna Izsvák

Viruses 2020, 12(11), 1303; https://doi.org/10.3390/v12111303 - 13 Nov 2020

Cited by 20 | Viewed by 4333

Abstract

The HML2 subfamily of HERV-K (henceforth HERV-K) represents the most recently endogenized retrovirus in the human genome. While the products of certain HERV-K genomic copies are expressed in normal tissues, they are upregulated in several pathological conditions, including various tumors. It remains unclear whether HERV-K(HML2)-encoded products overexpressed in cancer contribute to disease progression or are merely by-products of tumorigenesis. Here, we focus on the regulatory activities of the Long Terminal Repeats (LTR5_Hs) of HERV-K and the potential role of the HERV-K-encoded Rec in melanoma. Our regulatory genomics analysis of LTR5_Hs loci indicates that Melanocyte Inducing Transcription Factor (MITF) (also known as binds to a canonical E-box motif (CA(C/T)GTG) within these elements in proliferative type of melanoma, and that depletion of MITF results in reduced HERV-K expression. In turn, experimentally depleting Rec in a proliferative melanoma cell line leads to lower mRNA levels of MITF and its predicted target genes. Furthermore, Rec knockdown leads to an upregulation of epithelial-to-mesenchymal associated genes and an enhanced invasion phenotype of proliferative melanoma cells. Together these results suggest the existence of a regulatory loop between MITF and Rec that may modulate the transition from proliferative to invasive stages of melanoma. Because HERV-K(HML2) elements are restricted to hominoid primates, these findings might explain certain species-specific features of melanoma progression and point to some limitations of animal models in melanoma studies. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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13 pages, 8674 KiB

Open AccessArticle

Trim24 and Trim33 Play a Role in Epigenetic Silencing of Retroviruses in Embryonic Stem Cells

by Liad Margalit, Carmit Strauss, Ayellet Tal and Sharon Schlesinger

Viruses 2020, 12(9), 1015; https://doi.org/10.3390/v12091015 - 11 Sep 2020

Cited by 13 | Viewed by 5215

Abstract

Embryonic stem cells (ESC) have the ability to epigenetically silence endogenous and exogenous retroviral sequences. Trim28 plays an important role in establishing this silencing, but less is known about the role other Trim proteins play. The Tif1 family is a sub-group of the Trim family, which possess histone binding ability in addition to the distinctive RING domain. Here, we have examined the interaction between three Tif1 family members, namely Trim24, Trim28 and Trim33, and their function in retroviral silencing. We identify a complex formed in ESC, comprised of these three proteins. We further show that when Trim33 is depleted, the complex collapses and silencing efficiency of both endogenous and exogenous sequences is reduced. Similar transcriptional activation takes place when Trim24 is depleted. Analysis of the H3K9me3 chromatin modification showed a decrease in this repressive mark, following both Trim24 and Trim33 depletion. As Trim28 is an identified binding partner of the H3K9 methyltransferase ESET, this further supports the involvement of Trim28 in the complex. The results presented here suggest that a complex of Tif1 family members, each of which possesses different specificity and efficiency, contributes to the silencing of retroviral sequences in ESC. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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12 pages, 3910 KiB

Open AccessArticle

Human Endogenous Retrovirus Expression Is Associated with Head and Neck Cancer and Differential Survival

by Allison R. Kolbe, Matthew L. Bendall, Alexander T. Pearson, Doru Paul, Douglas F. Nixon, Marcos Pérez-Losada and Keith A. Crandall

Viruses 2020, 12(9), 956; https://doi.org/10.3390/v12090956 - 28 Aug 2020

Cited by 22 | Viewed by 5051

Abstract

Human endogenous retroviruses (HERVs) have been implicated in a variety of human diseases including cancers. However, technical challenges in analyzing HERV sequence data have limited locus-specific characterization of HERV expression. Here, we use the software Telescope (developed to identify expressed transposable elements from metatranscriptomic data) on 43 paired tumor and adjacent normal tissue samples from The Cancer Genome Atlas Program to produce the first locus-specific retrotranscriptome of head and neck cancer. Telescope identified over 3000 expressed HERVs in tumor and adjacent normal tissue, and 1078 HERVs were differentially expressed between the two tissue types. The majority of differentially expressed HERVs were expressed at a higher level in tumor tissue. Differentially expressed HERVs were enriched in members of the HERVH family. Hierarchical clustering based on HERV expression in tumor-adjacent normal tissue resulted in two distinct clusters with significantly different survival probability. Together, these results highlight the importance of future work on the role of HERVs across a range of cancers. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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17 pages, 6283 KiB

