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Genes & Development Dec 2023Long interspersed element 1 (LINE-1) is the only protein-coding transposon that is active in humans. LINE-1 propagates in the genome using RNA intermediates via... (Review)
Review
Long interspersed element 1 (LINE-1) is the only protein-coding transposon that is active in humans. LINE-1 propagates in the genome using RNA intermediates via retrotransposition. This activity has resulted in LINE-1 sequences occupying approximately one-fifth of our genome. Although most copies of LINE-1 are immobile, ∼100 copies are retrotransposition-competent. Retrotransposition is normally limited via epigenetic silencing, DNA repair, and other host defense mechanisms. In contrast, LINE-1 overexpression and retrotransposition are hallmarks of cancers. Here, we review mechanisms of LINE-1 regulation and how LINE-1 may promote genetic heterogeneity in tumors. Finally, we discuss therapeutic strategies to exploit LINE-1 biology in cancers.
Topics: Humans; Long Interspersed Nucleotide Elements; Neoplasms; RNA; Proteins; Epigenesis, Genetic
PubMed: 38092519
DOI: 10.1101/gad.351051.123 -
Nucleic Acids Research Dec 2023RNA-guided endonucleases form the crux of diverse biological processes and technologies, including adaptive immunity, transposition, and genome editing. Some of these...
RNA-guided endonucleases form the crux of diverse biological processes and technologies, including adaptive immunity, transposition, and genome editing. Some of these enzymes are components of insertion sequences (IS) in the IS200/IS605 and IS607 transposon families. Both IS families encode a TnpA transposase and a TnpB nuclease, an RNA-guided enzyme ancestral to CRISPR-Cas12s. In eukaryotes, TnpB homologs occur as two distinct types, Fanzor1s and Fanzor2s. We analyzed the evolutionary relationships between prokaryotic TnpBs and eukaryotic Fanzors, which revealed that both Fanzor1s and Fanzor2s stem from a single lineage of IS607 TnpBs with unusual active site arrangement. The widespread nature of Fanzors implies that the properties of this particular lineage of IS607 TnpBs were particularly suited to adaptation in eukaryotes. Biochemical analysis of an IS607 TnpB and Fanzor1s revealed common strategies employed by TnpBs and Fanzors to co-evolve with their cognate transposases. Collectively, our results provide a new model of sequential evolution from IS607 TnpBs to Fanzor2s, and Fanzor2s to Fanzor1s that details how genes of prokaryotic origin evolve to give rise to new protein families in eukaryotes.
Topics: Bacteria; DNA Transposable Elements; Endonucleases; Prokaryotic Cells; Transposases; Evolution, Molecular; Eukaryotic Cells
PubMed: 37971304
DOI: 10.1093/nar/gkad1053 -
Epigenetics & Chromatin Oct 2023Vitamin C (vitC) enhances the activity of 2-oxoglutarate-dependent dioxygenases, including TET enzymes, which catalyse DNA demethylation, and Jumonji-domain histone...
BACKGROUND
Vitamin C (vitC) enhances the activity of 2-oxoglutarate-dependent dioxygenases, including TET enzymes, which catalyse DNA demethylation, and Jumonji-domain histone demethylases. The epigenetic remodelling promoted by vitC improves the efficiency of induced pluripotent stem cell derivation, and is required to attain a ground-state of pluripotency in embryonic stem cells (ESCs) that closely mimics the inner cell mass of the early blastocyst. However, genome-wide DNA and histone demethylation can lead to upregulation of transposable elements (TEs), and it is not known how vitC addition in culture media affects TE expression in pluripotent stem cells.
RESULTS
Here we show that vitC increases the expression of several TE families, including evolutionarily young LINE-1 (L1) elements, in mouse ESCs. We find that TET activity is dispensable for L1 upregulation, and that instead it occurs largely as a result of H3K9me3 loss mediated by KDM4A/C histone demethylases. Despite increased L1 levels, we did not detect increased somatic insertion rates in vitC-treated cells. Notably, treatment of human ESCs with vitC also increases L1 protein levels, albeit through a distinct, post-transcriptional mechanism.
CONCLUSION
VitC directly modulates the expression of mouse L1s and other TEs through epigenetic mechanisms, with potential for downstream effects related to the multiple emerging roles of L1s in cellular function.
