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At least 19 recordsLinked to original sources
PubMed2025

Endogenous retroelements promote tolerance to dietary antigens.

Retroelements are transposable elements that represent a significant portion of eukaryotic genomes. Here, we show that constitutive expression of endogenous retroelements play a key regulatory role in the acquisition of food tolerance. Specifically, inhibition of retroelement reverse transcription abolishes tolerance to dietary antigens and promotes allergic responses. This phenomenon is associated with impaired regulatory T cell differentiation/accumulation and altered dendritic cell tolerogenic function. Mechanistically, innate sensing of retroelement-derived cDNA via cGAS/STING within gut epithelial cells promotes a local tolerogenic milieu. Thus, within the gut, immune reactivity to retroelements act as a local tonic signal required for regulatory T cell induction and differentiation, thereby preventing allergic responses to food. Collectively, these findings uncover retroelements as key regulatory elements and essential allies in maintaining immune tolerance.

Journal Article↗
PubMed1992

Retroelements in higher plants.

Representatives of several classes of retroelements have been characterized in a broad range of plant species, where they appear at variable and sometimes very high copy numbers. So far, only a very small number of plant elements have been shown to be active, and this activity seems to be restricted to specific situations of 'genomic shock'. Although it is not yet known whether the presence of retroelements is linked to the high level of variability found in plant genomes, it is now clear that retrotransposons are ancient and ubiquitous components of plant genomes, and could play an important role in plant evolution.

Biological Evolution↗
PubMed2025

Endogenous Retroelement Activation is Implicated in Interferon-α Production and Anti-Cyclic Citrullinated Peptide Autoantibody Generation in Early Rheumatoid Arthritis.

OBJECTIVE: Endogenous retroelements (EREs) stimulate type 1 interferon (IFN-I) production but have not been explored as potential interferonogenic triggers in rheumatoid arthritis (RA). We investigated ERE expression in early RA (eRA), a period in which IFN-I levels are increased. METHODS: ERE expression (long terminal repeat [LTR] 5, long interspersed nuclear element 1 [LINE-1], and short interspersed nuclear element [SINE]) in disease-modifying treatment-na&#xef;ve eRA whole-blood and bulk synovial tissue samples was examined by reverse transcription-polymerase chain reaction and NanoString alongside IFN-&#x3b1; activity. Circulating lymphocyte subsets, including B cell subsets, from patients with eRA and early psoriatic arthritis (ePsA) were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single-cell sequencing data were reinterrogated to identify repeat elements, and associations were explored. RESULTS: There was significant coexpression of all ERE classes and IFNA in eRA synovial tissue samples (n = 22, P < 0.0001) and significant positive associations between whole-blood LINE-1 expression (n = 56) and circulating IFN-&#x3b1; protein (P = 0.018) and anti-cyclic citrullinated peptide (anti-CCP) titers (P < 0.0001). ERE expression was highest in circulating eRA B cells, particularly na&#xef;ve B cells compared with ePsA, with possible ERE regulation by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase 1 transcription (SAMDH1) implicated and associations with IFNA again observed. Finally, in established RA synovium, LTRs, particularly human endogenous retroviral sequence K (HERVK), were most increased in RA compared with OA, in which, for all synovial subsets (monocytes, B cells, T cells, and fibroblasts), ERE expression associated with increased IFN-I signaling (P < 0.001). CONCLUSION: Peripheral blood and synovial ERE expression is examined for the first time in eRA, highlighting both a potential causal relationship between ERE and IFN-I production and an intriguing association with anti-CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.

Humans↗
PubMed2025

The mRNA export pathway licenses viral mimicry response and antitumor immunity by actively exporting nuclear retroelement transcripts.

