Journal articles: 'L1 retrotransposons'

1

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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9

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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10

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.

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11

Boissinot, S., and A. V. Furano. "The recent evolution of human L1 retrotransposons." Cytogenetic and Genome Research 110, no. 1-4 (2005): 402–6. http://dx.doi.org/10.1159/000084972.

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12

Kazazian Jr., H. H. "GENETICS: L1 Retrotransposons Shape the Mammalian Genome." Science 289, no. 5482 (August 18, 2000): 1152–53. http://dx.doi.org/10.1126/science.289.5482.1152.

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13

Kordiš, Dušsan, Nika Lovšin, and Franc Gubenšek. "Phylogenomic Analysis of the L1 Retrotransposons in Deuterostomia." Systematic Biology 55, no. 6 (December 1, 2006): 886–901. http://dx.doi.org/10.1080/10635150601052637.

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14

Farley, A. H. "More active human L1 retrotransposons produce longer insertions." Nucleic Acids Research 32, no. 2 (January 21, 2004): 502–10. http://dx.doi.org/10.1093/nar/gkh202.

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15

Richardson, Sandra R., Santiago Morell, and Geoffrey J. Faulkner. "L1 Retrotransposons and Somatic Mosaicism in the Brain." Annual Review of Genetics 48, no. 1 (November 23, 2014): 1–27. http://dx.doi.org/10.1146/annurev-genet-120213-092412.

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16

Nangia-Makker, Pratima, Rebecca Sarvis, Daniel W. Visscher, Juliet Bailey-Penrod, Avraham Raz, and Fazlul H. Sarkar. "Galectin-3 and L1 retrotransposons in human breast carcinomas." Breast Cancer Research and Treatment 49, no. 2 (May 1998): 171–83. http://dx.doi.org/10.1023/a:1005913810250.

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17

Smyshlyaev, G. A., and A. G. Blinov. "Evolution and biodiversity of L1 retrotransposons in angiosperm genomes." Russian Journal of Genetics: Applied Research 2, no. 1 (February 2012): 72–78. http://dx.doi.org/10.1134/s2079059712010133.

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18

Kazazian, Haig H., and John V. Moran. "The impact of L1 retrotransposons on the human genome." Nature Genetics 19, no. 1 (May 1998): 19–24. http://dx.doi.org/10.1038/ng0598-19.

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19

Muotri, Alysson R., Chunmei Zhao, Maria C. N. Marchetto, and Fred H. Gage. "Environmental influence on L1 retrotransposons in the adult hippocampus." Hippocampus 19, no. 10 (October 2009): 1002–7. http://dx.doi.org/10.1002/hipo.20564.

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20

Goodwin, Timothy J. D., Joanne E. Ormandy, and Russell T. M. Poulter. "L1-like non-LTR retrotransposons in the yeast Candida albicans." Current Genetics 39, no. 2 (April 27, 2001): 83–91. http://dx.doi.org/10.1007/s002940000181.

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21

Protasova, M. S., F. E. Gusev, A. P. Grigorenko, I. L. Kuznetsova, E. I. Rogaev, and T. V. Andreeva. "Quantitative analysis of L1-retrotransposons in Alzheimer’s disease and aging." Biochemistry (Moscow) 82, no. 8 (August 2017): 962–71. http://dx.doi.org/10.1134/s0006297917080120.

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22

Ichiyanagi, K., and N. Okada. "Mobility Pathways for Vertebrate L1, L2, CR1, and RTE Clade Retrotransposons." Molecular Biology and Evolution 25, no. 6 (January 14, 2008): 1148–57. http://dx.doi.org/10.1093/molbev/msn061.

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23

Suter, Catherine M., David I. Martin, and Robyn L. Ward. "Hypomethylation of L1 retrotransposons in colorectal cancer and adjacent normal tissue." International Journal of Colorectal Disease 19, no. 2 (March 1, 2004): 95–101. http://dx.doi.org/10.1007/s00384-003-0539-3.

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Bao, Weidong, and Jerzy Jurka. "Origin and evolution of LINE-1 derived “half-L1” retrotransposons (HAL1)." Gene 465, no. 1-2 (October 2010): 9–16. http://dx.doi.org/10.1016/j.gene.2010.06.005.

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25

Gilbert, Nicolas, Sheila Lutz, Tammy A. Morrish, and John V. Moran. "Multiple Fates of L1 Retrotransposition Intermediates in Cultured Human Cells." Molecular and Cellular Biology 25, no. 17 (September 1, 2005): 7780–95. http://dx.doi.org/10.1128/mcb.25.17.7780-7795.2005.

