Erratum: uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

AbstractSome chemotherapeutic agents which cause loss of DNA methylation have been recently shown to induce a state of “viral mimicry” involving upregulation of endogenous retroviruses (ERV) and a subsequent innate immune response. This approach may be useful in combination with immune checkpoint cancer therapies, but relatively little is known about normal cellular control of ERV suppression. The UHRF1 protein can interact with the maintenance methylation protein DNMT1 and is known to play an important role in epigenetic control in the cell. To examine potential roles of this protein in differentiated cells, we first established stable knockdowns in normal human lung fibroblasts. While these knockdown cells showed the expected loss of DNA methylation genome-wide, transcriptional changes were instead dominated by a single response, namely activation of innate immune signalling, consistent with viral mimicry. We confirmed using mechanistic approaches that activation of interferons and interferon-stimulated genes involved in double-stranded RNA detection was crucial to the response. ERVs were demethylated and transcriptionally activated in UHRF1 knockdown cells. As in these normal cell lines, ERV activation and interferon response also occurred following the transient loss of UHRF1 in both melanoma and colon cancer cell lines. Restoring UHRF1 in either transient- or stable knockdown systems abrogated ERV reactivation and interferon response, but without substantial restoration of DNA methylation. Rescued cell lines were hypersensitive to depletion of SETDB1, implicating H3K9me3 as crucial to UHRF1-mediated repression in the absence of DNA methylation. Confirming this, cells rescued with UHRF1 containing point mutations affecting H3K9me3 binding could not mediate silencing of ERV transcription or the innate immune response. Finally, by introducing similar point mutations in the mouse homologue, we could show that this pathway is conserved in mice. Our results therefore implicate UHRF1 as a key regulator of ERV suppression and strengthen the basis for cancer cell hypomethylation therapy.

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Systems Biology to Understand and Regulate Human Retroviral Proinflammatory Response

Frontiers in Immunology ◽

10.3389/fimmu.2021.736349 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mohamed Helmy ◽

Kumar Selvarajoo

Keyword(s):

Immune Response ◽

Systems Biology ◽

Transposable Elements ◽

Innate Immune Response ◽

Innate Immune ◽

Endogenous Retroviruses ◽

Therapeutic Approaches ◽

Genome Sequences ◽

Proinflammatory Response ◽

Novel Therapeutic

The majority of human genome are non-coding genes. Recent research have revealed that about half of these genome sequences make up of transposable elements (TEs). A branch of these belong to the endogenous retroviruses (ERVs), which are germline viral infection that occurred over millions of years ago. They are generally harmless as evolutionary mutations have made them unable to produce viral agents and are mostly epigenetically silenced. Nevertheless, ERVs are able to express by still unknown mechanisms and recent evidences have shown links between ERVs and major proinflammatory diseases and cancers. The major challenge is to elucidate a detailed mechanistic understanding between them, so that novel therapeutic approaches can be explored. Here, we provide a brief overview of TEs, human ERVs and their links to microbiome, innate immune response, proinflammatory diseases and cancer. Finally, we recommend the employment of systems biology approaches for future HERV research.

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Regulatory regions in natural transposable element insertions drive interindividual differences in response to immune challenges in Drosophila

Genome Biology ◽

10.1186/s13059-021-02471-3 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Anna Ullastres ◽

Miriam Merenciano ◽

Josefa González

Keyword(s):

Gene Expression ◽

Immune Response ◽

Transposable Elements ◽

Transposable Element ◽

Natural Populations ◽

Regulatory Elements ◽

Genomic Context ◽

Specific Expression ◽

Survival Capacity ◽

Immune Related Genes

Abstract Background Variation in gene expression underlies interindividual variability in relevant traits including immune response. However, the genetic variation responsible for these gene expression changes remains largely unknown. Among the non-coding variants that could be relevant, transposable element insertions are promising candidates as they have been shown to be a rich and diverse source of cis-regulatory elements. Results In this work, we use a population genetics approach to identify transposable element insertions likely to increase the tolerance of Drosophila melanogaster to bacterial infection by affecting the expression of immune-related genes. We identify 12 insertions associated with allele-specific expression changes in immune-related genes. We experimentally validate three of these insertions including one likely to be acting as a silencer, one as an enhancer, and one with a dual role as enhancer and promoter. The direction in the change of gene expression associated with the presence of several of these insertions is consistent with an increased survival to infection. Indeed, for one of the insertions, we show that this is the case by analyzing both natural populations and CRISPR/Cas9 mutants in which the insertion is deleted from its native genomic context. Conclusions We show that transposable elements contribute to gene expression variation in response to infection in D. melanogaster and that this variation is likely to affect their survival capacity. Because the role of transposable elements as regulatory elements is not restricted to Drosophila, transposable elements are likely to play a role in immune response in other organisms as well.

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Domestication of High-Copy Transposons Underlays the Wheat Small RNA Response to an Obligate Pathogen

Molecular Biology and Evolution ◽

10.1093/molbev/msz272 ◽

2019 ◽

Vol 37 (3) ◽

pp. 839-848 ◽

Cited By ~ 1

Author(s):

Manuel Poretti ◽

Coraline Rosalie Praz ◽

Lukas Meile ◽

Carol Kälin ◽

Luisa Katharina Schaefer ◽

...