Nuclear retroelement transcripts (RTs), which can be elicited both transcriptionally and posttranscriptionally, form double-stranded RNA (dsRNA) in cytosol to trigger the viral mimicry response (VMR) and antitumor immunity. However, the strength of the induced VMR varies tremendously across tumor types, and the underlying mechanisms remain poorly understood. Here, we demonstrate that the mRNA export pathway modulates the VMR through actively exporting nuclear RTs for cytosolic dsRNA formation after their induction. Tumor cells hijack this process for immune evasion through aberrant coactivator-associated arginine methyltransferase 1 (CARM1) expression. Mechanistically, we show that the cytoplasmic transportation of RTs by the mRNA export pathway is counteracted by the RNA exosome, which cleaves multiple transcripts within this pathway, including those encoding the essential DExD-box helicase 39A (DDX39A) and the adaptor protein ALYREF. CARM1 enhances the RNA exosome activity to attenuate the nuclear export of RTs by the mRNA export pathway through two synergistic mechanisms: (i) transcriptionally activating several RNA exosome components and (ii) posttranslationally methylating arginine 6 of the RNA exosome subunit EXOSC1, which protects it from proteasome-mediated degradation. Collectively, our study highlights the critical active regulatory role of the mRNA export pathway in transporting nuclear RTs into the cytosol for triggering the VMR and tumor immunity. Furthermore, we propose that enhancing the mRNA export pathway activity, either through CARM1 inhibition or RNA exosome modulation, could reinforce the therapeutic agent-induced VMR, thus holding the promise for overcoming tumor immune evasion and immunotherapy resistance.

Humans↗
PubMed2025

Evolution of antiviral host defenses against a backdrop of endogenous retroelements.

Mammalian hosts deploy a multitude of germ line-encoded mechanisms to detect and restrict virus infection. These mechanisms must avoid pathological responses to endogenous retroviruses and other endogenous retrotransposable elements (RTEs)-viruses and viruslike genomic parasites that have invaded the host germ line and are passed down the generations as host genes. Although the location, specificity, and sensitivity of innate pattern recognition receptors and restriction factors are tuned to facilitate discrimination of infecting viruses from those that are part of self, immune cross-reactions do occur. The RTE viral heritage may, therefore, compromise the ability of the host to respond to virus infection without risking pathology. Nevertheless, RTEs have the potential to be co-opted as an alarm amplification system, to be repurposed as antiviral factors, and to contribute to the evolution of antiviral genes.

Animals↗
PubMed1992

Ty1-copia group retrotransposons and the evolution of retroelements in the eukaryotes.

Ty1-copia group retrotransposons are among the best studied transposable elements in the eukaryotes. This review discusses the extent of these transposons in the eukaryote kingdoms and compares models for the evolution of these genetic elements in the light of recent phylogenetic data. These data show that the Ty1-copia group is widespread among invertebrate eukaryotes, especially in the higher plant kingdom, where these genetic elements are unusually common and heterogeneous in their sequence. The phylogenetic data also suggest that the present day spectrum of Ty1-copia group retrotransposons has been influenced both by divergence during vertical transmission down evolving lineages and by horizontal transmission between distantly related species. Lastly, the factors affecting Ty1-copia group retrotransposon copy number and sequence heterogeneity in eukaryotic genomes and the effects of transpositional quiescence and defective retrotransposons upon evolution of Ty1-copia group retrotransposons are discussed.

Amino Acid Sequence↗
PubMed1991

Retroelement particles as purification, presentation and targeting vehicles.

The manipulation of retrotransposon and retroviral particles to carry biologically active molecules is becoming feasible. In addition, recent experiments suggest that it may be possible to target these engineered particles to specific cell types. This has implications for gene therapy, biological drug delivery and vaccine design.

Antigens↗
PubMed2026

Mobile elements in pituitary neuroendocrine tumors: integrative evidence and future directions.

Mobile genetic elements (MGEs), including LINE-1 retrotransposons, Alu and SVA elements, and human endogenous retroviruses (HERVs), constitute nearly half of the human genome and are increasingly understood to influence multiple dimensions of cancer evolution. Yet, pituitary neuroendocrine tumors (PitNETs) remain almost absent from mobilome research, despite exhibiting genomic and epigenetic contexts permissive to retroelement activation. In this review, we synthesize current evidence linking MGEs to PitNET biology and delineate unresolved but testable mechanisms. Structural genomic studies demonstrate that Alu-mediated non-allelic homologous recombination contributes to germline mutagenesis in MEN1 and AIP, reinforcing the notion that repetitive DNA architecture shapes PitNET predisposition. Transcriptomic analyses reveal global derepression of transposable elements and LINE-1 hypomethylation in subsets of tumors, while mechanistic connections to chromatin instability emerge from recurrent ATRX/DAXX deficiency and TP53 inactivation, both established repressors of retroelements. Furthermore, the retrocopy-derived long non-coding RNA RPSAP52 exemplifies how mobilome-origin transcripts can be co-opted as oncogenic regulators in PitNETs, acting through HMGA2-dependent proliferative networks. Preliminary data also suggest endogenous retroviral activation, with consistent upregulation of HERV envelope genes across distinct tumor subtypes. Nevertheless, no study has yet systematically mapped somatic mobile-element insertions (MEIs), quantified LINE-1 protein activity, or profiled HERV expression at locus resolution in PitNETs. Mobilome biology represents a tractable and conceptually rich frontier with diagnostic, prognostic, and therapeutic potential in pituitary tumorigenesis.