Open AccessArticle

Inter-Strain Epigenomic Profiling Reveals a Candidate IAP Master Copy in C3H Mice

by Rita Rebollo, Mariana Galvão-Ferrarini, Liane Gagnier, Ying Zhang, Ardian Ferraj, Christine R. Beck, Matthew C. Lorincz and Dixie L. Mager

Viruses 2020, 12(7), 783; https://doi.org/10.3390/v12070783 - 21 Jul 2020

Cited by 7 | Viewed by 4307

Abstract

Insertions of endogenous retroviruses cause a significant fraction of mutations in inbred mice but not all strains are equally susceptible. Notably, most new Intracisternal A particle (IAP) ERV mutagenic insertions have occurred in C3H mice. We show here that strain-specific insertional polymorphic IAPs accumulate faster in C3H/HeJ mice, relative to other sequenced strains, and that IAP transcript levels are higher in C3H/HeJ embryonic stem (ES) cells compared to other ES cells. To investigate the mechanism for high IAP activity in C3H mice, we identified 61 IAP copies in C3H/HeJ ES cells enriched with H3K4me3 (a mark of active promoters) and, among those tested, all are unmethylated in C3H/HeJ ES cells. Notably, 13 of the 61 are specific to C3H/HeJ and are members of the non-autonomous 1Δ1 IAP subfamily that is responsible for nearly all new insertions in C3H. One copy is full length with intact open reading frames and hence potentially capable of providing proteins in trans to other 1Δ1 elements. This potential “master copy” is present in other strains, including 129, but its 5’ long terminal repeat (LTR) is methylated in 129 ES cells. Thus, the unusual IAP activity in C3H may be due to reduced epigenetic repression coupled with the presence of a master copy. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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Review

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21 pages, 2256 KiB

Open AccessReview

Host Gene Regulation by Transposable Elements: The New, the Old and the Ugly

by Rocio Enriquez-Gasca, Poppy A. Gould and Helen M. Rowe

Viruses 2020, 12(10), 1089; https://doi.org/10.3390/v12101089 - 26 Sep 2020

Cited by 23 | Viewed by 6742

Abstract

The human genome has been under selective pressure to evolve in response to emerging pathogens and other environmental challenges. Genome evolution includes the acquisition of new genes or new isoforms of genes and changes to gene expression patterns. One source of genome innovation is from transposable elements (TEs), which carry their own promoters, enhancers and open reading frames and can act as ‘controlling elements’ for our own genes. TEs include LINE-1 elements, which can retrotranspose intracellularly and endogenous retroviruses (ERVs) that represent remnants of past retroviral germline infections. Although once pathogens, ERVs also represent an enticing source of incoming genetic material that the host can then repurpose. ERVs and other TEs have coevolved with host genes for millions of years, which has allowed them to become embedded within essential gene expression programmes. Intriguingly, these host genes are often subject to the same epigenetic control mechanisms that evolved to combat the TEs that now regulate them. Here, we illustrate the breadth of host gene regulation through TEs by focusing on examples of young (The New), ancient (The Old), and disease-causing (The Ugly) TE integrants. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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22 pages, 753 KiB

