Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “LINE-1 retrotransposon”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1994

Expression of LINE-1 retrotransposons in human breast cancer.

BACKGROUND: Several diseases have been linked to the insertion of human LINE-1 retrotransposons (L1Hs) into structural genes. Recently, the element has been shown to be expressed in a variety of adult and pediatric germ cell cancers, leading to speculation that L1Hs-induced insertion mutations may play a role in the etiology of some neoplasias. METHODS: An L1Hs-encoded protein (p40) was assayed in breast cancer cell lines by Western blotting and in solid tumors by immunohistochemical staining and Western blotting. RESULTS: L1Hs retrotransposons are expressed in a significant number of human breast cancers: expression was detected in 7 of 8 malignant cell lines and in 9 of 12 primary infiltrating ductal carcinomas. No expression was detected in two nonmalignant breast epithelial cell lines, five malignant B- or T-cell lines, tissue from a normal breast, a primary breast sarcoma, or a primary medullary carcinoma of the breast. CONCLUSIONS: These results raise the possibility that L1Hs expression may contribute to the origin or progression of some breast cancers.

Breast↗
PubMed1992

Active LINE-1 retrotransposons in human testicular cancer.

An antibody to the protein encoded by the first open reading frame of the human LINE-1 (L1Hs) element was used to examine immunohistochemically 59 formalin-fixed, human testicular germ cell tumors. Six tumors were positive for L1Hs expression. In all cases the L1Hs-positive cells were epithelial and most had the very characteristic, undifferentiated appearance of embryonal carcinoma or yolk sac tumor cells. One L1Hs-positive tumor had metastasized to the lung and lymph nodes and the metastatic cells also expressed L1Hs. This is the first observation of widespread retrotransposon expression in human tissue. These observations raise the possibility that L1Hs-encoded proteins may function as oncoproteins in some cancers.

DNA Transposable Elements↗
PubMed2026

Immune pathway activation in gastric cancers with LINE-1 retrotransposon overexpression and homologous recombination deficiency.

There are only a few whole genome sequencing studies of human gastric cancer (GC) conducted so far. We performed comprehensive whole genome, bulk RNA, and methylation sequencing analyses of 100 samples of GC and adjacent normal tissue. In a smaller non-EBV/non-MSI subset (n = 23), we also performed proteomic profiling by mass spectrometry. We validated the proteomic findings in an independent dataset. Using this unprecedented dataset of human GC samples, we examined the extent of chromothripsis, homologous recombination deficiency, and retrotransposition, and correlated these events with patient outcomes. We found that chromothripsis occurred in 22% of GCs and correlated with poor prognosis. Multichromosomal chromothripsis was associated with a particularly high risk of death. Based on copy number (CN) signature analysis, we identified a distinct non-CN9 subgroup with significantly worse outcomes. Homologous recombination deficiency was present in 4% of GCs and was associated with overexpression of immune signaling pathways. Somatic retrotransposition events were most strongly associated with global hypomethylation. We also identified BYSL as a putative oncogenic driver within the 6p21 locus whose amplification is associated with poor prognosis. Collectively, our findings provide novel insights into the dysregulation of DNA stability and repair and their clinical relevance in human GCs.

Journal Article↗
PubMed1994

The dynamics of murine LINE-1 subfamily amplification.

We have examined the dynamics of replication of the mouse LINE-1 retrotransposon within a single large expanding LINE-1 family found in a particular population of Mus spretus. This family has reached thousands of copies per haploid genome within 0.1 to 0.2 Myr and accounts for most, if not all, LINE-1 replication since 0.4 Myr ago. The family shows only one split into two clades during this time. From these data we propose a model that links the evolution of LINE-1 to the dynamics of its migration among mouse populations. We hypothesize that selected LINE-1 elements, referred to as master sequences, each amplify a subfamily within a distinct mouse population before migrating into the global mouse population. When these master sequences come in contact with each other by migration, generally one continues to expand at the expense of the other. We further discuss potential tests of this model.