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ABSTRACT LINE-1 (L1) retrotransposons comprise ∼17% of human DNA, yet little is known about L1 integration. Here, we characterized 100 retrotransposition events in HeLa cells and show that distinct DNA repair pathways can resolve L1 cDNA retrotransposition intermediates. L1 cDNA resolution can lead to various forms of genetic instability including the generation of chimeric L1s, intrachromosomal deletions, intrachromosomal duplications, and intra-L1 rearrangements as well as a possible interchromosomal translocation. The L1 retrotransposition machinery also can mobilize U6 snRNA to new genomic locations, increasing the repertoire of noncoding RNAs that are mobilized by L1s. Finally, we have determined that the L1 reverse transcriptase can faithfully replicate its own transcript and has a base misincorporation error rate of ∼1/7,000 bases. These data indicate that L1 retrotransposition in transformed human cells can lead to a variety of genomic rearrangements and suggest that host processes act to restrict L1 integration in cultured human cells. Indeed, the initial steps in L1 retrotransposition may define a host/parasite battleground that serves to limit the number of active L1s in the genome.

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Chen, Jian-Min, Claude Férec, and David N. Cooper. "LINE-1 Endonuclease-Dependent Retrotranspositional Events Causing Human Genetic Disease: Mutation Detection Bias and Multiple Mechanisms of Target Gene Disruption." Journal of Biomedicine and Biotechnology 2006 (2006): 1–9. http://dx.doi.org/10.1155/jbb/2006/56182.

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LINE-1 (L1) elements are the most abundant autonomous non-LTR retrotransposons in the human genome. Having recently performed a meta-analysis of L1 endonuclease-mediated retrotranspositional events causing human genetic disease, we have extended this study by focusing on two key issues, namely, mutation detection bias and the multiplicity of mechanisms of target gene disruption. Our analysis suggests that whereas an ascertainment bias may have generally militated against the detection of autosomal L1-mediated insertions, autosomal L1 direct insertions could have been disproportionately overlooked owing to their unusually large size. Our analysis has also indicated that the mechanisms underlying the functional disruption of target genes by L1-mediated retrotranspositional events are likely to be dependent on several different factors such as the type of insertion (L1 direct, L1trans-drivenAlu, or SVA), the precise locations of the inserted sequences within the target gene regions, the length of the inserted sequences, and possibly also their orientation.

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Shi, Xi, Andrei Seluanov, and Vera Gorbunova. "Cell Divisions Are Required for L1 Retrotransposition." Molecular and Cellular Biology 27, no. 4 (December 4, 2006): 1264–70. http://dx.doi.org/10.1128/mcb.01888-06.

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ABSTRACT LINE-1 (L1) retrotransposons comprise a large fraction of genomic DNAs of many organisms. Many L1 elements are active and may generate potentially deleterious mutations by inserting into genes, yet little is known about the control of retrotransposition by the host. Here we examined whether retrotransposition depends on the cell cycle by using a retrotransposition assay with cultured human cells. We show that in both cancer cells and primary human fibroblasts, retrotransposition was strongly inhibited in the cells arrested in the G1, S, G2, or M stage of the cell cycle. Retrotransposition was also inhibited during cellular senescence in primary human fibroblasts. The levels of L1 transcripts were strongly reduced in arrested cells, suggesting that the reduction in L1 transcript abundance limits retrotransposition in nondividing cells. We hypothesize that inhibition of retrotransposition in nondividing cells protects somatic tissues from accumulation of deleterious mutations caused by L1 elements.

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Schöbel, Anja, Van Nguyen-Dinh, Gerald G. Schumann, and Eva Herker. "Hepatitis C virus infection restricts human LINE-1 retrotransposition in hepatoma cells." PLOS Pathogens 17, no. 4 (April 19, 2021): e1009496. http://dx.doi.org/10.1371/journal.ppat.1009496.