Humans↗
PubMed2024

PTGS is dispensable for the initiation of epigenetic silencing of an active transposon in Arabidopsis.

Transposable elements (TEs) are repressed in plants through transcriptional gene silencing (TGS), maintained epigenetic silencing marks such as DNA methylation. However, the mechanisms by which silencing is first installed remain poorly understood in plants. Small interfering (si)RNAs and post-transcriptional gene silencing (PTGS) are believed to mediate the initiation of TGS by guiding the first deposition of DNA methylation. To determine how this silencing installation works, we took advantage of &#xc9;VAD&#xc9; (EVD), an endogenous retroelement in Arabidopsis, able to recapitulate true de novo silencing with a sequence of PTGS followed by a TGS. To test whether PTGS is required for TGS, we introduce active EVD into RNA-DEPENDENT-RNA-POLYMERASE-6 (RDR6) mutants, an essential PTGS component. EVD activity and silencing are monitored across several generations. In the absence of PTGS, silencing of EVD is still achieved through installation of RNA-directed DNA methylation (RdDM). Our study shows that PTGS is dispensable for de novo EVD silencing. Although we cannot rule out that PTGS might facilitate TGS, or control TE activity, initiation of epigenetic silencing can take place in its absence.

Arabidopsis↗
PubMed1992

Hepadnaviral assembly is initiated by polymerase binding to the encapsidation signal in the viral RNA genome.

Hepadnaviruses, as well as other pararetroviruses, express their pol (P) gene product unfused to the preceding core gene implying that these retroelements have developed a mechanism for initiating assembly and replication that is principally different from the one used by retroviruses and retrotransposons. We have analysed this mechanism for the human hepatitis B virus by using a newly developed, highly sensitive detection method based upon radiolabelling of the P protein at newly introduced target sites for protein kinase A. The results obtained demonstrate that polymerase encapsidation depends on the concomittant encapsidation of the HBV RNA pregenome and that packaging of the viral RNA, in turn, depends on the presence of P protein. Loss of P protein encapsidation by mutations inactivating the HBV RNA encapsidation signal epsilon could be compensated by trans-complementation with recombinant RNA molecules carrying the epsilon sequence. Thus, in contrast to retroviral replication, the interaction of the hepadnaviral P protein and the RNA genome at its packaging signal appears to be crucial for initiating the formation of replication-competent nucleocapsids. Furthermore, RNA control of P protein packaging stringently limits the number of polymerase molecules that can be encapsidated.

Capsid↗
PubMed1992

Molecular analysis of the yeast Ty4 element: homology with Ty1, copia, and plant retrotransposons.

The element; Ty4 is a retrotransposon present in low copy number in the genome of Saccharomyces cerevisiae [Stucka et al., Nucleic Acids Res. 17 (1989) 4993-5001]. We have determined the complete nucleotide sequence of one such element from a particular strain and compared it to the other two elements occurring in this strain. The genomic organization of Ty4 is homologous to that found in other retrotransposons of the Ty1-copia group. The internal part of the element contains two large open reading frames (TY4A and TY4B) overlapping by 226 bp in a + 1 mode. TY4A reveals characteristics of the gag portion of retrotransposons and retroviruses, while TY4B consists of a protease, an integrase, a reverse transcriptase, and an RNase H domain (in that order). Our analyses suggest that only one of these copies might be transpositionally active. Sequence comparisons at the amino acid level show that the domains in Ty4 diverge considerably from those of other retrotransposons. The greatest similarity is seen between the reverse transcriptases (50%), the proteases (40%), and the integrases (30%) of Ty4, Ty1/2 and copia, respectively, whereas the degree of similarity for all other entities of these elements is much lower. Considering evolutionary aspects of the retrotransposons, we have to conclude that Ty4 has diverged at an early stage from the progenitors of other known retroelements and represents a novel and independent subgroup of the Ty1-copia class of retrotransposons.

Amino Acid Sequence↗
PubMed2025

Biochemical assays for AID/APOBECs and the identification of AID/APOBEC inhibitors.