Keyword(s):

Immune Response ◽

Transposable Elements ◽

Small Rna ◽

Wheat Genome ◽

Wide Spread ◽

Evolutionary Mechanisms ◽

Plant Genomes ◽

Evolutionary Force ◽

Obligate Pathogen ◽

Powdery Mildew Pathogen

Abstract Plant genomes have evolved several evolutionary mechanisms to tolerate and make use of transposable elements (TEs). Of these, transposon domestication into cis-regulatory and microRNA (miRNA) sequences is proposed to contribute to abiotic/biotic stress adaptation in plants. The wheat genome is derived at 85% from TEs, and contains thousands of miniature inverted-repeat transposable elements (MITEs), whose sequences are particularly prone for domestication into miRNA precursors. In this study, we investigate the contribution of TEs to the wheat small RNA immune response to the lineage-specific, obligate powdery mildew pathogen. We show that MITEs of the Mariner superfamily contribute the largest diversity of miRNAs to the wheat immune response. In particular, MITE precursors of miRNAs are wide-spread over the wheat genome, and highly conserved copies are found in the Lr34 and QPm.tut-4A mildew resistance loci. Our work suggests that transposon domestication is an important evolutionary force driving miRNA functional innovation in wheat immunity.

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uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

Frontiers in Immunology ◽

10.3389/fimmu.2021.627926 ◽

2021 ◽

Vol 12 ◽

Author(s):

Elena Magnani ◽

Filippo Macchi ◽

Bhavani P. Madakashira ◽

Chi Zhang ◽

Fatima Alaydaroos ◽

...

Keyword(s):

Dna Methylation ◽

Immune Response ◽

Cell Death ◽

Transposable Elements ◽

Cellular Damage ◽

Interferon Response ◽

Type I ◽

Dna Hypomethylation ◽

Direct Role ◽

Double Stranded Rna

Activation of transposable elements (TEs) can cause cellular damage. Cytoplasmic nucleic acid sensing pathways evolved to detect pathogens, but can also serve to cull cells with inappropriate TE activation as TEs can be viral mimetics. Epigenetic silencing of TEs is mediated in part by DNA methylation, but it is not clear if TE activation or the immune system contribute to the cellular damage caused by loss of DNA methylation. Here, we provide mechanistic insight into the observation of an activated interferon response in the liver of zebrafish larvae with deletion in critical components of the DNA methylation machinery, uhrf1 and dnmt1. We focus on dissecting the relationship between DNA methylation, TE activation and induction of an immune response through cytoplasmic DNA and double stranded RNA sensing pathways and identify tnfa as a mediator of cell death in the liver of these mutants. Integrated RNAseq and methylome analysis identified LTR transposons as the most upregulated in these mutants and also the most methylated in control larvae, indicating a direct role of DNA methylation in suppressing this TE subclass. RNAseq analysis from these same samples revealed expression signatures of a type-I interferon response and of tnfa activation, mimicking the pattern of gene expression in virally infected cells. CRISPR/Cas9 mediated depletion of the cellular antiviral sensors sting and mavs reduced expression of interferon response genes and tnfa depletion dramatically reduced cell death in uhrf1 mutant livers. This suggests that the antiviral response induced by DNA hypomethylation and TE activation in the liver is mediated by the signaling pathways activated by both cytoplasmic double stranded RNA and DNA and that tnfa mediates cell death as a potential mechanism to eliminate these damaged cells.

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Transposable elements have contributed human regulatory regions that are activated upon bacterial infection

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0332 ◽

2020 ◽

Vol 375 (1795) ◽

pp. 20190332 ◽

Cited By ~ 2

Author(s):

Lucia Bogdan ◽

Luis Barreiro ◽

Guillaume Bourque

Keyword(s):

Gene Expression ◽

Immune Response ◽

Transposable Elements ◽

Cell Activation ◽

Immune Cell ◽

Regulation Of Gene Expression ◽

Interferon Response ◽

Human Interferon ◽

Trait Locus ◽

Accessible Chromatin

Transposable elements (TEs) are increasingly recognized as important contributors to mammalian regulatory systems. For instance, they have been shown to play a role in the human interferon response, but their involvement in other mechanisms of immune cell activation remains poorly understood. Here, we investigated the profile of accessible chromatin enhanced in stimulated human macrophages using ATAC-seq to assess the role of different TE subfamilies in regulating gene expression following an immune response. We found that both previously identified and new repeats belonging to the MER44, THE1, Tigger3 and MLT1 families provide 14 subfamilies that are enriched in differentially accessible chromatin and found near differentially expressed genes. These TEs also harbour binding motifs for several candidate transcription factors, including important immune regulators AP-1 and NF-κB, present in 96% of accessible MER44B and 83% of THE1C instances, respectively. To more directly assess their regulatory potential, we evaluated the presence of these TEs in regions putatively affecting gene expression, as defined by quantitative trait locus (QTL) analysis, and found that repeats are also contributing to accessible elements near QTLs. Together, these results suggest that a number of TE families have contributed to the regulation of gene expression in the context of the immune response to infection in humans. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

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