Academic literature on the topic 'L1 retrotransposons'
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Journal articles on the topic "L1 retrotransposons"
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Mita, Paolo, and Jef D. Boeke. "Cycling to Maintain and Improve Fitness: Line-1 Modes of Nuclear Entrance and Retrotransposition." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 6 (May 3, 2018): 491–94. http://dx.doi.org/10.1177/2472555218767842.
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The LINE-1/L1 retrotransposon is a transposable element still active in the human genome. Most retrotransposons in the genome are inactive or repressed by several host mechanisms. In specific contexts, active L1 retrotransposons may evade repression and copy themselves into new genomic loci. Despite a general knowledge of the L1 life cycle, little was known about the dynamics of L1 proteins and function during the different stages of the host cell cycle. Our work highlighted a well-orchestrated localization of L1 proteins and mRNA that take advantage of mitotic nuclear membrane breakdown. Once in the nucleus, L1 ribonucleoproteins (RNPs) are able to retrotranspose during the S phase when L1 retrotransposition peaks. Our conclusions highlight previously unappreciated features of the L1 life cycle, such as the differences between cytoplasmic and nuclear RNPs and the cycling of L1 ORF1 protein and L1 activity during progression through the cell cycle. These new observations are discussed here in light of the evolutionary arms race between L1 retrotransposons and the host cell.
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Reiner, Benjamin C., Glenn A. Doyle, Andrew E. Weller, Rachel N. Levinson, Esin Namoglu, Alicia Pigeon, Emilie Dávila Perea, et al. "Restriction Enzyme Based Enriched L1Hs Sequencing (REBELseq): A Scalable Technique for Detection of Ta Subfamily L1Hs in the Human Genome." G3: Genes|Genomes|Genetics 10, no. 5 (March 4, 2020): 1647–55. http://dx.doi.org/10.1534/g3.119.400613.
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Long interspersed element-1 retrotransposons (LINE-1 or L1) are ∼6 kb mobile DNA elements implicated in the origins of many Mendelian and complex diseases. The actively retrotransposing L1s are mostly limited to the L1 human specific (L1Hs) transcriptional active (Ta) subfamily. In this manuscript, we present REBELseq as a method for the construction of Ta subfamily L1Hs-enriched next-generation sequencing libraries and bioinformatic identification. REBELseq was performed on DNA isolated from NeuN+ neuronal nuclei from postmortem brain samples of 177 individuals and empirically-driven bioinformatic and experimental cutoffs were established. Putative L1Hs insertions passing bioinformatics cutoffs were experimentally validated. REBELseq reliably identified both known and novel Ta subfamily L1Hs insertions distributed throughout the genome. Differences in the proportion of individuals possessing a given reference or non-reference retrotransposon insertion were identified. We conclude that REBELseq is an unbiased, whole genome approach to the amplification and detection of Ta subfamily L1Hs retrotransposons.
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Zhang, Ao, Beihua Dong, Aurélien J. Doucet, John B. Moldovan, John V. Moran, and Robert H. Silverman. "RNase L restricts the mobility of engineered retrotransposons in cultured human cells." Nucleic Acids Research 42, no. 6 (December 25, 2013): 3803–20. http://dx.doi.org/10.1093/nar/gkt1308.
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Abstract Retrotransposons are mobile genetic elements, and their mobility can lead to genomic instability. Retrotransposon insertions are associated with a diverse range of sporadic diseases, including cancer. Thus, it is not a surprise that multiple host defense mechanisms suppress retrotransposition. The 2′,5′-oligoadenylate (2-5A) synthetase (OAS)-RNase L system is a mechanism for restricting viral infections during the interferon antiviral response. Here, we investigated a potential role for the OAS-RNase L system in the restriction of retrotransposons. Expression of wild type (WT) and a constitutively active form of RNase L (NΔ385), but not a catalytically inactive RNase L mutant (R667A), impaired the mobility of engineered human LINE-1 (L1) and mouse intracisternal A-type particle retrotransposons in cultured human cells. Furthermore, WT RNase L, but not an inactive RNase L mutant (R667A), reduced L1 RNA levels and subsequent expression of the L1-encoded proteins (ORF1p and ORF2p). Consistently, confocal immunofluorescent microscopy demonstrated that WT RNase L, but not RNase L R667A, prevented formation of L1 cytoplasmic foci. Finally, siRNA-mediated depletion of endogenous RNase L in a human ovarian cancer cell line (Hey1b) increased the levels of L1 retrotransposition by ∼2-fold. Together, these data suggest that RNase L might function as a suppressor of structurally distinct retrotransposons.