Activation-induced cytidine deaminase (AID) and apolipoprotein B-mRNA editing catalytic polypeptide 3 (APOBEC3 or A3) proteins belong to the AID/APOBEC family of cytidine deaminases. While AID mediates somatic hypermutation and class-switch recombination in adaptive immunity, A3s restrict viruses and retroelements by hypermutation. Mis-regulated expression and off-target activity of AID/A3 can cause genome-wide mutations promoting oncogenesis, immune evasion, and therapeutic resistance due to tumor and viral evolution. In these contexts, inhibition of AID/A3 represents a promising therapeutic approach. Competitive inhibition could be achieved with different strategies: one class would be small molecules that bind in the catalytic pocket (active site) and block access for the substrate cytidine. Another type of larger molecule inhibitor would bind the enzymes' surface more broadly and compete with the binding of the polynucleotide substrates prior to deamination catalysis. Several biochemical assays developed to assess AID/A3 activity can be employed to screen for potential inhibitors. These include in cellulo and in vitro activity-based as well as binding-based assays. In this chapter, we discuss the key considerations for designing robust enzyme assays and provide an overview of assays that we and others have established or modified for specific applications in AID/A3 enzymology, including measurement of inhibition. We provide detailed protocols for the two most widely used in vitro enzyme assays that directly measure the activities of purified AID/A3s on DNA and/or RNA substrates, namely, the gel-based alkaline cleavage assay and multiple variations of PCR/sequencing-based assays.

Cytidine Deaminase↗
PubMed2024

Structure and Methyl-lysine Binding Selectivity of the HUSH Complex Subunit MPP8.

The Human Silencing Hub (HUSH) guards the genome from the pathogenic effects of retroelement expression. Composed of MPP8, TASOR, and Periphilin-1, HUSH recognizes actively transcribed retrotransposed sequences by the presence of long (>1.5-kb) nascent transcripts without introns. HUSH recruits effectors that alter chromatin structure, degrade transcripts, and deposit transcriptionally repressive epigenetic marks. Here, we report the crystal structure of the C-terminal domain (CTD) of MPP8 necessary for HUSH activity. The MPP8 CTD consists of five ankyrin repeats followed by a domain with structural homology to the PINIT domains of Siz/PIAS-family SUMO E3 ligases. AlphaFold3 modeling of the MPP8-TASOR complex predicts that a SPOC domain and a domain with a novel fold in TASOR form extended interaction interfaces with the MPP8 CTD. Point mutations at these interfaces resulted in loss of HUSH-dependent transcriptional repression in a cell-based reporter assay, validating the AlphaFold3 model. The MPP8 chromodomain, known to bind the repressive mark H3K9me3, bound with similar or higher affinity to sequences in the H3K9 methyltransferase subunits SETDB1, ATF7IP, G9a, and GLP. Hence, MPP8 promotes heterochromatinization by recruiting H3K9 methyltransferases. Our work identifies novel structural elements in MPP8 required for HUSH complex assembly and silencing, thereby fulfilling vital functions in controlling retrotransposons.

Humans↗
PubMed2026

Noncanonical Transcription and Splicing Shape the Colorectal Cancer Immunopeptidome in MSI and MSS Tumors.

Treatment with immune checkpoint inhibitors in colorectal cancer (CRC) has largely benefited patients with microsatellite instability-high (MSI-H) and not the larger proportion of patient with microsatellite-stable (MSS) tumors. This clinical dichotomy has fueled the view that high mutational burden is the dominant driver of tumor immunogenicity and that MSS CRC fails to respond because it is "antigen poor". To directly test this premise and define the origins of presented tumor antigens, we integrated HLA class I immunopeptidomics and matched RNA-seq from 26 primary CRC tumors spanning MSI-H and MSS subtypes. Using patient-specific canonical and cancer-specific proteogenomic databases, we identified 115,292 unique major histocompatibility complex (MHC)-associated peptides (MAPs) across 61 HLA alleles, with a mean of 9292 MAPs per tumor and no significant difference in MAP counts between MSI-H and MSS tumors. In toto, we identified 266 tumor antigens, all coded by unmutated genomic sequences, comprising 70 aberrantly expressed tumor-specific antigens (aeTSAs) and 196 tumor-associated antigens (TAAs). In our cohort, MSS tumors presented more TAAs and a comparable number of aeTSAs per tumor relative to MSI-H tumors. In TCGA-COAD stratified analyses (483 tumors), MSS tumors yielded more presentable aeTSAs and TAAs per patient than MSI-H tumors. Across both subtypes, aeTSAs arose predominantly from intronic translation, UTR usage, retroelement activation, and germline-like transcription, including recurrent aeTSAs from PIWIL1, L1TD1, and endogenous retroviral loci. Together, these data demonstrate that MSS CRC is not antigen poor and highlight noncanonical translation as a major, previously underappreciated contributor to the CRC immunopeptidome.

