Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

L1 mobile element expression causes multiple types of toxicity.

ABSTRACT: LINE-1 (L1) retrotransposons represent one of the most successful families of autonomous retroelements, accounting for at least 17% of the human genome. The expression of these elements can be deleterious to a cell. L1 expression has been shown to result in insertional mutagenesis, genomic deletions and rearrangements as well as double-strand DNA breaks. Also, L1 expression has been linked to the induction of apoptosis. These recent discoveries, in addition to correlations of L1 expression with cancer progression, prompted us to further characterize the effect of L1 expression on cellular viability. We show a marked decrease in the overall cellular vitality with expression of the L1 that was primarily dependent on the second open reading frame (ORF2). Both the endonuclease and reverse transcriptase domains of ORF2 can individually contribute to the deleterious effects of L1 expression. L1 decreases cellular viability both by the previously reported apoptotic signaling, but also by inducing a senescence-like state.

SUBMITTER: Wallace NA

PROVIDER: S-EPMC3760205 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

L1 mobile element expression causes multiple types of toxicity.

Wallace Nicholas A NA Belancio Victoria P VP Deininger Prescott L PL

Gene 20080503 1-2

LINE-1 (L1) retrotransposons represent one of the most successful families of autonomous retroelements, accounting for at least 17% of the human genome. The expression of these elements can be deleterious to a cell. L1 expression has been shown to result in insertional mutagenesis, genomic deletions and rearrangements as well as double-strand DNA breaks. Also, L1 expression has been linked to the induction of apoptosis. These recent discoveries, in addition to correlations of L1 expression with ...[more]

PMID: 18555620

Similar Datasets

Integrated Mobile Element Scanning (ME-Scan) method for identifying multiple types of polymorphic mobile element insertions.

Project description:Background:Mobile elements are ubiquitous components of mammalian genomes and constitute more than half of the human genome. Polymorphic mobile element insertions (pMEIs) are a major source of human genomic variation and are gaining research interest because of their involvement in gene expression regulation, genome integrity, and disease. Results:Building on our previous Mobile Element Scanning (ME-Scan) protocols, we developed an integrated ME-Scan protocol to identify three major active families of human mobile elements, AluYb, L1HS, and SVA. This approach selectively amplifies insertion sites of currently active retrotransposons for Illumina sequencing. By pooling the libraries together, we can identify pMEIs from all three mobile element families in one sequencing run. To demonstrate the utility of the new ME-Scan protocol, we sequenced 12 human parent-offspring trios. Our results showed high sensitivity (>?90%) and accuracy (>?95%) of the protocol for identifying pMEIs in the human genome. In addition, we also tested the feasibility of identifying somatic insertions using the protocol. Conclusions:The integrated ME-Scan protocol is a cost-effective way to identify novel pMEIs in the human genome. In addition, by developing the protocol to detect three mobile element families, we demonstrate the flexibility of the ME-Scan protocol. We present instructions for the library design, a sequencing protocol, and a computational pipeline for downstream analyses as a complete framework that will allow researchers to easily adapt the ME-Scan protocol to their own projects in other genomes.

| S-EPMC7035633 | biostudies-literature

The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology.

Project description:Mobile element insertions (MEIs) represent ∼25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale. Using both Illumina WGS data and simulations, we demonstrate that MELT outperforms existing MEI discovery tools in terms of speed, scalability, specificity, and sensitivity, while also detecting a broader spectrum of MEI-associated features. Several run modes were developed to perform MEI discovery on local and cloud systems. In addition to using MELT to discover MEIs in modern humans as part of the 1000 Genomes Project, we also used it to discover MEIs in chimpanzees and ancient (Neanderthal and Denisovan) hominids. We detected diverse patterns of MEI stratification across these populations that likely were caused by (1) diverse rates of MEI production from source elements, (2) diverse patterns of MEI inheritance, and (3) the introgression of ancient MEIs into modern human genomes. Overall, our study provides the most comprehensive map of MEIs to date spanning chimpanzees, ancient hominids, and modern humans and reveals new aspects of MEI biology in these lineages. We also demonstrate that MELT is a robust platform for MEI discovery and analysis in a variety of experimental settings.

| S-EPMC5668948 | biostudies-literature

Boron Toxicity Causes Multiple Effects on Malus domestica Pollen Tube Growth.

Project description:Boron is an important micronutrient for plants. However, boron is also toxic to cells at high concentrations, although the mechanism of this toxicity is not known. This study aimed to evaluate the effect of boron toxicity on Malus domestica pollen tube growth and its possible regulatory pathway. Our results showed that a high concentration of boron inhibited pollen germination and tube growth and led to the morphological abnormality of pollen tubes. Fluorescent labeling coupled with a scanning ion-selective electrode technique detected that boron toxicity could decrease [Ca(2+)]c and induce the disappearance of the [Ca(2+)]c gradient, which are critical for pollen tube polar growth. Actin filaments were therefore altered by boron toxicity. Immuno-localization and fluorescence labeling, together with fourier-transform infrared analysis, suggested that boron toxicity influenced the accumulation and distribution of callose, de-esterified pectins, esterified pectins, and arabinogalactan proteins in pollen tubes. All of the above results provide new insights into the regulatory role of boron in pollen tube development. In summary, boron likely plays a structural and regulatory role in relation to [Ca(2+)]c, actin cytoskeleton and cell wall components and thus regulates Malus domestica pollen germination and tube polar growth.

| S-EPMC4768074 | biostudies-literature

LEAP: L1 Element Amplification Protocol.