Animals↗
PubMed2026

Epigenetic drift and LINE-1 activation in aging brain: Implications for neurodegenerative disease.

Brain aging and age-associated neurological diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), are largely attributed to epigenetic drift which is characterized by the gradual accumulation of alterations in neural cell methylation patterns over time. These methylation changes are particularly evident in transposable element (TE)-derived sequences such as Long interspersed element-1 (LINE-1) which comprises approximately 17% of the human genome. During aging, LINE-1 elements gradually lose their methylation, as well as the regulatory safeguard mechanisms that usually keep them inactive. This repression loss can lead to LINE-1 reactivation, contributing to harmful effects including genomic instability, neuroinflammation, and more. Together these findings indicate that impaired epigenetic maintenance, especially in repetitive genome regions, plays a key role in biological aging of neurons and glial cells. In this narrative review, we discuss the methylation dynamics and regulatory mechanisms of LINE-1 retrotransposons, their activation processes during aging, and contribution to age-associated neurological diseases. We also highlight the potential of targeting LINE-1 methylation to restore methylation homeostasis, epigenetic stability and delay brain aging.

Humans↗
PubMed1992

Studies on p40, the leucine zipper motif-containing protein encoded by the first open reading frame of an active human LINE-1 transposable element.

Full-length human LINE-1 retrotransposons encode p40 proteins with varying electrophoretic mobilities under denaturing conditions. The p40 expressed from the first open reading frame in the LINE-1 copy designated L1.2A co-electrophoreses with the endogenous p40 in human teratocarcinoma cells. This finding is consistent with previous data indicating that L1.2A is an active element. The amino acid sequence in the central region of the L1.2A p40 accounts, at least in part, for its characteristic mobility. This region includes sequences which can, in principle, form a leucine zipper.

Amino Acid Sequence↗
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

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↗
PubMed1995

Polymorphic sequences encoding the first open reading frame protein from LINE-1 ribonucleoprotein particles.

The mouse LINE-1 (L1) retrotransposon contains two open reading frames (ORFs). Three classes of the protein encoded by the first open reading frame (ORF1) are expressed in the mouse embryonal carcinoma cell line, F9; the apparent molecular sizes of these proteins are 41.3, 43, and 43.5 kDa. Two of these three proteins (41.3 and 43 kDa) are translated in vitro from full-length, sense-strand L1 RNA isolated from ribonucleoprotein particles. A reverse transcription-polymerase chain reaction approach was used to clone the ORF1 region from RNA isolated from ribonucleoprotein particles, then the coding capacity of these clones was examined using in vitro transcription and translation. Multiple sequences that encode ORF1 were recovered by this approach, indicating that multiple loci of L1 in the mouse genome are expressed in F9 cells. In addition, L1 sequences with intact ORF1 regions appear to be selectively enriched in the ribonucleoprotein particles.

Animals↗
PubMed2026

Transcriptional perturbation of LINE-1 elements reveals their cis-regulatory potential.

Long interspersed element-1 (LINE-1 or&#xa0;L1) retrotransposons constitute the largest transposable element family in mammalian genomes and contribute prominently to inter- and intra-individual genetic variation. Although most L1 elements are inactive, some evolutionary younger elements remain intact and genetically competent for transcription and occasionally retrotransposition. Despite being generally more abundant in gene-poor regions, intact or full-length L1s (FL-L1) are also enriched around specific classes of genes and on the eutherian X chromosome. How proximal FL-L1 may affect nearby gene expression remains unclear. Here, we examine this systematically using engineered mouse embryonic stem cells (ESCs) in which expression of one active L1 subfamily is perturbed. We find that FL-L1 activation leads to the misregulation of ~1024 genes, whereas FL-L1 repression affects ~81 genes. In most cases (68%), misexpressed genes contain an intronic FL-L1 or lie near a FL-L1 (<&#x2009;260&#x2009;kb). Gene ontology analysis shows that upon L1 activation, upregulated genes are enriched for neuronal function-related terms, suggesting that some L1 elements may have evolved to control neuronal gene networks. These results illustrate the cis-regulatory potential of FL-L1 elements and suggest a broader role for L1s than originally anticipated.