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LINE-1 (L1) retrotransposons are autonomous transposable elements that can affect gene expression and genome integrity. Potential consequences of exogenous viral infections for L1 activity have not been studied to date. Here, we report that hepatitis C virus (HCV) infection causes a significant increase of endogenous L1-encoded ORF1 protein (L1ORF1p) levels and translocation of L1ORF1p to HCV assembly sites at lipid droplets. HCV replication interferes with retrotransposition of engineered L1 reporter elements, which correlates with HCV RNA-induced formation of stress granules and can be partially rescued by knockdown of the stress granule protein G3BP1. Upon HCV infection, L1ORF1p localizes to stress granules, associates with HCV core in an RNA-dependent manner and translocates to lipid droplets. While HCV infection has a negative effect on L1 mobilization, L1ORF1p neither restricts nor promotes HCV infection. In summary, our data demonstrate that HCV infection causes an increase of endogenous L1 protein levels and that the observed restriction of retrotransposition of engineered L1 reporter elements is caused by sequestration of L1ORF1p in HCV-induced stress granules.

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Sookdeo, Akash, Manuel Ruiz-García, Horacio Schneider, and Stéphane Boissinot. "Contrasting Rates of LINE-1 Amplification among New World Primates of the Atelidae Family." Cytogenetic and Genome Research 154, no. 4 (2018): 217–28. http://dx.doi.org/10.1159/000490481.

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LINE-1 (L1) retrotransposons constitute the dominant category of transposons in mammalian genomes. L1 elements are active in the vast majority of mammals, and only a few cases of L1 extinction have been documented. The only possible case of extinction in primates was suggested for South American spider monkeys. However, these previous studies were based on a single species. We revisited this question with a larger phylogenetic sample, covering all 4 genera of Atelidae and 3 species of spider monkeys. We used an enrichment method to clone recently inserted L1 elements and performed an evolutionary analysis of the sequences. We were able to identify young L1 elements in all taxa, suggesting that L1 is probably still active in all Atelidae examined. However, we also detected considerable variations in the proportion of recent elements indicating that the rate of L1 amplification varies among Atelidae by a 3-fold factor. The extent of L1 amplification in Atelidae remains overall lower than in other New World monkeys. Multiple factors can affect the amplification of L1, such as the demography of the host and the control of transposition. These factors are discussed in the context of host life history.

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30

Boissinot, S. "The Insertional History of an Active Family of L1 Retrotransposons in Humans." Genome Research 14, no. 7 (June 14, 2004): 1221–31. http://dx.doi.org/10.1101/gr.2326704.

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Ohshima, Kazuhiko. "Parallel Relaxation of Stringent RNA Recognition in Plant and Mammalian L1 Retrotransposons." Molecular Biology and Evolution 29, no. 11 (July 13, 2012): 3255–59. http://dx.doi.org/10.1093/molbev/mss147.

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Newkirk, Simon J., Lingqi Kong, Mason M. Jones, Chase E. Habben, Victoria L. Dilts, Ping Ye, and Wenfeng An. "Subfamily-specific quantification of endogenous mouse L1 retrotransposons by droplet digital PCR." Analytical Biochemistry 601 (July 2020): 113779. http://dx.doi.org/10.1016/j.ab.2020.113779.

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Higashino, Saneyuki, Tomoyuki Ohno, Koichi Ishiguro, and Yasunori Aizawa. "Polymorphic L1 retrotransposons are frequently in strong linkage disequilibrium with neighboring SNPs." Gene 541, no. 1 (May 2014): 55–59. http://dx.doi.org/10.1016/j.gene.2014.03.008.

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Graham, Todd, and Stephane Boissinot. "The Genomic Distribution of L1 Elements: The Role of Insertion Bias and Natural Selection." Journal of Biomedicine and Biotechnology 2006 (2006): 1–5. http://dx.doi.org/10.1155/jbb/2006/75327.

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LINE-1 (L1) retrotransposons constitute the most successful family of retroelements in mammals and account for as much as 20% of mammalian DNA. L1 elements can be found in all genomic regions but they are far more abundant in AT-rich, gene-poor, and low-recombining regions of the genome. In addition, the sex chromosomes and some genes seem disproportionately enriched in L1 elements. Insertion bias and selective processes can both account for this biased distribution of L1 elements. L1 elements do not appear to insert randomly in the genome and this insertion bias can at least partially explain the genomic distribution of L1. The contrasted distribution of L1 and Alu elements suggests that postinsertional processes play a major role in shaping L1 distribution. The most likely mechanism is the loss of recently integrated L1 elements that are deleterious (negative selection) either because of disruption of gene function or their ability to mediate ectopic recombination. By comparison, the retention of L1 elements because of some positive effect is limited to a small fraction of the genome. Understanding the respective importance of insertion bias and selection will require a better knowledge of insertion mechanisms and the dynamics of L1 inserts in populations.