Open AccessReview

Silencing and Transcriptional Regulation of Endogenous Retroviruses: An Overview

by Franziska K. Geis and Stephen P. Goff

Viruses 2020, 12(8), 884; https://doi.org/10.3390/v12080884 - 13 Aug 2020

Cited by 100 | Viewed by 11608

Abstract

Almost half of the human genome is made up of transposable elements (TEs), and about 8% consists of endogenous retroviruses (ERVs). ERVs are remnants of ancient exogenous retrovirus infections of the germ line. Most TEs are inactive and not detrimental to the host. They are tightly regulated to ensure genomic stability of the host and avoid deregulation of nearby gene loci. Histone-based posttranslational modifications such as H3K9 trimethylation are one of the main silencing mechanisms. Trim28 is one of the identified master regulators of silencing, which recruits most prominently the H3K9 methyltransferase Setdb1, among other factors. Sumoylation and ATP-dependent chromatin remodeling factors seem to contribute to proper localization of Trim28 to ERV sequences and promote Trim28 interaction with Setdb1. Additionally, DNA methylation as well as RNA-mediated targeting of TEs such as piRNA-based silencing play important roles in ERV regulation. Despite the involvement of ERV overexpression in several cancer types, autoimmune diseases, and viral pathologies, ERVs are now also appreciated for their potential positive role in evolution. ERVs can provide new regulatory gene elements or novel binding sites for transcription factors, and ERV gene products can even be repurposed for the benefit of the host. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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22 pages, 3319 KiB

Open AccessReview

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers

by Jessica L. Elmer and Anne C. Ferguson-Smith

Viruses 2020, 12(8), 810; https://doi.org/10.3390/v12080810 - 27 Jul 2020

Cited by 10 | Viewed by 3661

Abstract

Approximately 10 percent of the mouse genome consists of endogenous retroviruses (ERVs), relics of ancient retroviral infections that are classified based on their relatedness to exogenous retroviral genera. Because of the ability of ERVs to retrotranspose, as well as their cis-acting regulatory potential due to functional elements located within the elements, mammalian ERVs are generally subject to epigenetic silencing by DNA methylation and repressive histone modifications. The mobilisation and expansion of ERV elements is strain-specific, leading to ERVs being highly polymorphic between inbred mouse strains, hinting at the possibility of the strain-specific regulation of ERVs. In this review, we describe the existing evidence of mouse strain-specific epigenetic control of ERVs and discuss the implications of differential ERV regulation on epigenetic inheritance models. We consider Krüppel-associated box domain (KRAB) zinc finger proteins as likely candidates for strain-specific ERV modifiers, drawing on insights gained from the study of the strain-specific behaviour of transgenes. We conclude by considering the coevolution of KRAB zinc finger proteins and actively transposing ERV elements, and highlight the importance of cross-strain studies in elucidating the mechanisms and consequences of strain-specific ERV regulation. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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19 pages, 972 KiB

Open AccessReview

Endogenous Retroviruses Walk a Fine Line between Priming and Silencing

by Harrison Cullen and Andrea J. Schorn

Viruses 2020, 12(8), 792; https://doi.org/10.3390/v12080792 - 23 Jul 2020

Cited by 14 | Viewed by 4832

Abstract

Endogenous retroviruses (ERVs) in mammals are closely related to infectious retroviruses and utilize host tRNAs as a primer for reverse transcription and replication, a hallmark of long terminal repeat (LTR) retroelements. Their dependency on tRNA makes these elements vulnerable to targeting by small RNAs derived from the 3′-end of mature tRNAs (3′-tRFs), which are highly expressed during epigenetic reprogramming and potentially protect many tissues in eukaryotes. Here, we review some key functions of ERV reprogramming during mouse and human development and discuss how small RNA-mediated silencing maintains genome stability when ERVs are temporarily released from heterochromatin repression. In particular, we take a closer look at the tRNA primer binding sites (PBS) of two highly active ERV families in mice and their sequence variation that is shaped by the conflict of successful tRNA priming for replication versus evasion of silencing by 3′-tRFs. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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17 pages, 760 KiB

Open AccessReview

Human Endogenous Retrovirus K in Cancer: A Potential Biomarker and Immunotherapeutic Target

by Gislaine Curty, Jez L. Marston, Miguel de Mulder Rougvie, Fabio E. Leal, Douglas F. Nixon and Marcelo A. Soares

