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Trends in Microbiology Apr 2024Endogenous retroviruses (ERVs) are evolutionary remnants of retroviral infections in which the viral genome became embedded as a dormant regulatory element within the... (Review)
Review
Endogenous retroviruses (ERVs) are evolutionary remnants of retroviral infections in which the viral genome became embedded as a dormant regulatory element within the host germline. When ERVs become activated, they comprehensively rewire genomic regulatory networks of the host and facilitate critical developmental events, such as preimplantation development and placentation, in a manner specific to species, developmental stage, and tissues. However, accumulating evidence suggests that aberrant ERV transcription compromises genome stability and has been implicated in cellular senescence and various pathogenic processes, underscoring the significance of host genomic surveillance mechanisms. Here, we revisit the prominent functions of ERVs in early development and highlight their emerging roles in mammalian post-implantation development and organogenesis. We also discuss their implications for aging and pathological processes such as microbial infection, immune response. Furthermore, we discuss recent advances in stem-cell-based models, single-cell omics, and genome editing technologies, which serve as beacons illuminating the versatile nature of ERVs in mammalian development and health.
Topics: Animals; Endogenous Retroviruses; Mammals; Genomics; Biological Evolution; Genome, Viral
PubMed: 37802660
DOI: 10.1016/j.tim.2023.09.006 -
Cell Reports Jun 2023The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging-associated molecular mechanisms remain unclear. Here, using...
The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging-associated molecular mechanisms remain unclear. Here, using physiologically aged non-human primates (NHPs), we depicted a comprehensive landscape of FL aging with multidimensional profiling encompassing bulk and single-nucleus transcriptomes, quantitative proteome, and DNA methylome. Conjoint analysis across these molecular and neuropathological layers underscores nuclear lamina and heterochromatin erosion, resurrection of endogenous retroviruses (ERVs), activated pro-inflammatory cyclic GMP-AMP synthase (cGAS) signaling, and cellular senescence in post-mitotic neurons of aged NHP and human FL. Using human embryonic stem-cell-derived neurons recapitulating cellular aging in vitro, we verified the loss of B-type lamins inducing resurrection of ERVs as an initiating event of the aging-bound cascade in post-mitotic neurons. Of significance, these aging-related cellular and molecular changes can be alleviated by abacavir, a nucleoside reverse transcriptase inhibitor, either through direct treatment of senescent human neurons in vitro or oral administration to aged mice.
Topics: Animals; Mice; Endogenous Retroviruses; Nuclear Lamina; Aging; Cellular Senescence; Neurons; Primates
PubMed: 37261950
DOI: 10.1016/j.celrep.2023.112593 -
Nature Reviews. Molecular Cell Biology Mar 2024Human endogenous retroviruses (HERVs) are abundant sequences that persist within the human genome as remnants of ancient retroviral infections. These sequences became... (Review)
Review
Human endogenous retroviruses (HERVs) are abundant sequences that persist within the human genome as remnants of ancient retroviral infections. These sequences became fixed and accumulate mutations or deletions over time. HERVs have affected human evolution and physiology by providing a unique repertoire of coding and non-coding sequences to the genome. In healthy individuals, HERVs participate in immune responses, formation of syncytiotrophoblasts and cell-fate specification. In this Review, we discuss how endogenized retroviral motifs and regulatory sequences have been co-opted into human physiology and how they are tightly regulated. Infections and mutations can derail this regulation, leading to differential HERV expression, which may contribute to pathologies including neurodegeneration, pathological inflammation and oncogenesis. Emerging evidence demonstrates that HERVs are crucial to human health and represent an understudied facet of many diseases, and we therefore argue that investigating their fundamental properties could improve existing therapies and help develop novel therapeutic strategies.
Topics: Humans; Endogenous Retroviruses; Carcinogenesis
PubMed: 37872387
DOI: 10.1038/s41580-023-00674-z -
Science (New York, N.Y.) Jun 2023Horizontal gene transfer, the movement of genetic material between species, has been reported across all major eukaryotic lineages. However, the underlying mechanisms of...
