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Cell Jan 2023Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to...
Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process is largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. The activation of ERVs was also observed in organs of aged primates and mice as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.
Topics: Aged; Animals; Humans; Mice; Aging; Cellular Senescence; Endogenous Retroviruses; Primates
PubMed: 36610399
DOI: 10.1016/j.cell.2022.12.017 -
Nature Apr 2023B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS...
B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
Topics: Animals; Humans; Mice; Adenocarcinoma of Lung; Carcinoma, Non-Small-Cell Lung; Disease Models, Animal; Endogenous Retroviruses; Immunotherapy; Lung; Lung Neoplasms; Tumor Microenvironment; B-Lymphocytes; Cohort Studies; Antibodies
PubMed: 37046094
DOI: 10.1038/s41586-023-05771-9 -
Cell Jul 2021The microbiota plays a fundamental role in regulating host immunity. However, the processes involved in the initiation and regulation of immunity to the microbiota...
The microbiota plays a fundamental role in regulating host immunity. However, the processes involved in the initiation and regulation of immunity to the microbiota remain largely unknown. Here, we show that the skin microbiota promotes the discrete expression of defined endogenous retroviruses (ERVs). Keratinocyte-intrinsic responses to ERVs depended on cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING) signaling and promoted the induction of commensal-specific T cells. Inhibition of ERV reverse transcription significantly impacted these responses, resulting in impaired immunity to the microbiota and its associated tissue repair function. Conversely, a lipid-enriched diet primed the skin for heightened ERV- expression in response to commensal colonization, leading to increased immune responses and tissue inflammation. Together, our results support the idea that the host may have co-opted its endogenous virome as a means to communicate with the exogenous microbiota, resulting in a multi-kingdom dialog that controls both tissue homeostasis and inflammation.
Topics: Animals; Bacteria; Chromosomes, Bacterial; Diet, High-Fat; Endogenous Retroviruses; Homeostasis; Inflammation; Interferon Type I; Keratinocytes; Membrane Proteins; Mice, Inbred C57BL; Microbiota; Nucleotidyltransferases; Retroelements; Signal Transduction; Skin; T-Lymphocytes; Transcription, Genetic; Mice
PubMed: 34166614
DOI: 10.1016/j.cell.2021.05.020 -
Genome Biology May 2021Endogenous retroviruses (ERVs) are emerging as promising therapeutic targets in cancer. As remnants of ancient retroviral infections, ERV-derived regulatory elements... (Review)
Review
Endogenous retroviruses (ERVs) are emerging as promising therapeutic targets in cancer. As remnants of ancient retroviral infections, ERV-derived regulatory elements coordinate expression from gene networks, including those underpinning embryogenesis and immune cell function. ERV activation can promote an interferon response, a phenomenon termed viral mimicry. Although ERV expression is associated with cancer, and provisionally with autoimmune and neurodegenerative diseases, ERV-mediated inflammation is being explored as a way to sensitize tumors to immunotherapy. Here we review ERV co-option in development and innate immunity, the aberrant contribution of ERVs to tumorigenesis, and the wider biomedical potential of therapies directed at ERVs.
Topics: Animals; Carcinogenesis; DNA Transposable Elements; Endogenous Retroviruses; Gene Regulatory Networks; Humans; Immunity, Innate; Neoplasms
PubMed: 33971937
DOI: 10.1186/s13059-021-02357-4 -
Cancer Cell Nov 2021ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell...
ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8 T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.
Topics: CD8-Positive T-Lymphocytes; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Drug Resistance, Neoplasm; Endogenous Retroviruses; Gene Expression Profiling; Genomics; Humans; Immune Checkpoint Inhibitors; Kidney Neoplasms; Nivolumab; Prospective Studies; Receptors, Antigen, T-Cell; Sequence Analysis, RNA; Single-Cell Analysis; Tumor Escape; Tumor Microenvironment; Exome Sequencing
PubMed: 34715028
DOI: 10.1016/j.ccell.2021.10.001 -
Viruses Aug 2020Almost 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... (Review)
Review
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.
Topics: Animals; Chromatin Assembly and Disassembly; DNA Methylation; Endogenous Retroviruses; Gene Expression Regulation; Gene Silencing; Host Microbial Interactions; Humans; Mice; Retroviridae Infections; Transcription, Genetic
PubMed: 32823517
DOI: 10.3390/v12080884 -
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 -
Nature Genetics Aug 2022Most endogenous retroviruses (ERVs) in mammals are incapable of retrotransposition; therefore, why ERV derepression is associated with lethality during early development...
Most endogenous retroviruses (ERVs) in mammals are incapable of retrotransposition; therefore, why ERV derepression is associated with lethality during early development has been a mystery. Here, we report that rapid and selective degradation of the heterochromatin adapter protein TRIM28 triggers dissociation of transcriptional condensates from loci encoding super-enhancer (SE)-driven pluripotency genes and their association with transcribed ERV loci in murine embryonic stem cells. Knockdown of ERV RNAs or forced expression of SE-enriched transcription factors rescued condensate localization at SEs in TRIM28-degraded cells. In a biochemical reconstitution system, ERV RNA facilitated partitioning of RNA polymerase II and the Mediator coactivator into phase-separated droplets. In TRIM28 knockout mouse embryos, single-cell RNA-seq analysis revealed specific depletion of pluripotent lineages. We propose that coding and noncoding nascent RNAs, including those produced by retrotransposons, may facilitate 'hijacking' of transcriptional condensates in various developmental and disease contexts.
Topics: Animals; Embryonic Stem Cells; Endogenous Retroviruses; Heterochromatin; Mammals; Mice; Nuclear Bodies; Retroelements
PubMed: 35864192
DOI: 10.1038/s41588-022-01132-w -
Cell Jan 2022
Topics: Disease; Endogenous Retroviruses; Humans; Immunity
PubMed: 35063077
DOI: 10.1016/j.cell.2021.12.028 -
Viruses Dec 2020As guest editors, we are pleased to present this Special Issue on endogenous retroviruses (ERVs) and their impact on mammalian development and disease [...].
As guest editors, we are pleased to present this Special Issue on endogenous retroviruses (ERVs) and their impact on mammalian development and disease [...].
Topics: Animals; Disease Susceptibility; Embryonic Development; Endogenous Retroviruses; Humans
PubMed: 33339171
DOI: 10.3390/v12121446