Animals↗
PubMed2025

STING inhibits LINE-1 retrotransposition through sorting ORF1p to lysosomes for degradation.

The cyclic dinucleotide sensor stimulator of interferon (IFN) genes (STING) is known for its critical role in interferon and inflammatory responses. In addition, STING also has functions independent of interferon induction. In this study, we report that STING restricts the mobilization of the cellular retrotransposon long interspersed nuclear element 1 (LINE-1) independent of cGAS and interferon induction. LINE-1 is the only active autonomous retrotransposable element in the human genome and its transposition can cause genetic and autoimmune diseases. STING inhibition of LINE-1 requires its dimerization. Mechanistically, STING interacts with LINE-1 ORF1p, then the complex translocates to the ER-Golgi intermediate compartment (ERGIC) and the Golgi followed by sorting to Rab7-positive lysosomes for degradation. Our data unveil a function of STING in maintaining host genome integrity by restricting LINE-1 retrotransposition via an IFN-independent mechanism.

Humans↗
PubMed1993

A discrete LINE-1 transcript in mouse blastocysts.

The LINE-1 (L1) repetitive elements of mammalian genomes are retrotransposons lacking LTRs; L1-encoded reverse transcriptase probably mediates an important step in the generation of new copies. Most L1 transcripts are nonspecific, but discrete full length transcripts are present in embryonal carcinoma cells. We report here an abundant L1 transcript in mouse blastocysts but not in oocytes. The transcript is about 8 kb, sense strand, polyadenylated, and includes the 5' end of the two open reading frames. We propose that retrotransposition which generates pseudogenes and mammalian SINES as well as the L1 family occurs around the blastocyst stage of the germ cell cycle.

Animals↗
PubMed1992

Identification of an internal cis-element essential for the human L1 transcription and a nuclear factor(s) binding to the element.

L1 (LINE-1) is a long interspersed repetitive sequence derived from a retrotransposon. Transfection studies using the CAT gene as a reporter demonstrated that the first 155bp in the human L1 sequence contains an element(s) responsible for the promoter activity in HeLa cells. The transcription was shown to initiate at the first nucleotide of the L1 sequence in the transgene. Three prominent nuclear protein binding sites were found in the 5' region of the L1 sequence by DNaseI footprint analysis. One of the binding sites, designated as site A located at +3 to +26, was shown to be essential for the L1 transcription because the mutation at the site A caused almost complete loss of the promoter activity. A sequence AAGATGGCC at +11 to +19 in the site A was defined as a target core element for the protein binding. The site A-binding protein (designated TFL1-A) was found in various types of cells including an embryonic teratocarcinoma cell line. These results indicate that an internal short element located at the very 5' terminal of L1 sequence and the nuclear factor binding to the element play a crucial role in the transcription of human L1.

Amino Acid Sequence↗
PubMed1993

LINE-1: a human transposable element.

Among the 10(5) LINE-1 sequences (L1Hs) in the human genome are one or more 6-kb segments that are active retrotransposons. Expression of these retrotransposons appears to be favored in cells of germ line origin, as well as in some other tumor cells of epithelial origin. In such cells, the product of the first L1Hs open reading frame (ORF), a protein called p40, is detectable; p40 has no apparent similarity to gag proteins, but contains a leucine zipper region which may be responsible for the occurrence of p40 multimers. Transcription of L1Hs initiates at residue 1 although the transcriptional regulatory regions are downstream in the first 670 bp of the 5' untranslated region; deletion of a YY1-binding site in the first 20 bp reduces transcription by fivefold. Translation of the second ORF, which encodes reverse transcriptase, is independent of the translation of the frame encoding p40.

Amino Acid Sequence↗
PubMed1990

Selective cloning and sequence analysis of the human L1 (LINE-1) sequences which transposed in the relatively recent past.