Horizontal gene transfer, the movement of genetic material between species, has been reported across all major eukaryotic lineages. However, the underlying mechanisms of transfer and their impact on genome evolution are still poorly understood. While studying the evolutionary origin of a selfish element in the nematode , we discovered that , ancient virus-like transposons related to giant viruses and virophages, are one of the long-sought vectors of horizontal gene transfer. We found that gained a novel herpesvirus-like fusogen in nematodes, leading to the widespread exchange of cargo genes between extremely divergent species, bypassing sexual and genetic barriers spanning hundreds of millions of years. Our results show how the union between viruses and transposons causes horizontal gene transfer and ultimately genetic incompatibilities in natural populations.
Topics: Animals; Caenorhabditis; Gene Transfer, Horizontal; Viruses; DNA Transposable Elements; Genetic Vectors; Biological Evolution
PubMed: 37384706
DOI: 10.1126/science.ade0705 -
Molecular Cell Dec 2023Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most...
Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.
Topics: Endogenous Retroviruses; RNA, Nuclear; Epigenesis, Genetic; Heterochromatin; Gene Expression
PubMed: 37995687
DOI: 10.1016/j.molcel.2023.10.036 -
Cell Sep 2023Tn7-like transposons have co-opted CRISPR-Cas systems to facilitate the movement of their own DNA. These CRISPR-associated transposons (CASTs) are promising tools for...
Tn7-like transposons have co-opted CRISPR-Cas systems to facilitate the movement of their own DNA. These CRISPR-associated transposons (CASTs) are promising tools for programmable gene knockin. A key feature of CASTs is their ability to recruit Tn7-like transposons to nuclease-deficient CRISPR effectors. However, how Tn7-like transposons are recruited by diverse CRISPR effectors remains poorly understood. Here, we present the cryo-EM structure of a recruitment complex comprising the Cascade complex, TniQ, TnsC, and the target DNA in the type I-B CAST from Peltigera membranacea cyanobiont 210A. Target DNA recognition by Cascade induces conformational changes in Cas6 and primes TniQ recruitment through its C-terminal domain. The N-terminal domain of TniQ is bound to the seam region of the TnsC spiral heptamer. Our findings provide insights into the diverse mechanisms for the recruitment of Tn7-like transposons to CRISPR effectors and will aid in the development of CASTs as gene knockin tools.
Topics: CRISPR-Associated Proteins; CRISPR-Cas Systems; DNA Transposable Elements; Gene Knock-In Techniques; Cryoelectron Microscopy; Ascomycota
PubMed: 37557170
DOI: 10.1016/j.cell.2023.07.010 -
Nature Communications Aug 2023Prion-like spreading of protein misfolding is a characteristic of neurodegenerative diseases, but the exact mechanisms of intercellular protein aggregate dissemination...
Prion-like spreading of protein misfolding is a characteristic of neurodegenerative diseases, but the exact mechanisms of intercellular protein aggregate dissemination remain unresolved. Evidence accumulates that endogenous retroviruses, remnants of viral germline infections that are normally epigenetically silenced, become upregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis and tauopathies. Here we uncover that activation of endogenous retroviruses affects prion-like spreading of proteopathic seeds. We show that upregulation of endogenous retroviruses drastically increases the dissemination of protein aggregates between cells in culture, a process that can be inhibited by targeting the viral envelope protein or viral protein processing. Human endogenous retrovirus envelopes of four different clades also elevate intercellular spreading of proteopathic seeds, including pathological Tau. Our data support a role of endogenous retroviruses in protein misfolding diseases and suggest that antiviral drugs could represent promising candidates for inhibiting protein aggregate spreading.
Topics: Humans; Endogenous Retroviruses; Protein Aggregates; Amyotrophic Lateral Sclerosis; Antiviral Agents; Prions
PubMed: 37596282
DOI: 10.1038/s41467-023-40632-z -
Nature Communications Oct 2023Shading in combination with extended photoperiods can cause exaggerated stem elongation (ESE) in soybean, leading to lodging and reduced yields when planted at...