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Vazquez, Berta N., Joshua K. Thackray, Nicolas G. Simonet, Sanjay Chahar, Noriko Kane-Goldsmith, Simon J. Newkirk, Suman Lee, et al. "SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina." Nucleic Acids Research 47, no. 15 (June 21, 2019): 7870–85. http://dx.doi.org/10.1093/nar/gkz519.

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Abstract Long interspersed elements-1 (LINE-1, L1) are retrotransposons that hold the capacity of self-propagation in the genome with potential mutagenic outcomes. How somatic cells restrict L1 activity and how this process becomes dysfunctional during aging and in cancer cells is poorly understood. L1s are enriched at lamin-associated domains, heterochromatic regions of the nuclear periphery. Whether this association is necessary for their repression has been elusive. Here we show that the sirtuin family member SIRT7 participates in the epigenetic transcriptional repression of L1 genome-wide in both mouse and human cells. SIRT7 depletion leads to increased L1 expression and retrotransposition. Mechanistically, we identify a novel interplay between SIRT7 and Lamin A/C in L1 repression. Our results demonstrate that SIRT7-mediated H3K18 deacetylation regulates L1 expression and promotes L1 association with elements of the nuclear lamina. The failure of such activity might contribute to the observed genome instability and compromised viability in SIRT7 knockout mice. Overall, our results reveal a novel function of SIRT7 on chromatin organization by mediating the anchoring of L1 to the nuclear envelope, and a new functional link of the nuclear lamina with transcriptional repression.

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Casavant, N. Carol, Rhonda N. Lee, Amy N. Sherman, and Holly A. Wichman. "Molecular Evolution of Two Lineages of L1 (LINE-1) Retrotransposons in the California Mouse, Peromyscus californicus." Genetics 150, no. 1 (September 1, 1998): 345–57. http://dx.doi.org/10.1093/genetics/150.1.345.

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Abstract The large number of L1 [long interspersed elements (LINE)-1] sequences found in the genome is due to the insertion of copies of the retrotransposon over evolutionary time. The majority of copies appear to be replicates of a few active, or “master” templates. A continual replacement of master templates over time gives rise to lineages distinguishable by their own unique set of shared-sequence variants. A previous analysis of L1 sequences in deer mice, Peromyscus maniculatus and P. leucopus, revealed two active L1 lineages, marked by different rates of evolution, whose most recent common ancestor predates the expansion of the Peromyscus species. Here we exploit lineage-specific, shared-sequence variants to reveal a paucity of Lineage 2 sequences in at least one species, P. californicus. The dearth of Lineage 2 copies in P. californicus suggests that Lineage 2 may have been unproductive until after the most recent common ancestor of P. californicus and P. maniculatus. We also show that Lineage 1 appears to have a higher rate of evolution in P. maniculatus relative to either P. californicus or P. leucopus. As a phylogenetic tool, L1 lineage-specific variants support a close affinity between P. californicus and P. eremicus relative to the other species examined.

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Honda, Tomoyuki, and Md Rahman. "Profiling of LINE-1-Related Genes in Hepatocellular Carcinoma." International Journal of Molecular Sciences 20, no. 3 (February 2, 2019): 645. http://dx.doi.org/10.3390/ijms20030645.

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Hepatocellular carcinoma (HCC) is a prime public health concern that accounts for most of the primary liver malignancies in humans. The most common etiological factor of HCC is hepatitis B virus (HBV). Despite recent advances in treatment strategies, there has been little success in improving the survival of HCC patients. To develop a novel therapeutic approach, evaluation of a working hypothesis based on different viewpoints might be important. Long interspersed element 1 (L1) retrotransposons have been suggested to play a role in HCC. However, the molecular machineries that can modulate L1 biology in HBV-related HCC have not been well-evaluated. Here, we summarize the profiles of expression and/or activation status of L1-related genes in HBV-related HCC, and HBV- and HCC-related genes that may impact L1-mediated tumorigenesis. L1 restriction factors appear to be suppressed by HBV infection. Since some of the L1 restriction factors also limit HBV, these factors may be exhausted in HBV-infected cells, which causes de-suppression of L1. Several HBV- and HCC-related genes that interact with L1 can affect oncogenic processes. Thus, L1 may be a novel prime therapeutic target for HBV-related HCC. Studies in this area will provide insights into HCC and other types of cancers.

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Stenz, Ludwig. "The L1-dependant and Pol III transcribed Alu retrotransposon, from its discovery to innate immunity." Molecular Biology Reports 48, no. 3 (March 2021): 2775–89. http://dx.doi.org/10.1007/s11033-021-06258-4.