Project description:Long INterspersed Element-1 (LINE-1 or L1) retrotransposons encode two proteins (ORF1p and ORF2p) that are required for retrotransposition. The L1 element amplification protocol (LEAP) assays the ability of L1 ORF2p to reverse transcribe L1 RNA in vitro. Ultracentrifugation or immunoprecipitation is used to isolate L1 ribonucleoprotein particle (RNP) complexes from cultured human cells transfected with an engineered L1 expression construct. The isolated RNPs are incubated with an oligonucleotide that contains a unique sequence at its 5' end and a thymidine-rich sequence at its 3' end. The addition of dNTPs to the reaction allows L1 ORF2p bound to L1 RNA to generate L1 cDNA. The resultant L1 cDNAs then are amplified using polymerase chain reaction (PCR) and the products are visualized by gel electrophoresis. Sequencing the resultant PCR products then allows product verification. The LEAP assay has been instrumental in determining how mutations in L1 ORF1p and ORF2p affect L1 reverse transcriptase (RT) activity. Furthermore, the LEAP assay has revealed that the L1 ORF2p RT can extend a DNA primer with mismatched 3' terminal bases when it is annealed to an L1 RNA template. As the LINE-1 biology field gravitates toward studying cellular proteins that regulate LINE-1, molecular genetic and biochemical approaches such as LEAP, in conjunction with the LINE-1-cultured cell retrotransposition assay, are essential to dissect the molecular mechanism of L1 retrotransposition.

| S-EPMC5070798 | biostudies-literature

The frequency and inter-relationship of PD-L1 expression and tumour mutational burden across multiple types of advanced solid tumours in China.

Project description:BackgroundPD-L1 expression and tumour mutational burden (TMB) are both associated with the responses of multiple tumours to immune checkpoint inhibitor (ICI) therapy. However, their prevalence and correlations may differ in different types of advanced solid tumours.MethodsPD-L1 expression, TMB, and PD-1+ Tils (tumour-infiltrating lymphocytes) infiltration and their relationships were assessed in 6668 advanced solid tumour specimens across 25 tumour types. CD8+ T cell infiltration was analysed in 347 NSCLC samples. The associations of these biomarkers with the therapeutic effect of PD-1 inhibitor were analysed in a cohort of NSCLC samples.ResultsPD-L1 expression levels and TMB in different tumour types varied widely and their relationship was not significantly correlated in most cancer types, with only a small association across all specimens (Spearman R = 0.059). PD-1+ Tils infiltration was positively correlated with PD-L1 expression across all samples (Spearman R = 0.3056). However, there is no such correlation between PD-1+ Tils infiltration and TMB. In NSCLC samples, CD8+ T cell infiltration was correlated with PD-1+ Tils infiltration and PD-L1 expression but not with TMB (Spearman R = 0.4117, 0.2045, and 0.0007, respectively). Patients in the CR/PR group (anti-PD-1 therapy) had higher levels of PD-L1 expression, TMB, PD-1+ Tils, and CD8+ T cell infiltration, and many patients in this group exhibited concomitantly elevated levels of multiple biomarkers.ConclusionsOur results showed the PD-L1 expression status and TMB in various types of advanced solid tumours in Chinese patients and their relationships with PD-1+ Tils and CD8+ T cell infiltration, which may inform ICI treatment.

| S-EPMC7397649 | biostudies-literature

Oncogenic JAK2V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms.

Project description:Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2V617F-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2V617F-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2V617F-myeloproliferative neoplasms (MPNs) compared to healthy individuals and declined upon JAK2 inhibition. JAK2V617F mutational burden, pSTAT3, and PD-L1 expression were highest in primary MPN patient-derived monocytes, megakaryocytes, and platelets. PD-1 (programmed death receptor 1) inhibition prolonged survival in human MPN xenograft and primary murine MPN models. This effect was dependent on T cells. Mechanistically, PD-L1 surface expression in JAK2V617F-mutant cells affected metabolism and cell cycle progression of T cells. In summary, we report that in MPN, constitutive JAK2/STAT3/STAT5 activation, mainly in monocytes, megakaryocytes, and platelets, caused PD-L1-mediated immune escape by reducing T cell activation, metabolic activity, and cell cycle progression. The susceptibility of JAK2V617F-mutant MPN to PD-1 targeting paves the way for immunomodulatory approaches relying on PD-1 inhibition.

| S-EPMC6034655 | biostudies-literature

Polymorphic mobile element insertions contribute to gene expression and alternative splicing in human tissues.