Topics: Humans; Animals; Mice; Ascorbic Acid; Mouse Embryonic Stem Cells; Long Interspersed Nucleotide Elements; DNA Methylation; Histone Demethylases; DNA; Demethylation; Jumonji Domain-Containing Histone Demethylases
PubMed: 37845773
DOI: 10.1186/s13072-023-00514-6 -
International Journal of Molecular... Dec 2023Long interspersed element-1 (LINE-1; L1s) are mobile genetic elements that comprise nearly 20% of the human genome. L1s have been shown to have important functions in...
Long interspersed element-1 (LINE-1; L1s) are mobile genetic elements that comprise nearly 20% of the human genome. L1s have been shown to have important functions in various biological processes, and their dysfunction is thought to be linked with diseases and cancers. However, the roles of the repetitive elements are largely not understood. While the CRISPR activation (CRISPRa) system based on catalytically deadCas9 (dCas9) is widely used for genome-wide interrogation of gene function and genetic interaction, few studies have been conducted on L1s. Here, we report using the CRISPRa method to efficiently activate L1s in human L02 cells, a derivative of the HeLa cancer cell line. After CRISPRa, the young L1 subfamilies such as L1HS/L1PA1 and L1PA2 are found to be expressed at higher levels than the older L1s. The L1s with high levels of transcription are closer to full-length and are more densely occupied by the YY1 transcription factor. The activated L1s can either be mis-spliced to form chimeric transcripts or act as alternative promoters or enhancers to facilitate the expression of neighboring genes. The method described here can be used for studying the functional roles of young L1s in cultured cells of interest.
Topics: Humans; Clustered Regularly Interspaced Short Palindromic Repeats; Long Interspersed Nucleotide Elements; Genome, Human; HeLa Cells; Promoter Regions, Genetic
PubMed: 38203595
DOI: 10.3390/ijms25010424 -
The Journal of Clinical Investigation Jul 2023The most active human endogenous retrovirus K (HERV-K) subtype, HML-2, has been implicated as a driver of oncogenesis in several cancers. However, the presence and...
The most active human endogenous retrovirus K (HERV-K) subtype, HML-2, has been implicated as a driver of oncogenesis in several cancers. However, the presence and function of HML-2 in malignant gliomas has remained unclear. In this issue of the JCI, Shah and colleagues demonstrate HML-2 overexpression in glioblastoma (GBM) and its role in maintaining the cancer stem cell phenotype. Given that stem-like cells are considered responsible for GBM heterogeneity and treatment resistance, targeting the stem cell niche may reduce tumor recurrence and improve clinical outcomes. The findings provide a foundation for future studies to determine whether antiretroviral and/or immunotherapy approaches targeting HML-2 could be used as therapeutics for GBM.
Topics: Humans; Endogenous Retroviruses; Glioblastoma; Neoplasm Recurrence, Local
PubMed: 37395278
DOI: 10.1172/JCI170885 -
Nature Communications Sep 2023Most Drosophila transposable elements are LTR retrotransposons, some of which belong to the genus Errantivirus and share structural and functional characteristics with...
Most Drosophila transposable elements are LTR retrotransposons, some of which belong to the genus Errantivirus and share structural and functional characteristics with vertebrate endogenous retroviruses. Like endogenous retroviruses, it is unclear whether errantiviruses retain some infectivity and transposition capacity. We created conditions where control of the Drosophila ZAM errantivirus through the piRNA pathway was abolished leading to its de novo reactivation in somatic gonadal cells. After reactivation, ZAM invaded the oocytes and severe fertility defects were observed. While ZAM expression persists in the somatic gonadal cells, the germline then set up its own adaptive genomic immune response by producing piRNAs against the constantly invading errantivirus, restricting invasion. Our results suggest that although errantiviruses are continuously repressed by the piRNA pathway, they may retain their ability to infect the germline and transpose, thus allowing them to efficiently invade the germline if they are expressed.
Topics: Animals; Female; Drosophila; Ovary; Drosophila melanogaster; Germ Cells; Drosophila Proteins; Endogenous Retroviruses; RNA, Small Interfering; DNA Transposable Elements
PubMed: 37773253
DOI: 10.1038/s41467-023-41733-5 -
Nature Communications Dec 2023Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer's disease (AD). Mobilization of transposable elements (TEs) in...
Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer's disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.
Topics: Humans; Alzheimer Disease; DNA Transposable Elements; Amyloid beta-Peptides; Up-Regulation; Neurogenesis; Immunity, Innate; Hippocampus
PubMed: 38049398
DOI: 10.1038/s41467-023-43728-8 -
Virulence Dec 2024Enterohemorrhagic (EHEC) is an important zoonotic pathogen that is a major cause of foodborne diseases in most developed and developing countries and can cause... (Review)
Review
Enterohemorrhagic (EHEC) is an important zoonotic pathogen that is a major cause of foodborne diseases in most developed and developing countries and can cause uncomplicated diarrhoea, haemorrhagic colitis, and haemolytic uraemic syndrome. O islands (OIs), which are unique genomic islands in EHEC O157:H7, are composed of 177 isolated genomic features and harbour 26% of the total genes that are absent in the non-pathogenic K-12 genome. In the last twenty years, many OI-encoded proteins have been characterized, including proteins regulating virulence, motility, and acid resistance. Given the critical role of regulatory proteins in the systematic and hierarchical regulation of bacterial biological processes, this review summarizes the OI-encoded regulatory proteins in EHEC O157:H7 characterized to date, emphasizing OI-encoded regulatory proteins for bacterial virulence, motility, and acid resistance. This summary will be significant for further exploration and understanding of the virulence and pathogenesis of EHEC O157:H7.
Topics: Humans; Genomic Islands; Escherichia coli O157; Transcription Factors; Enterohemorrhagic Escherichia coli; Virulence; Escherichia coli Infections; Escherichia coli Proteins
PubMed: 38357901
DOI: 10.1080/21505594.2024.2313407 -
Trends in Genetics : TIG Aug 2023Transposable elements (TEs) are mobile genetic sequences present within host genomes. TEs can contribute to the evolution of host traits, since transposition is... (Review)
Review
Transposable elements (TEs) are mobile genetic sequences present within host genomes. TEs can contribute to the evolution of host traits, since transposition is mutagenic and TEs often contain host regulatory and protein coding sequences. We review cases where TEs influence animal colouration, reporting major patterns and outstanding questions. TE-induced colouration phenotypes typically arise via introduction of novel regulatory sequences and splice sites, affecting pigment cell development or pigment synthesis. We discuss if particular TE types may be more frequently involved in the evolution of colour variation in animals, given that examples involving long terminal repeat (LTR) elements appear to dominate. Currently, examples of TE-induced colouration phenotypes in animals mainly concern model and domesticated insect and mammal species. However, several influential recent examples, coupled with increases in genome sequencing, suggest cases reported from wild species will increase considerably.
Topics: Animals; DNA Transposable Elements; Chromosome Mapping; Base Sequence; Mammals; Evolution, Molecular
PubMed: 37183153
DOI: 10.1016/j.tig.2023.04.005 -
Gut Microbes 2024strains can be broadly classified into two groups based on whether they contain or lack a chromosomal region known as the pathogenicity island ( PAI). Colonization of... (Review)
Review
strains can be broadly classified into two groups based on whether they contain or lack a chromosomal region known as the pathogenicity island ( PAI). Colonization of the human stomach with PAI-positive strains is associated with an increased risk of gastric cancer and peptic ulcer disease, compared to colonization with PAI-negative strains. The PAI encodes a secreted effector protein (CagA) and components of a type IV secretion system (Cag T4SS) that delivers CagA and non-protein substrates into host cells. Animal model experiments indicate that CagA and the Cag T4SS stimulate a gastric mucosal inflammatory response and contribute to the development of gastric cancer. In this review, we discuss recent studies defining structural and functional features of CagA and the Cag T4SS and mechanisms by which strains containing the PAI promote the development of gastric cancer and peptic ulcer disease.
Topics: Animals; Humans; Bacterial Proteins; Antigens, Bacterial; Helicobacter pylori; Stomach Neoplasms; Genomic Islands; Gastrointestinal Microbiome; Peptic Ulcer; Helicobacter Infections
PubMed: 38391242
DOI: 10.1080/19490976.2024.2314201