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Ostertag, Eric M., and Haig H. Kazazian Jr. "Biology of Mammalian L1 Retrotransposons." Annual Review of Genetics 35, no. 1 (December 2001): 501–38. http://dx.doi.org/10.1146/annurev.genet.35.102401.091032.
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Schulz, Wolfgang A. "L1 Retrotransposons in Human Cancers." Journal of Biomedicine and Biotechnology 2006 (2006): 1–12. http://dx.doi.org/10.1155/jbb/2006/83672.
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Retrotransposons like L1 are silenced in somatic cells by a variety of mechanisms acting at different levels. Protective mechanisms include DNA methylation and packaging into inactive chromatin to suppress transcription and prevent recombination, potentially supported by cytidine deaminase editing of RNA. Furthermore, DNA strand breaks arising during attempted retrotranspositions ought to activate cellular checkpoints, and L1 activation outside immunoprivileged sites may elicit immune responses. A number of observations indicate that L1 sequences nevertheless become reactivated in human cancer. Prominently, methylation of L1 sequences is diminished in many cancer types and full-length L1 RNAs become detectable, although strong expression is restricted to germ cell cancers. L1 elements have been found to be enriched at sites of illegitimate recombination in many cancers. In theory, lack of L1 repression in cancer might cause transcriptional deregulation, insertional mutations, DNA breaks, and an increased frequency of recombinations, contributing to genome disorganization, expression changes, and chromosomal instability. There is however little evidence that such effects occur at a gross scale in human cancers. Rather, as a rule, L1 repression is only partly alleviated. Unfortunately, many techniques commonly used to investigate genetic and epigenetic alterations in cancer cells are not well suited to detect subtle effects elicited by partial reactivation of retroelements like L1 which are present as abundant, but heterogeneous copies. Therefore, effects of L1 sequences exerted on the local chromatin structure, on the transcriptional regulation of individual genes, and on chromosome fragility need to be more closely investigated in normal and cancer cells.
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Mukherjee, Somnath, Deepak Sharma, and Kailash C. Upadhyaya. "L1 Retrotransposons Are Transcriptionally Active in Hippocampus of Rat Brain." Prague Medical Report 117, no. 1 (2016): 42–53. http://dx.doi.org/10.14712/23362936.2016.4.
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LINE1 (L1) is an autonomous, non-LTR retrotransposon and the L1 family of retrotransposons constitute around 17%, 20% and 23% in the human, mouse and rat genomes respectively. Under normal physiological conditions, the retroelements remain by and large transcriptionally silent but are activated in response to biotic and abiotic stress conditions and during perturbation in cellular metabolism. They have also been shown to be transiently activated under certain developmental programs. Using RT-PCR, we show that the L1 elements are transcriptionally active in the hippocampus region of the brain of four-month-old rat under normal conditions without any apparent stress. Twenty non-redundant LINE1-specific reverse transcriptase (RTase) sequences form ORF2 region were isolated, cloned and sequenced. Full length L1 element sequences complementary to the isolated sequences were retrieved from the L1 database. In silico analysis was used to determine the presence of these retroelements proximal (up to 10 kb) to the genes transcriptionally active in the hippocampus. Many important genes were found to be in close proximity of the transcriptionally active L1 elements. Transcriptional activation of the elements possibly affects the expression of the neighbouring genes.
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Martin, Sandra L., and Frederic D. Bushman. "Nucleic Acid Chaperone Activity of the ORF1 Protein from the Mouse LINE-1 Retrotransposon." Molecular and Cellular Biology 21, no. 2 (January 15, 2001): 467–75. http://dx.doi.org/10.1128/mcb.21.2.467-475.2001.
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ABSTRACT Non-LTR retrotransposons such as L1 elements are major components of the mammalian genome, but their mechanism of replication is incompletely understood. Like retroviruses and LTR-containing retrotransposons, non-LTR retrotransposons replicate by reverse transcription of an RNA intermediate. The details of cDNA priming and integration, however, differ between these two classes. In retroviruses, the nucleocapsid (NC) protein has been shown to assist reverse transcription by acting as a “nucleic acid chaperone,” promoting the formation of the most stable duplexes between nucleic acid molecules. A protein-coding region with an NC-like sequence is present in most non-LTR retrotransposons, but no such sequence is evident in mammalian L1 elements or other members of its class. Here we investigated the ORF1 protein from mouse L1 and found that it does in fact display nucleic acid chaperone activities in vitro. L1 ORF1p (i) promoted annealing of complementary DNA strands, (ii) facilitated strand exchange to form the most stable hybrids in competitive displacement assays, and (iii) facilitated melting of an imperfect duplex but stabilized perfect duplexes. These findings suggest a role for L1 ORF1p in mediating nucleic acid strand transfer steps during L1 reverse transcription.
