Physiological and Pathological Transcriptional Activation of Endogenous Retroelements Assessed by RNA-Sequencing of B Lymphocytes (original) (raw)
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Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues
Genome Medicine
Background Endogenous retroelements (EREs) constitute about 42% of the human genome and have been implicated in common human diseases such as autoimmunity and cancer. The dominant paradigm holds that EREs are expressed in embryonic stem cells (ESCs) and germline cells but are repressed in differentiated somatic cells. Despite evidence that some EREs can be expressed at the RNA and protein levels in specific contexts, a system-level evaluation of their expression in human tissues is lacking. Methods Using RNA sequencing data, we analyzed ERE expression in 32 human tissues and cell types, including medullary thymic epithelial cells (mTECs). A tissue specificity index was computed to identify tissue-restricted ERE families. We also analyzed the transcriptome of mTECs in wild-type and autoimmune regulator (AIRE)-deficient mice. Finally, we developed a proteogenomic workflow combining RNA sequencing and mass spectrometry (MS) in order to evaluate whether EREs might be translated and gene...
Virology, 2008
Endogenous retroviruses (ERVs) constitute approximately 8-10% of the human and mouse genome. Some autoimmune diseases are attributed to the altered expression of ERVs. In this study, we examined the ERV expression profiles in lymphoid tissues and analyzed their biological properties. Tissues (spleen, thymus, and lymph nodes [axillary, inguinal, and mesenteric]) from C57BL/6J mice were analyzed for differential murine ERV (MuERV) expression by RT-PCR examination of polymorphic U3 sequences. Each tissue had a unique profile of MuERV expression. A genomic map identifying 60 putative MuERVs was established using 22 unique U3s as probes and their biological properties (primer binding site, coding potential, transcription regulatory element, tropism, recombination event, and integration age) were characterized. Interestingly, 12 putative MuERVs retained intact coding potentials for all three polypeptides essential for virus assembly and replication. We suggest that MuERV expression is differentially regulated in conjunction with the transcriptional environment of individual lymphoid tissues.
Detecting endogenous retrovirus-driven tissue-specific gene transcription
Genome biology and evolution, 2015
Transposable elements (TEs) comprise approximately half of the human genome, and several independent lines of investigation have demonstrated their role in rewiring gene expression during development, evolution, and oncogenesis. The identification of their regulatory effects has largely been idiosyncratic, by linking activity with isolated genes. Their distribution throughout the genome raises critical questions - do these elements contribute to broad tissue-and lineage-specific regulation? If so, in what manner, as enhancers, promoters, RNAs? Here, we devise a novel approach to systematically dissect the genome-wide consequences of TE insertion on gene expression, and test the hypothesis that classes of endogenous retrovirus long terminal repeats (LTRs) exert tissue-specific regulation of adjacent genes. Using correlation of expression patterns across 18 tissue types, we reveal the tissue-specific uncoupling of gene expression due to 62 different LTR classes. These patterns are spe...
Locus specific human endogenous retroviruses reveal new lymphoma subtypes
bioRxiv (Cold Spring Harbor Laboratory), 2023
The heterogeneity of cancers are driven by diverse mechanisms underlying oncogenesis such as differential 'cell-of-origin' (COO) progenitors, mutagenesis, and viral infections. Classification of B-cell lymphomas have been defined by considering these characteristics. However, the expression and contribution of transposable elements (TEs) to B cell lymphoma oncogenesis or classification have been overlooked. We hypothesized that incorporating TE signatures would increase the resolution of B-cell identity during healthy and malignant conditions. Here, we present the first comprehensive, locus-specific characterization of TE expression in benign germinal center (GC) B-cells, diffuse large B-cell lymphoma (DLBCL), Epstein-Barr virus (EBV)positive and EBV-negative Burkitt lymphoma (BL), and follicular lymphoma (FL). Our findings demonstrate unique human endogenous retrovirus (HERV) signatures in the GC and lymphoma subtypes whose activity can be used in combination with gene expression to define B-cell lineage in lymphoid malignancies, highlighting the potential of retrotranscriptomic analyses as a tool in lymphoma classification, diagnosis, and the identification of novel treatment groups. .
Proceedings of the National Academy of Sciences of the United States of America, 2015
Genome stability relies on epigenetic mechanisms that enforce repression of endogenous retroviruses (ERVs). Current evidence suggests that distinct chromatin-based mechanisms repress ERVs in cells of embryonic origin (histone methylation dominant) vs. more differentiated cells (DNA methylation dominant). However, the latter aspect of this model has not been tested. Remarkably, and in contrast to the prevailing model, we find that repressive histone methylation catalyzed by the enzyme SETDB1 is critical for suppression of specific ERV families and exogenous retroviruses in committed B-lineage cells from adult mice. The profile of ERV activation in SETDB1-deficient B cells is distinct from that observed in corresponding embryonic tissues, despite the loss of repressive chromatin modifications at all ERVs. We provide evidence that, on loss of SETDB1, ERVs are activated in a lineage-specific manner depending on the set of transcription factors available to target proviral regulatory ele...