Shading in combination with extended photoperiods can cause exaggerated stem elongation (ESE) in soybean, leading to lodging and reduced yields when planted at high-density in high-latitude regions. However, the genetic basis of plant height in adaptation to these regions remains unclear. Here, through a genome-wide association study, we identify a plant height regulating gene on chromosome 13 (PH13) encoding a WD40 protein with three main haplotypes in natural populations. We find that an insertion of a Ty1/Copia-like retrotransposon in the haplotype 3 leads to a truncated PH13 with reduced interaction with GmCOP1s, resulting in accumulation of STF1/2, and reduced plant height. In addition, PH13 allele has been strongly selected for genetic improvement at high latitudes. Deletion of both PH13 and its paralogue PHP can prevent shade-induced ESE and allow high-density planting. This study provides insights into the mechanism of shade-resistance and offers potential solutions for breeding high-yielding soybean cultivar for high-latitude regions.
Topics: Glycine max; Genome-Wide Association Study; Plant Breeding; Phenotype; Retroelements
PubMed: 37884530
DOI: 10.1038/s41467-023-42608-5 -
Biochemistry. Biokhimiia Nov 2023Transposable elements (TEs) comprise a significant part of eukaryotic genomes being a major source of genome instability and mutagenesis. Cellular defense systems... (Review)
Review
Transposable elements (TEs) comprise a significant part of eukaryotic genomes being a major source of genome instability and mutagenesis. Cellular defense systems suppress the TE expansion at all stages of their life cycle. Piwi proteins and Piwi-interacting RNAs (piRNAs) are key elements of the anti-transposon defense system, which control TE activity in metazoan gonads preventing inheritable transpositions and developmental defects. In this review, we discuss various regulatory mechanisms by which small RNAs combat TE activity. However, active transposons persist, suggesting these powerful anti-transposon defense mechanisms have a limited capacity. A growing body of evidence suggests that increased TE activity coincides with genome reprogramming and telomere lengthening in different species. In the Drosophila fruit fly, whose telomeres consist only of retrotransposons, a piRNA-mediated mechanism is required for telomere maintenance and their length control. Therefore, the efficacy of protective mechanisms must be finely balanced in order not only to suppress the activity of transposons, but also to maintain the proper length and stability of telomeres. Structural and functional relationship between the telomere homeostasis and LINE1 retrotransposon in human cells indicates a close link between selfish TEs and the vital structure of the genome, telomere. This relationship, which permits the retention of active TEs in the genome, is reportedly a legacy of the retrotransposon origin of telomeres. The maintenance of telomeres and the execution of other crucial roles that TEs acquired during the process of their domestication in the genome serve as a type of payment for such a "service."
Topics: Animals; Humans; Retroelements; Drosophila melanogaster; RNA, Small Interfering; Drosophila; Drosophila Proteins; Telomere; DNA Transposable Elements
PubMed: 38105195
DOI: 10.1134/S0006297923110068 -
Nature Communications Oct 2023Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize...
Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize with immunotherapies, mediated by the de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here, we use deep RNA sequencing from cancer cell lines treated with DNA methyltransferase inhibitor (DNMTi) and/or Histone deacetylase inhibitor (HDACi), to assemble a de novo transcriptome and identify several thousand ERV-derived, treatment-induced novel polyadenylated transcripts (TINPATs). Using immunopeptidomics, we demonstrate the human leukocyte antigen (HLA) presentation of 45 spectra-validated treatment-induced neopeptides (t-neopeptides) arising from TINPATs. We illustrate the potential of the identified t-neopeptides to elicit a T-cell response to effectively target cancer cells. We further verify the presence of t-neopeptides in AML patient samples after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight the potential of ERV-derived neoantigens in epigenetic and immune therapies.
Topics: Humans; Endogenous Retroviruses; Histone Deacetylase Inhibitors; Neoplasms; T-Lymphocytes; Histocompatibility Antigens Class I
PubMed: 37872136
DOI: 10.1038/s41467-023-42417-w