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Bodea, Gabriela O., Eleanor G. Z. McKelvey, and Geoffrey J. Faulkner. "Retrotransposon-induced mosaicism in the neural genome." Open Biology 8, no. 7 (July 2018): 180074. http://dx.doi.org/10.1098/rsob.180074.
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Over the past decade, major discoveries in retrotransposon biology have depicted the neural genome as a dynamic structure during life. In particular, the retrotransposon LINE-1 (L1) has been shown to be transcribed and mobilized in the brain. Retrotransposition in the developing brain, as well as during adult neurogenesis, provides a milieu in which neural diversity can arise. Dysregulation of retrotransposon activity may also contribute to neurological disease. Here, we review recent reports of retrotransposon activity in the brain, and discuss the temporal nature of retrotransposition and its regulation in neural cells in response to stimuli. We also put forward hypotheses regarding the significance of retrotransposons for brain development and neurological function, and consider the potential implications of this phenomenon for neuropsychiatric and neurodegenerative conditions.
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Farkash, Evan A., and Eline T. Luning Prak. "DNA Damage and L1 Retrotransposition." Journal of Biomedicine and Biotechnology 2006 (2006): 1–8. http://dx.doi.org/10.1155/jbb/2006/37285.
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Barbara McClintock was the first to suggest that transposons are a source of genome instability and that genotoxic stress assisted in their mobilization. The generation of double-stranded DNA breaks (DSBs) is a severe form of genotoxic stress that threatens the integrity of the genome, activates cell cycle checkpoints, and, in some cases, causes cell death. Applying McClintock's stress hypothesis to humans, are L1 retrotransposons, the most active autonomous mobile elements in the modern day human genome, mobilized by DSBs? Here, evidence that transposable elements, particularly retrotransposons, are mobilized by genotoxic stress is reviewed. In the setting of DSB formation, L1 mobility may be affected by changes in the substrate for L1 integration, the DNA repair machinery, or the L1 element itself. The review concludes with a discussion of the potential consequences of L1 mobilization in the setting of genotoxic stress.
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Carreira, Patricia E., Sandra R. Richardson, and Geoffrey J. Faulkner. "L1 retrotransposons, cancer stem cells and oncogenesis." FEBS Journal 281, no. 1 (November 28, 2013): 63–73. http://dx.doi.org/10.1111/febs.12601.
Full textDissertations / Theses on the topic "L1 retrotransposons"
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Wagstaff, John Francis. "Generating bioinformatic resources for L1-dependent retrotransposons." Thesis, University of Leicester, 2014. http://hdl.handle.net/2381/29050.
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Human retrotransposons are genetic elements that copy themselves into new locations in the genome by way of an RNA intermediate. They are extremely numerous making up at least 45% of human DNA. Retrotransposon insertions are a major source of inter-human genetic variation, and have been known to cause disease. They are also intrinsically difficult to analyse in genomes due to their highly repetitive nature. In humans there are three currently active retro-transposable elements: LINE-1, Alu and SVA. LINE-1 is an independent element and Alu and SVA parasitise the LINE-1 retrotransposition machinery. There are experimental ways of discovering and analysing such elements, but they require significant investment, while human sequence datasets containing potentially usable data are multiplying at an ever increasing rate. In particular there are now many assembled human genome sequences as well as new sources of whole genome high throughput sequencing data, such as the 1000 Genomes Project. For this reason this study is devoted to using bioinformatic approaches to extract new knowledge about human retrotransposons from the existing datasets. Previous efforts, by past members of this research group, have been devoted to analysing the genomic variation of the LINE-1 element itself. However this study focuses on the extraction of presence / absence variation in the LINE-1 -dependent elements, Alu and SVA. In addition to building software to extract this information from a wide variety of data sources, this project has also involved making the information data available to non-specialist researchers in the form of a website. The tools developed and described here utilise generic design principles, enabling rapid, largely automated updating, necessary with the constant expansion of the underlying data.
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Rahbari, Raheleh. "Activity of endogenous L1 retrotransposons in human embryonal cells." Thesis, University of Leicester, 2012. http://hdl.handle.net/2381/10143.