L1 (LINE-1), a long interspersed repetitive DNA family of mammalian genomes, is thought to be a sequence family derived from a retrotransposon-like element(s), but its actively transposable unit(s) has not been identified yet. We developed a novel method for selective isolation of the human L1 sequences which transposed in a relatively recent past and may have still retained a feature of the 'active L1' unit. From the inspection of the nucleotide sequences, we conjectured that the 'active L1' or 'nearly active L1' units should have a high content of the CpG dinucleotide sequence, a mutation hot spot sequence, and contain several sites for rare cutters such as BssH II and Nar I at their 5' terminal regions. Using these rare cutter sites as selection markers, the L1 sequences were isolated, which had the high content of CpG at the 5' terminal regions and over 90% homology to L1 transcripts found in a human teratocarcinoma cell line. These L1s were shown to be 'relatively new L1' units which had integrated into chromosomes within these several million years during evolution. From the sequence data of these L1s and L1 cDNA, a consensus sequence of the 5' terminal region of high CpG L1s were constructed. A region of the consensus sequence showed about 69% homology to the 5' terminal region of Drosophila jockey element.

Animals↗
PubMed1990

SLACS retrotransposon from Trypanosoma brucei gambiense is similar to mammalian LINEs.

We have characterized a retrotransposon in Trypanosoma brucei gambiense uniquely associated with the spliced-leader (SL) RNA gene cluster (Spliced Leader Associated Conserved Sequence, SLACS). There are nine copies of SLACS and DNA sequence analysis of one shows the hallmarks of Line-1 like elements. SLACS has generated a 49 bp target DNA duplication at its insertion site and its 3'-end is preceded by a poly(A) stretch. Two putative open reading frames (ORFs) span 75% of the element. ORF1 has CysHis motif associated with the retroviral gag polypeptide while ORF2 shows homology with reverse transcriptase sequences. Its 5'-end contains a repeated segment of a 185 bp that varies in copy number in different SLACS insertions. Retrotransposon-like sequences inserted into the SL-RNA genes occur in several hemoflagellates. These elements may represent a related family which has maintained its target site specificity.

Amino Acid Sequence↗
PubMed1995

L1 (LINE-1) retrotransposable elements provide a "fossil" record of the phylogenetic history of murid rodents.

The single most difficult problem in phylogenetic analysis is deciding whether a shared taxonomic character is due to common ancestry or one that appeared independently due to convergence, parallelism, or reversion to an ancestral state. Mammalian L1 retrotransposons undergo periodic amplifications in which multiple copies of the elements are interspersed in the genome. Because these elements apparently are transmitted only by inheritance and are retained in the genome, a shared L1 amplification event can only be an inherited ancestral character. We propose that L1 amplification events can be an excellent tool for analyzing mammalian evolution and demonstrate here how we addressed several refractory problems in rodent systematics using L1 DNA as a taxonomic character.

Animals↗
PubMed2025

L1 insertion intermediates recombine with one another or with DNA breaks to form genome rearrangements.

LINE-1 retrotransposition is common in human cancers and rearrangements at insertion sites can contribute to cancer-driving oncogene amplifications and promote genome instability. However, the mechanisms underlying rearrangements of L1 retrotransposition intermediates are poorly understood. To address this gap, we developed GFP-based recombination reporter assays to study the formation of L1 retrotransposition-mediated rearrangements. Using these reporters combined with long-read sequencing approaches, we find that L1 retrotransposition intermediates can recombine with distal DNA breaks to generate chromosomal rearrangements. We also find that two distinct L1 insertion intermediates can recombine with each other to generate chromosomal rearrangements. Both types of rearrangements depend on L1-encoded ORF2p endonuclease and reverse transcriptase activities. Using these reporters, we discover that L1 retrotransposition-mediated rearrangements are robustly induced when the recombining sequences share homology and that their formation requires the homologous recombination factor BRCA1. Given the repetitive nature of our genome, these findings highlight the risk of L1 insertion intermediates becoming substrates for aberrant recombination and promoting genome instability.

L1 retrotransposons↗