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AbstractThe 300 bp dimeric repeats digestible by AluI were discovered in 1979. Since then, Alu were involved in the most fundamental epigenetic mechanisms, namely reprogramming, pluripotency, imprinting and mosaicism. These Alu encode a family of retrotransposons transcribed by the RNA Pol III machinery, notably when the cytosines that constitute their sequences are de-methylated. Then, Alu hijack the functions of ORF2 encoded by another transposons named L1 during reverse transcription and integration into new sites. That mechanism functions as a complex genetic parasite able to copy-paste Alu sequences. Doing that, Alu have modified even the size of the human genome, as well as of other primate genomes, during 65 million years of co-evolution. Actually, one germline retro-transposition still occurs each 20 births. Thus, Alu continue to modify our human genome nowadays and were implicated in de novo mutation causing diseases including deletions, duplications and rearrangements. Most recently, retrotransposons were found to trigger neuronal diversity by inducing mosaicism in the brain. Finally, boosted during viral infections, Alu clearly interact with the innate immune system. The purpose of that review is to give a condensed overview of all these major findings that concern the fascinating physiology of Alu from their discovery up to the current knowledge.

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Lucier, J. F., J. Perreault, J. F. Noel, G. Boire, and J. P. Perreault. "RTAnalyzer: a web application for finding new retrotransposons and detecting L1 retrotransposition signatures." Nucleic Acids Research 35, Web Server (May 8, 2007): W269—W274. http://dx.doi.org/10.1093/nar/gkm313.

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Verneau, O., F. Catzeflis, and A. V. Furano. "Determining and dating recent rodent speciation events by using L1 (LINE-1) retrotransposons." Proceedings of the National Academy of Sciences 95, no. 19 (September 15, 1998): 11284–89. http://dx.doi.org/10.1073/pnas.95.19.11284.

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Hu, Tianxiang, Wenhu Pi, and Dorothy Tuan. "Non-Coding RNAs Transcribed from ERV-9 LTR Retrotransposons Regulate Erythropoiesis." Blood 124, no. 21 (December 6, 2014): 1340. http://dx.doi.org/10.1182/blood.v124.21.1340.1340.

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Abstract Long noncoding RNAs (lncRNAs) regulate diverse cellular processes in development, differentiation and malignancy. In human cells, over 80% of the lncRNAs contain retrotransposon sequences transcribed from Alu, L1 and LTR retrotransposons, which comprise ~40% of the human genome. The functional significance of the retrotransposon lncRNAs is largely unknown. The human genome contains ~4000 copies of the ERV-9 LTR retrotransposon, which exhibits strong enhancer activity and initiates synthesis of ERV-9 lncRNAs in erythroid progenitor cells. Recently, we discovered that depletion of the ERV-9 lncRNAs in human erythroid progenitor cells cultured ex vivo from peripheral blood CD34+ cells inhibited ex vivo erythropoiesis. Whole genome RNA sequencing (RNA-seq) found that depletion of ERV-9 lncRNAs significantly suppressed transcription of 608 genes including ~50 key erythroid genes. We hypothesize that the ERV-9 lncRNAs together with the ERV-9 LTR act in cis to regulate transcription of these key erythroid genes and other genes to set up a transcriptional network that promotes erythropoiesis. In the human b-globin gene locus, we showed previously that the ERV-9 LTR retrotransposon performs a beneficial biological function: The ERV-9 LTR enhancer binds NF-Y and GATA-1 and -2 to assemble an LTR-pol II transcription complex, which transcribes long, noncoding RNAs (lncRNAs) from the LTR R-U5 regions through the downstream locus control region (LCR) and intergenic DNAs to reach and activate transcription of b-globin gene 70 kb away. In this tracking and transcription (T&T) mechanism of long-range LTR enhancer function, the ERV-9 lncRNAs could be merely by-products of the tracking and transcribing process of the LTR complex without any functional significance. However, we found recently that depletion of the ERV-9 lncRNAs suppressed transcription of the entire human globin gene locus, diminished occupancies of NF-Y, GATA-1 and -2 and pol II at the ERV-9 LTR and reduced the looping frequency of the ERV-9 LTR with the globin gene locus in erythroid progenitor cells. Thus, the ERV-9 lncRNAs acted in cis to facilitate assembly of the LTR-pol II complex and modulate long-range LTR enhancer function in transcriptional activation of b-globin gene. Genome-wide, whether the ERV-9 lncRNAs transcribed from other gene loci perform similar biological function is under investigation. Disclosures No relevant conflicts of interest to declare.