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Recent high throughput studies have led to the discovery of de novo L1 retrotransposition in malignant somatic cells, as well as large numbers of novel insertions, many of which are highly active in cell culture assays. These data suggest that L1 elements are robustly active, undergoing extensive diversification in contemporary human genomes. Despite this there is little direct evidence of endogenous L1 retrotransposition in the human germline or early embryogenesis: data from very rare disease causing insertions is indirect, subject to strong acquisition bias, and is often equivocal with respect to the origin of the insertions. For L1s to be evolutionarily successful they must retrotranspose during early human development or in the germline, in order to transmit copies to the next generation. The purpose of this thesis was to develop sensitive and yet robust methods to screen human embryos and embryonic cell models for de novo full-length endogenous L1 insertions. We developed a new high throughput sequencing technique, which was able to recover single molecule retrotransposition events. Based on this technique we identified 172 candidate novel L1 insertions in a total of three human embryos, represented by whole-genome amplified DNA of individually dissected blastomeres and the remaining blastocyst tissue. 57 of these insertions are potentially genuine de novo endogenous L1 insertions. Moreover, we have identified a candidate germline specific L1 insertion from a healthy adult donor. Therefore, this study has detected candidate de novo L1 retrotransposition events in human embryos and germlines, using an approach that enables complete validation and characterization of the insertions, despite operating at the single molecule and single cell level. We consider this technical innovation will be most significant in the ongoing dissection of how L1, the dominant human transposon, is actively driving the evolution of modern human genomes.
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Kuciak, Monika. "L1 retrotransposon activity : insights from genomic and molecular studies." Thesis, Lyon, École normale supérieure, 2011. http://www.theses.fr/2011ENSL0702.
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Les rétrotransposons L1 sont les seuls éléments transposables autonomes et actifs chez l'Homme et constituent 20% de notre ADN. Ils prolifèrent via un intermédiaire ARN et un processus couplé de réverse transcription et d'intégration, appelé rétrotransposition, et médié par une particule ribonucléoprotéique (RNP). Les L1s sautent de façon active dans les cellules germinales, les cellules souches embryonnaires et l'embryon précoce, ce qui provoque parfois de nouvelles maladies génétiques. Cependant ils sont considérés comme éteints dans la plupart des tissus somatiques. Dans le but d'explorer l'importance et les conséquences de la rétrotransposition des L1s chez l'Homme, nous avons développé une approche de cartographie des L1s actifs dans le génome humain, en combinant amplification sélective des sites d'insertion et séquençage à haut-débit. Nous avons utilisé cette stratégie afin d'obtenir la cartographie différentielle des L1s dans deux lignées cellulaires humaines apparentées. Ainsi, nous avons découvert plusieurs insertions de L1 présentes uniquement dans la lignée fille mais absente dans la lignée parentale, démontrant pour la première fois que les éléments L1 endogènes humains sont capables de mobilité dans des lignées de cellules somatiques en culture. D'autre part, afin d'éclaircir les déterminants qui dictent l'intégration des L1s, nous avons développé un test direct de réverse transcription in vitro à partir de RNP L1 natives partiellement purifiées de cellules humaines. Ceci nous a permis de montrer que la réverse transcriptase du L1 participe à la sélection du site d'insertion, ajoutant une couche additionnelle de spécificité après l'endonucléase L1. En conclusion, notre travail met en lumière la flexibilité de la machinerie des L1s, une propriété qui a certainement participé à l'efficacité de l'invasion des génomes de mammifères par ces éléments génétiques mobilesL1 retrotransposons are the only autonomous and active transposable elements in humans and comprise as much as 20% of our DNA. They proliferate via an RNA intermediate and a coupled reverse transcription and integration process, called retrotransposition and mediated by an L1-encoded ribonucleoprotein particle (RNP). L1s are actively jumping in germ cells, embryonic stem cells and in the early embryo, occasionally leading to de novo genetic diseases, but are considered silent in most somatic tissues. To comprehensively map active L1 elements in the human genome and to further explore the importance and consequences of L1 retrotransposition in humans, we combined selective amplification of L1 insertion sites and high-throughput sequencing. We applied this strategy to obtain a differential map of L1 insertions in two related human cultured cell lines and to question the possibility that endogenous L1 elements could be jumping in somatic cultured cells. We discovered several L1 insertions only present in the daughter cell line but absent in the parental cell line, demonstrating for the first time that retrotransposition of endogenous L1s takes place in a human somatic cell line. To get insights into the determinants of L1 integration, we have also developed a novel reverse transcription assay using partially purified native L1 RNPs. This enabled us to show that the L1 reverse transcriptase participates to insertion site selection, adding a second layer of specificity beyond the L1 endonuclease. Finally our work highlights the flexibility of the L1 machinery, which certainly participates to the efficient spreading of L1 elements within mammalian genomes
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Sultana, Tania. "L'influence du contexte génomique sur la sélection du site d'intégration par les rétrotransposons humains L1." Thesis, Université Côte d'Azur (ComUE), 2016. http://www.theses.fr/2016AZUR4133.