Immune responses to endogenous retroelements: taking the bad with the good
Nature Reviews Immunology, 2016
The ultimate form of parasitism and evasion of host immunity is for the parasite genome to enter the germ line of the host species. Retroviruses have invaded the host germ line on the grandest scale, and this is evident in the extraordinary abundance of endogenous retroelements in the genome of all vertebrate species that have been studied. Many of these endogenous retroelements have retained viral characteristics; some also the capacity to replicate and, consequently, the potential to trigger host innate and adaptive immune responses. However, although retroelements are mainly recognized for their pathogenic potential, recent evidence suggests that this 'enemy within' may also have beneficial roles in tuning host immune reactivity. In this Review, we discuss how the immune system recognizes and is shaped by endogenous retroelements.
Genome Research, 2019
Dysregulated endogenous retroelements (EREs) are increasingly implicated in the initiation, progression, and immune surveillance of human cancer. However, incomplete knowledge of ERE activity limits mechanistic studies. By using pan-cancer de novo transcript assembly, we uncover the extent and complexity of ERE transcription. The current assembly doubled the number of previously annotated transcripts overlapping with long-terminal repeat (LTR) elements, several thousand of which were expressed specifically in one or a few related cancer types. Exemplified in melanoma, LTR-overlapping transcripts were highly predictable, disease prognostic, and closely linked with molecularly defined subtypes. They further showed the potential to affect disease-relevant genes, as well as produce novel cancer-specific antigenic peptides. This extended view of LTR elements provides the framework for functional validation of affected genes and targets for cancer immunotherapy.
Transposable elements, including endogenous retroviruses (ERVs), comprise almost 45% of the human genome. This could represent a significant pathogenic burden but it is becoming more evident that many of these elements have a positive contribution to make to normal human physiology. In particular, the contributions of human ERVs (HERVs) to gene regulation and the expression of noncoding RNAs has been revealed with the help of new and emerging genomic technologies. HERVs have the common provirus structure of coding open reading frames (ORFs) flanked by two long-terminal repeats (LTRs). However, over the course of evolution and as a consequence of host defence mechanisms, most of the sequences contain INDELs, mutations or have been reduced to single LTRs by recombination. These INDELs and mutations reduce HERV activity. However, there is a trade-off for the host cells in that HERVs can provide beneficial sources of genetic variation but with this benefit comes the risk of pathogenic activity and spread within the genome. For example, the LTRs are of critical importance as they contain promoter sequences and can regulate not only HERV expression but that of human genes. This is true even when the LTRs are located in intergenic regions or are in antisense orientation to the rest of the gene. Uncontrolled, this promoter activity could disrupt normal gene expression or transcript processing (e.g., splicing). Thus, control of HERVs and particularly their LTRs is essential for the cell to manage these elements and this control is achieved at multiple levels, including epigenetic regulations that permit HERV expression in the germline but silence it in most somatic tissues. We will discuss some of the common epigenetic mechanisms and how they affect HERV expression, providing detailed discussions of HERVs in stem cell, placenta and cancer biology.
Cancers, 2021
Simple Summary Retroelements are endogenous DNA elements present in the human genome. They have a key role in tumorigenesis and cancer progression. Several studies have reported their expression as biomarkers and immunotherapeutic targets to cancer. Their expression can be induced by epigenetic alteration and virus infections. Retroelement overexpression has been shown in distinct types of cancer, such as breast cancer, melanoma, renal cell carcinoma and prostate cancer. However, studies on other specific types of cancer, such as in cervical cancer, are scarce. Here we explored the expression of retroelements in cervical cancer as well as their interplay with HPV infection and their association with expression of neighboring genes. We find expression of retroelements specific to cervical cancer, associated with tumor histological type and HPV infection, as a new target as biomarkers and for immune therapy approaches. Abstract Retroelements are expressed in diverse types of cancer an...
Murine endogenous retroviruses and their transcriptional potentials
Mammalian Genome, 2004
Viral transcripts from endogenous retroviruses (ERVs) have been detected from patients with multiple sclerosis, breast cancer, leukemia, and schizophrenia (Karlsson et al. 2001; Depil et al. 2002; Portis 2002; Wang-Johanning et al. 2003). While it is unknown whether the presence of the viral transcripts implicates ERVs in the pathological response, ERVs contain the necessary elements for regulating expression of host genes surrounding proviral integration sites (Majors 1990). With approximately 10% of the mouse genome and 8% of the human genome containing retrovirus-like elements, it is likely that some of these elements may participate in controlling gene expression in normal and stress conditions (Lander et al. 2001; Waterston et al. 2002).While ERVs within the human genome are inactive, there are transcription regulatory elements and coding sequences of viral genes within the retroviral sequences that are still intact (Schon et al. 2001). ERVs can affect gene expression in three way ...