Project description:BackgroundMobile elements are a major source of structural variants in the human genome, and some mobile elements can regulate gene expression and transcript splicing. However, the impact of polymorphic mobile element insertions (pMEIs) on gene expression and splicing in diverse human tissues has not been thoroughly studied. The multi-tissue gene expression and whole genome sequencing data generated by the Genotype-Tissue Expression (GTEx) project provide a great opportunity to systematically evaluate the role of pMEIs in regulating gene expression in human tissues.ResultsUsing the GTEx whole genome sequencing data, we identify 20,545 high-quality pMEIs from 639 individuals. Coupling pMEI genotypes with gene expression profiles, we identify pMEI-associated expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) in 48 tissues. Using joint analyses of pMEIs and other genomic variants, pMEIs are predicted to be the potential causal variant for 3522 eQTLs and 3717 sQTLs. The pMEI-associated eQTLs and sQTLs show a high level of tissue specificity, and these pMEIs are enriched in the proximity of affected genes and in regulatory elements. Using reporter assays, we confirm that several pMEIs associated with eQTLs and sQTLs can alter gene expression levels and isoform proportions, respectively.ConclusionOverall, our study shows that pMEIs are associated with thousands of gene expression and splicing variations, indicating that pMEIs could have a significant role in regulating tissue-specific gene expression and transcript splicing. Detailed mechanisms for the role of pMEIs in gene regulation in different tissues will be an important direction for future studies.

| S-EPMC7385971 | biostudies-literature

E622, a miniature, virulence-associated mobile element.

Project description:Miniature inverted terminal repeat elements (MITEs) are nonautonomous mobile elements that have a significant impact on bacterial evolution. Here we characterize E622, a 611-bp virulence-associated MITE from Pseudomonas syringae, which contains no coding region but has almost perfect 168-bp inverted repeats. Using an antibiotic coupling assay, we show that E622 is transposable and can mobilize an antibiotic resistance gene contained between its borders. Its predicted parent element, designated TnE622, has a typical transposon structure with a three-gene operon, consisting of resolvase, integrase, and exeA-like genes, which is bounded by the same terminal inverted repeats as E622. A broader genome level survey of the E622/TnE622 inverted repeats identified homologs in Pseudomonas, Salmonella, Shewanella, Erwinia, Pantoea, and the cyanobacteria Nostoc and Cyanothece, many of which appear to encompass known virulence genes, including genes encoding toxins, enzymes, and type III secreted effectors. Its association with niche-specific genetic determinants, along with its persistence and evolutionary diversification, indicates that this mobile element family has played a prominent role in the evolution of many agriculturally and clinically relevant pathogenic bacteria.

| S-EPMC3256676 | biostudies-literature

Characterizing mobile element insertions in 5675 genomes.

Project description:Mobile element insertions (MEIs) are a major class of structural variants (SVs) and have been linked to many human genetic disorders, including hemophilia, neurofibromatosis, and various cancers. However, human MEI resources from large-scale genome sequencing are still lacking compared to those for SNPs and SVs. Here, we report a comprehensive map of 36 699 non-reference MEIs constructed from 5675 genomes, comprising 2998 Chinese samples (∼26.2×, NyuWa) and 2677 samples from the 1000 Genomes Project (∼7.4×, 1KGP). We discovered that LINE-1 insertions were highly enriched in centromere regions, implying the role of chromosome context in retroelement insertion. After functional annotation, we estimated that MEIs are responsible for about 9.3% of all protein-truncating events per genome. Finally, we built a companion database named HMEID for public use. This resource represents the latest and largest genomewide study on MEIs and will have broad utility for exploration of human MEI findings.

| S-EPMC8934628 | biostudies-literature

Cytoplasmic expression of mouse prion protein causes severe toxicity in Caenorhabditis elegans.

Project description:To test if Caenorhabditis elegans could be established as a model organism for prion study, we created transgenic C. elegans expressing the cytosolic form of the mouse prion protein, MoPrP(23-231), which lacks the N-terminal signal sequence and the C-terminal glycosylphosphatidylinisotol (GPI) anchor site. We report here that transgenic worms expressing MoPrP(23-231)-CFP exhibited a wide range of distinct phenotypes: from normal growth and development, reduced mobility and development delay, complete paralysis and development arrest, to embryonic lethality. Similar levels of MoPrP(23-231)-CFP were produced in animals exhibiting these distinct phenotypes, suggesting that MoPrP(23-231)-CFP might have misfolded into distinct toxic species. In combining with the observation that mutations in PrP that affect prion pathogenesis also affect the toxic phenotypes in C. elegans, we conclude that the prion protein-folding mechanism is similar in mammals and C. elegans. Thus, C. elegans can be a useful model organism for prion research.

| S-EPMC2587115 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data