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Les rétrotransposons L1 (Long INterspersed Element-1) sont des éléments génétiques mobiles dont l'activité contribue à la dynamique du génome humain par mutagenèse insertionnelle. Les conséquences génétiques et épigénétiques d'une nouvelle insertion, et la capacité d'un L1 à être remobilisé, sont directement liées au site d’intégration dans le génome. Aussi, l’analyse des sites d’intégration des L1s est capitale pour comprendre leur impact fonctionnel - voire pathogène -, en particulier lors de la tumorigenèse ou au cours du vieillissement, et l’évolution de notre génome. Dans ce but, nous avons induit de façon expérimentale la rétrotransposition d'un élément L1 actif plasmidique dans des cellules en culture. Puis, nous avons cartographié les insertions obtenues de novo dans le génome humain grâce à une méthode de séquençage à haut-débit, appelée ATLAS-seq. Finalement, les sites pré-intégratifs identifiés par cette approche ont été analysés en relation avec un grand jeu de données publiques regroupant les caractéristiques structurales, génétiques ou épigénétiques de ces loci. Ces expériences ont révélé que les éléments L1 s’intègrent préférentiellement dans des régions de la chromatine faiblement exprimées et renfermant des activateurs faibles. Nous avons aussi trouvé plusieurs positions chromosomiques qui constituent des points chauds d'intégrations récurrentes. Nos résultats indiquent que la distribution des insertions de L1 de novo n’est pas aléatoire, que ce soit à l’échelle chromosomique ou à plus petite échelle, et ouvrent la porte à l'identification des déterminants moléculaires qui contrôlent la distribution chromosomique des L1s dans notre génomeRetrotransposons are mobile genetic elements that employ an RNA intermediate and a reverse transcription step for their replication. Long INterspersed Elements-1 (LINE-1 or L1) form the only autonomously active retrotransposon family in humans. Although most copies are defective due to the accumulation of mutations, each individual genome contains an average of 100 retrotransposition-competent L1 copies, which contribute to the dynamics of contemporary human genomes. L1 integration sites in the host genome directly determine the genetic consequences of the integration and the fate of the integrated copy. Thus, where L1 integrates in the genome, and whether this process is random, is critical to our understanding of human genome evolution, somatic genome plasticity in cancer and aging, and host-parasite interactions. To characterize L1 insertion sites, rather than studying endogenous L1 which have been subjected to evolutionary selective pressure, we induced de novo L1 retrotransposition by transfecting a plasmid-borne active L1 element into HeLa S3 cells. Then, we mapped de novo insertions in the human genome at nucleotide resolution by a dedicated deep-sequencing approach, named ATLAS-seq. Finally, de novo insertions were examined for their proximity towards a large number of genomic features. We found that L1 preferentially integrates in the lowly-expressed and weak enhancer chromatin segments. We also detected several hotspots of recurrent L1 integration. Our results indicate that the distribution of de novo L1 insertions is non-random both at local and regional scales, and pave the way to identify potential cellular factors involved in the targeting of L1 insertions
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Jachowicz, Joanna Weronika. "Molecular mechanisms underlying heterochromatin formation in the mouse embryo." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ094/document.
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Afin d'étudier la formation de l'hétérochromatine dans l’embryon préimplantatoire de souris, je me suis concentrée sur deux régions génétiques différentes - répétitions péricentriques et L1 éléments transposables - dans le but notamment de découvrir les mécanismes qui conduisent à la répression et le rôle distinct qu’ils peuvent jouer pendant le processus de développement et la division cellulaire. Mes expériences montrent que l’organisation spatiale spécifique des domaines péricentriques est essentielle pour leur répression ainsi que pour leur organisation correcte. De plus, mes résultats suggèrent que les défauts d’organisation de l’hétérochromatine conduisent à des défauts de division cellulaire et de prolifération. La seconde partie de ma thèse montre que la réglementation stricte de L1 éléments transposables est nécessaire pour le développement préimplantatoire d'embryons de souris. En outre, représente la première tentative pour élucider la biologie des éléments L1 dans l’embryon précoce de souris par l’utilisation de modificateurs de transcription ciblés spécifiquementTo study the formation of heterochromatin in mouse preimplantation embryo, I focused on two different genetic regions – pericentric repeats and L1 transposable elements - in order to investigate the mechanisms that lead to their repression and the distinct role that these regions can play during the process of development and cell division. My experiments show that the specific spatial organization of pericentric domains is essential for their repression and for their correct organization. Moreover, my findings suggest that defects in organization of heterochromatin lead to improper cell division and proliferation. The second part of my thesis shows that the tight regulation of L1 transposable elements is required for the preimplantation development of mouse embryos. Additionally, it is the first attempt to elucidate the biology of L1 elements in the early mouse embryo through the use of targeted transcription modifiers
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Peressini, Lopez Paula. "Activité du rétrotransposon L1 dans les cellules musculaires." Electronic Thesis or Diss., Université Côte d'Azur, 2020. http://theses.univ-cotedazur.fr/2020COAZ6007.