Humans↗
PubMed1992

In vivo production of a stable single-stranded cDNA in Saccharomyces cerevisiae by means of a bacterial retron.

Gram-negative bacteria such as Myxococcus xanthus, Stigmatella aurantiaca, and Escherichia coli contain retroelements called retrons. Retrons consist of the msr-msd region and the gene for reverse transcriptase (RT), which are essential for the production of the branched RNA-linked ms-DNA (multicopy single-stranded DNA). In this study, we attempted to produce msDNA in the yeast Saccharomyces cerevisiae. Retron Ec67 from E. coli, which is responsible for the production of msDNA-Ec67, was cloned under the GAL10 promoter in a 2-microns-based plasmid. msDNA thus produced was detected by extending the 3' end of the msDNA by avian myeloblastosis virus RT. This yielded a main product of 117 nucleotides. Treatment of this product with RNase A resulted in a DNA of 105 nucleotides. These results are in good agreement with the structure of msDNA-Ec67. The production of msDNA-Ec67 was further confirmed by Southern blot hybridization. The msDNA production was dependent upon the bacterial RT gene in the clone and was increased severalfold when the RT gene of retron Ec67 was placed in front of the msr-msd region. The potential of msDNA as a eukaryotic vector producing a stable single-stranded DNA as well as RNA is discussed.

Base Sequence↗
PubMed2026

A chromosome-scale assembly for the genome of southern corn rootworm, Diabrotica undecimpunctata.

Diabrotica undecimpunctata ssp. howardi, the southern corn rootworm or eastern 12-spotted cucumber beetle, is a generalist insect herbivore that causes damage and yield loss to several crops in North America including maize. Unresolved phylogenetic relationships within and among D. undecimpunctata subspecies are impacting current quarantine policies. We report the chromosome-level haploid genome assembly, icDiaUnde3, constructed using HiFi and Hi-C read data from a single male D. undecimpunctata collected and identified as subspecies howardi based on geographic location and morphology. The primary 1.74 Gbp assembly is scaffolded into 11 chromosome-length scaffolds representing 9 autosomes, a single X chromosome and a supernumerary (B) chromosome (scaffold N50&#x2009;=&#x2009;162.8 Mb and L50&#x2009;=&#x2009;5). Ab initio and evidence-based structural reference sequence (RefSeq) annotations predicted 18,959 protein-coding genes, in which 99.2% of the 1,367 Benchmark Universal Single-Copy Orthologs from Insecta were complete. Repeat elements occupy 1.26 Gbp (72.33%) of the icDiaUnde3 assembly, with nearly 36% predicted to be retroelements. Alignment of whole chromosomes from icDiaUnde3 with those previously assembled from Diabrotica spp. predicted 2 and 6 autosomal inversions with D. balteata and D. virgifera virgifera, respectively. The mitochondrial genome had an annotated gene order and orientation conserved among beetles. The icDiaUnde3 reference genome assembly is a vital resource for taxonomic, comparative, and functional studies to enhance sustainable crop production.

agriculture↗
PubMed1992

Similarity between the Myxococcus xanthus and Stigmatella aurantiaca reverse transcriptase genes associated with multicopy, single-stranded DNA.

To determine the evolutional relationship of bacterial retroelements of Myxococcus xanthus and Stigmatella aurantiaca, the nucleotide sequence of 3,060 bases encompassing msr, msd, and the upstream region of msd (downstream of msr) of S. aurantiaca DW4 was determined and compared with the same region from M. xanthus. An open reading frame was found 92 bases upstream of msd which encoded a polypeptide of 480 amino acid residues having 73% identity with the reverse transcriptase of M. xanthus. Together with high homologies in msr (86%) and msd (81%) regions, the present data indicate that the reverse transcriptase genes as well as the retrons of M. xanthus (retron-Mx162) and S. aurantiaca (retron-Sa163) were derived from a common progenitor retron which possibly before the two myxobacterial species diverged.

Amino Acid Sequence↗