Viruses 2020, 12(7), 726; https://doi.org/10.3390/v12070726 - 6 Jul 2020

Cited by 48 | Viewed by 7021

Abstract

In diseases where epigenetic mechanisms are changed, such as cancer, many genes show altered gene expression and inhibited genes become activated. Human endogenous retrovirus type K (HERV-K) expression is usually inhibited in normal cells from healthy adults. In tumor cells, however, HERV-K mRNA expression has been frequently documented to increase. Importantly, HERV-K-derived proteins can act as tumor-specific antigens, a class of neoantigens, and induce immune responses in different types of cancer. In this review, we describe the function of the HERV-K HML-2 subtype in carcinogenesis as biomarkers, and their potential as targets for cancer immunotherapy. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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17 pages, 1422 KiB

Open AccessReview

Role of Viruses in the Pathogenesis of Multiple Sclerosis

by Rachael E. Tarlinton, Ekaterina Martynova, Albert A. Rizvanov, Svetlana Khaiboullina and Subhash Verma

Viruses 2020, 12(6), 643; https://doi.org/10.3390/v12060643 - 13 Jun 2020

Cited by 73 | Viewed by 12523

Abstract

Multiple sclerosis (MS) is an immune inflammatory disease, where the underlying etiological cause remains elusive. Multiple triggering factors have been suggested, including environmental, genetic and gender components. However, underlying infectious triggers to the disease are also suspected. There is an increasing abundance of evidence supporting a viral etiology to MS, including the efficacy of interferon therapy and over-detection of viral antibodies and nucleic acids when compared with healthy patients. Several viruses have been proposed as potential triggering agents, including Epstein–Barr virus, human herpesvirus 6, varicella–zoster virus, cytomegalovirus, John Cunningham virus and human endogenous retroviruses. These viruses are all near ubiquitous and have a high prevalence in adult populations (or in the case of the retroviruses are actually part of the genome). They can establish lifelong infections with periods of reactivation, which may be linked to the relapsing nature of MS. In this review, the evidence for a role for viral infection in MS will be discussed with an emphasis on immune system activation related to MS disease pathogenesis. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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15 pages, 1503 KiB

Open AccessReview

High-Throughput Sequencing is a Crucial Tool to Investigate the Contribution of Human Endogenous Retroviruses (HERVs) to Human Biology and Development

by Maria Paola Pisano, Nicole Grandi and Enzo Tramontano

Viruses 2020, 12(6), 633; https://doi.org/10.3390/v12060633 - 11 Jun 2020

Cited by 15 | Viewed by 4482

Abstract

Human Endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that represent a large fraction of our genome. Their transcriptional activity is finely regulated in early developmental stages and their expression is modulated in different cell types and tissues. Such activity has an impact on human physiology and pathology that is only partially understood up to date. Novel high-throughput sequencing tools have recently allowed for a great advancement in elucidating the various HERV expression patterns in different tissues as well as the mechanisms controlling their transcription, and overall, have helped in gaining better insights in an all-inclusive understanding of the impact of HERVs in biology of the host. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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17 pages, 1311 KiB

Open AccessReview

SETDB1-Mediated Silencing of Retroelements

by Kei Fukuda and Yoichi Shinkai

Viruses 2020, 12(6), 596; https://doi.org/10.3390/v12060596 - 30 May 2020

Cited by 60 | Viewed by 9739

Abstract

SETDB1 (SET domain bifurcated histone lysine methyltransferase 1) is a protein lysine methyltransferase and methylates histone H3 at lysine 9 (H3K9). Among other H3K9 methyltransferases, SETDB1 and SETDB1-mediated H3K9 trimethylation (H3K9me3) play pivotal roles for silencing of endogenous and exogenous retroelements, thus contributing to genome stability against retroelement transposition. Furthermore, SETDB1 is highly upregulated in various tumor cells. In this article, we describe recent advances about how SETDB1 activity is regulated, how SETDB1 represses various types of retroelements such as L1 and class I, II, and III endogenous retroviruses (ERVs) in concert with other epigenetic factors such as KAP1 and the HUSH complex and how SETDB1-mediated H3K9 methylation can be maintained during replication. Full article

(This article belongs to the Special Issue Endogenous Retroviruses in Development and Disease)

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