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Près de la moitié du génome humain provient d'éléments transposables (TE). Parmi eux, l'élément LINE-1 ou L1 (Long INterspersed Element-1) forme la seule famille d'éléments transposables actuellement active et autonome chez l'Homme. Bien que des centaines de milliers de copies soient dispersées dans le génome humain, seules 80 à 100 d'entre elles sont encore compétentes pour la rétrotransposition, c'est-à-dire capables de se reproduire par un mécanisme de "copier-coller" via un ARN intermédiaire et une étape de transcription inverse. L'activité des L1s peut avoir des conséquences délétères, en particulier par mutagenèse insertionnelle. Elle est néanmoins étroitement régulée au niveau transcriptionnel et post-transcriptionnel. Inversement, des facteurs d'hôtes spécifiques sont nécessaires pour accomplir le cycle réplicatif des L1s. Lorsqu'elles se produisent dans la lignée germinale ou dans l'embryon précoce, les insertions de L1 peuvent être transmises à la génération suivante. La rétrotransposition des L1s a également été décrite dans certains tissus somatiques, comme dans les tumeurs épithéliales et dans le cerveau, à la fois dans les cellules progénitrices neurales et dans les neurones différenciés. Néanmoins, les niveaux d’expression des L1 compétents pour la rétrotransposition, et leur mobilisation, dans d'autres tissus somatiques restent incertains.Ici, nous avons étudié l'activité des rétrotransposons L1 dans les cellules musculaires squelettiques humaines et murines. Nous montrons que la protéine du L1 la plus abondante, ORF1p, qui est essentielle à la rétrotransposition, est indétectable dans nos conditions expérimentales, dans des échantillons murins ou humains de muscle squelettique, alors qu'elle est facilement détectable dans les cellules cancéreuses ou dans les testicules. De même, elle n'est pas détectée dans les myoblastes immortalisés d’origine murine ou humaine. En revanche, nous avons découvert que le L1 est capable de rétrotransposition dans les myoblastes humains et murins lorsqu'elle est exprimée à partir d'un plasmide ou d'une copie intégrée avec un promoteur constitutif ou inductible, respectivement. En conclusion, si l'expression du L1 est inférieure à la limite de détection dans le muscle, les myoblastes sont bien permissifs à la rétrotransposition, ce qui indique que ces cellules expriment tous les facteurs cellulaires nécessaires pour réaliser ce processus, et n'expriment pas de facteurs de restriction significatifs qui bloqueraient la rétrotransposition.Dans l'ensemble, nos résultats suggèrent que l'activité somatique des L1s pourrait ne pas être restreinte au cerveau ou aux cellules cancéreuses, mais pourrait également avoir lieu dans les muscles dans des conditions environnementales ou pathologiques qui déclencheraient leur expressionAlmost half of the human genome derives from transposable elements (TE). Among them, the Long INterspersed Element-1 (LINE-1 or L1) forms the only currently active and autonomous transposable element family in humans. Although hundreds of thousands L1 copies are dispersed in the human genome, only 80-100 of them are still retrotransposition competent, i.e. able to replicate by a “copy-and-paste” mechanism via an RNA intermediate and a reverse transcription step. On the one hand, L1 activity can have deleterious consequences, such as insertional mutagenesis, and is tightly regulated at the transcriptional or post-transcriptional levels. However, specific host factors are necessary for completion of L1 replication cycle. When occurring in the germline or in the early embryo, L1 insertions can be transmitted to the next generation. Somatic retrotransposition has been also described in epithelial tumors and in the brain, both in neural progenitor cells and differentiated neurons. Nevertheless, the extent of L1 expression and mobilization in other somatic tissues remains unclear.Here, we investigated the activity of L1 retrotransposons in human and mouse skeletal muscle cells. We show that the most abundant L1 protein, ORF1p, which is essential to retrotransposition, is undetectable under our experimental conditions, in mouse or human muscle samples, while it is readily detected in cancer cells or in testis. Similarly, it was undetected in immortalized mouse or human myoblasts. However, we found that L1 is capable of retrotransposition in human and mouse myoblasts when expressed from a plasmid or from an integrated copy with a constitutive or inducible promoter, respectively. In conclusion, while L1 expression is under the limit of detection in muscle, myoblasts are permissive to retrotransposition, indicating that these cells express all the cellular factors necessary to achieve this process, and do not express significant restriction factors that would prevent retrotransposition.Altogether, our findings suggest that somatic L1 activity could not be confined to the brain or cancer cells, but could also occur in muscles under environmental or pathological conditions that would unleash L1 expression
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Viollet, Sébastien. "Mécanismes moléculaires de la rétrotransposition de l'élément L1 humain." Thesis, Nice, 2014. http://www.theses.fr/2014NICE4133.
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L’élément L1 (Long Interspersed Nuclear Element 1 ou L1) est le seul rétrotransposon autonome et actif connu dans notre génome, représentant 17% de celui-ci. Capable de se répliquer grâce à un intermédiaire à ARN et un mécanisme de transcription inverse initiée au site d’intégration, il encode deux protéines ORF1p et ORF2p, qui s’associent à l’ARN L1 pour former une particule ribonucléoprotéique (RNP). L’élément L1 rétrotranspose préférentiellement en cis : un L1 défectif est complémenté en trans par un élément fonctionnel de façon inefficace. Ce travail s'intéresse à deux étapes clefs du cycle réplicatif du L1 : l'assemblage de la RNP L1 en cis ou en trans afin d’explorer le mécanisme de la cis-préférence et la spécificité de l’initiation de la reverse transcription initiée. Nous avons d’abord comparé deux méthodes d’analyse de l’activité RT. Puis, nous avons montré l’importance de la complémentarité entre queue poly(A) de l’ARN L1 et site d’intégration durant l’initiation de la RT, ainsi que l’impact de mésappariements terminaux éventuels. Enfin, nous avons étudié les bases biochimiques de la cis-préférence, à travers la coexpression et la purification de deux éléments distincts étiquetés, ce qui nous a permis de suivre l'assemblage et l'activité de leurs RNPs respectives. Nos données suggèrent que ORF1p et ORF2p peuvent lier en trans l’ARN L1 de façon efficace et que la cis-préférence pourrait nécessiter des quantités limitantes de L1The Long Interspersed Nuclear Element 1 (LINE-1 ou L1) is the only known active and autonomous retrotransposon in the human genome and constitutes around 17% of our genomic DNA. The L1 element is able to replicate through an RNA intermediate by a mechanism called target-primed reverse transcription and encodes two proteins ORF1p and ORF2p, which associate with the L1 RNA to form a ribonucleoprotein particle (RNP). L1 preferentially retrotranspose in cis: a defective L1 can only be rescued in trans at low levels by a replication-competent copy. During this work, we focused on two essential steps of the L1 replication cycle: the assembly of the L1 RNP in cis or in trans to explore the mechanism of the cis-preference and the specificity of L1 reverse transcription priming. First, we compared two different methods to detect L1 RT activity. Then, we showed the importance of base-pairing between the poly(A) tail of the L1 RNA and the integration site to prime reverse transcription and the impact of potential mismatches. Finally, we investigated the biochemical basis of the cis-preference through the coexpression and purification of two different tagged L1 elements, which allowed us to follow the assembly and activity of their RNP. Our data suggest that binding of ORF1p and ORF2p in trans is efficient and that the cis-preference might requires limiting L1 levels
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Ruhla, Stephan [Verfasser]. "Methoden zum Nachweis aktiver L1-Retrotransposons / von Stephan Ruhla." 2007. http://d-nb.info/985664304/34.
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Belém, Cláudia Garcia. "Retrotransposition and Ageing-associated Neuronal Function Decline." Master's thesis, 2019. http://hdl.handle.net/10362/61565.
Full textAbstract:
The world population is progressively ageing. It is estimated that by 2050, almost onefifth
of the world population will be aged 65 years or more. Despite the significant increases
in life expectancy observed in the last century, health span remained unchanged. Therefore,
people live longer but in suboptimal conditions, which frequently lead to the development
of age-related diseases, like neurodegenerative diseases. Understanding the molecular and
cellular mechanisms underlying ageing and neurodegeneration is crucial and could provide
the means to delay, mitigate or even revert the deteriorating e↵ects associated with age-related
neurodegeneration. Recent studies have correlated increased expression of retrotransposable
elements (REs) with age, which is likely due to the tendency of RE silencing mechanisms to fail
with age. Furthermore, it was reported in flies that young individuals with a neurodegenerative
decline had premature expression of REs in their brain. However, it remains unclear whether
RE expression and mobilization are the cause or a consequence of the age-associated neuron
functional decline.
The aim of this dissertation is to determine if RE expression in the central nervous system
causes an age-associated neuronal function decline. To answer this, we developed a heterologous
and naïve inducible RE system that allows specific expression of a human long interspersed
nuclear element 1 (LINE-1 or L1) in Drosophila melanogaster neurons. Negative geotaxis assays
were performed in flies aged 2, 20, and 40 days after eclosion to assess the age-associated
neurofunctional decline.
Results revealed that the forced expression of L1 in neurons throughout lifespan does not
a↵ect neuronal function. However, both in vivo and in vitro experiments failed to demonstrate
retrotransposition events in the fly. These findings suggest that additional human factors are
required in L1 retrotransposition. Future studies will focus on determining retrotransposition capacity of L1 in the fly genome.
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Janoušek, Václav. "Recentně aktivní L1 a B1 retrotransposony v myším genomu." Master's thesis, 2010. http://www.nusl.cz/ntk/nusl-295871.
Full textAbstract:
The work focuses on two recently active retrotransposon families in the house mouse genome. They are L1 and B1 retrotransposons. The aim of the work was to find polymorphic retrotransposon insertions caused by their recent activity. Two genomes of mouse inbred strains derived from the different house mouse subspecies were compared. The BACends from MSM/Ms derived from M. m. molossinus were compared with the reference genome of C57BL/6J derived mostly from M. m. domesticus. The set of output insertions was classified into several subfamilies of B1 a L1 families. The presence/absence of these insertions was tested using PCR in all three house mouse subspecies and also in two sister species (M. spretus and M. macedonicus). The particular subfamilies differed with regard to presence in latter species. Despite the supposed lack of activity of older L1 families (F2 and F3) they persist in house mouse population as an ancestral polymorphism. Unlike L1 subfamilies, B1 subfamilies appear to be active in house mouse genome for longer period of time. Also the difference between the whole families L1 and B1was observed. Thus, according to my data L1 family seems to be recently more active than B1 family.
Book chapters on the topic "L1 retrotransposons"
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Ade, Catherine M., Geraldine Servant, Maria E. Morales, and Astrid M. Roy-Engel. "Environment, Cellular Signaling, and L1 Activity." In Human Retrotransposons in Health and Disease, 157–94. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-48344-3_7.
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Newkirk, Simon J., and Wenfeng An. "L1 Regulation in Mouse and Human Germ Cells." In Human Retrotransposons in Health and Disease, 29–61. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-48344-3_2.
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Sanchez-Luque, Francisco J., Sandra R. Richardson, and Geoffrey J. Faulkner. "Retrotransposon Capture Sequencing (RC-Seq): A Targeted, High-Throughput Approach to Resolve Somatic L1 Retrotransposition in Humans." In Methods in Molecular Biology, 47–77. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-3372-3_4.
Full textConference papers on the topic "L1 retrotransposons"
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Nikolaeva, Elena I. "Genetics and psychophysiology of ADHD and autism." In 2nd International Neuropsychological Summer School named after A. R. Luria “The World After the Pandemic: Challenges and Prospects for Neuroscience”. Ural University Press, 2020. http://dx.doi.org/10.15826/b978-5-7996-3073-7.12.
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The paper discusses the brain mechanisms of autism and attention deficit hyperactivity disorder. It is shown that these disorders are associated with different genetic causes that create certain psychophysiological mechanisms. Nevertheless, their diagnosis is interrelated. Moreover, a child is often first diagnosed with ADHD, and then the diagnosis is changed to “autism spectrum disease”. Among the most common causes of the disease is the behavior of retrotransposons. Retrotransposons (also called transposons via intermediate RNA) are genetic elements that can amplify themselves in the genome. These DNA sequences use a “copy and paste” mechanism, whereby they are first transcribed into RNA and then converted back to identical DNA sequences via reverse transcription, and these sequences are then inserted into the genome at target sites. In humans, retro elements take up 42 % of the DNA. The conclusion is made that for the formation of an individual profile of gene expression in the neuron, the most important is the phenomenon of somatic mosaicism, due to the process of L1 retrotransposition, in addition to the classical described mechanisms of differentiation. The number of such events and their localization is significant as they are likely to contribute to the development of both autism and ADHD.
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Xia, Zhouchunyang, Dawn Cochrane, Michael Anglesio, Winnie Yang, Miguel Alcaide, Tayyebeh Nazeran, Janine Senz, et al. "Abstract B22: Capturing L1 retrotransposon-mediated DNA transductions in endometriosis associated ovarian cancers as a way to track tumor development." In Abstracts: AACR Special Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; October 1-4, 2017; Pittsburgh, PA. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1557-3265.ovca17-b22.
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