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Hayward, Bruce E., Mary Zavanelli, and Anthony V. Furano. "Recombination Creates Novel L1 (LINE-1) Elements in Rattus norvegicus." Genetics 146, no. 2 (June 1, 1997): 641–54. http://dx.doi.org/10.1093/genetics/146.2.641.

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Mammalian L1 (long interspersed repeated DNA, LINE-1) retrotransposons consist of a 5′ untranslated region (UTR) with regulatory properties, two protein encoding regions (ORF I, ORF II, which encodes a reverse transcriptase) and a 3′ UTR. L1 elements have been evolving in mammals for >100 million years and this process continues to generate novel L1 subfamilies in modern species. Here we characterized the youngest known subfamily in Rattus norvegicus, L1mlvi2, and unexpectedly found that this element has a dual ancestry. While its 3′ UTR shares the same lineage as its nearest chronologically antecedent subfamilies, L13 and L14, its ORF I sequence does not. The L1mlvi2 ORF I was derived from an ancestral ORF I sequence that was the evolutionary precursor of the L13 and L14 ORF I. We suggest that an ancestral ORF I sequence was recruited into the modern L1mlvi2 subfamily by recombination that possibly could have resulted from template strand switching by the reverse transcriptase during L1 replication. This mechanism could also account for some of the structural features of rodent L1 5′ UTR and ORF I sequences including one of the more dramatic features of L1 evolution in mammals, namely the repeated acquisition of novel 5′ UTRs.

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Barbieri, Daniela, Emilie Elvira-Matelot, Yanis Pelinski, Laetitia Genève, Bérengère de Laval, Gayathri Yogarajah, Christian Pecquet, Stefan N. Constantinescu, and Françoise Porteu. "Thrombopoietin protects hematopoietic stem cells from retrotransposon-mediated damage by promoting an antiviral response." Journal of Experimental Medicine 215, no. 5 (April 3, 2018): 1463–80. http://dx.doi.org/10.1084/jem.20170997.

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Maintenance of genomic integrity is crucial for the preservation of hematopoietic stem cell (HSC) potential. Retrotransposons, spreading in the genome through an RNA intermediate, have been associated with loss of self-renewal, aging, and DNA damage. However, their role in HSCs has not been addressed. Here, we show that mouse HSCs express various retroelements (REs), including long interspersed element-1 (L1) recent family members that further increase upon irradiation. Using mice expressing an engineered human L1 retrotransposition reporter cassette and reverse transcription inhibitors, we demonstrate that L1 retransposition occurs in vivo and is involved in irradiation-induced persistent γH2AX foci and HSC loss of function. Thus, RE represents an important intrinsic HSC threat. Furthermore, we show that RE activity is restrained by thrombopoietin, a critical HSC maintenance factor, through its ability to promote a potent interferon-like, antiviral gene response in HSCs. This uncovers a novel mechanism allowing HSCs to minimize irradiation-induced injury and reinforces the links between DNA damage, REs, and antiviral immunity.

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Guidez, Fabien, Laetitia Durand, Valerie Vidal, William Puszyk, David Grimwade, Ellen Solomon, and Christine Chomienne. "Identification of PLZF-Dmrs in Hematopoiesis Highlight a Novel Role of PLZF As a Guardian of Hematopoietic Genome Integrity." Blood 124, no. 21 (December 6, 2014): 2904. http://dx.doi.org/10.1182/blood.v124.21.2904.2904.

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Abstract Background: The eucaryotic genome is organized in chromatin domains which affect its function. This organization is partly established by special architectural and transcriptional factors specific to the cellular context. In an hematopoietic context, PLZF (Promyelocytic Leukemia Zinc Finger protein), a member of the family of POK repressor proteins, is directly implicated in the regulation of epigenetic modifications by tethering DNA methyltransferases (DNMT) and histone deacetylases (HDAC) to specific genomic targets. We have previously shown that PLZF transcriptional activation is controlled by acetylation of specific lysine residues (K647/650/653) affecting its nuclear localization. PLZF is mainly expressed in CD34 positive cells and has been shown to be crucial in the maintenance of hematopoietic stem cells (HSC). However, the epigenetic role of PLZF in HSC protection and maintenance is not yet understood. Methodology: We created PLZF functional knock-in mouse models by introducing PLZF lysine mutants with altered epigenetic functions at the PLZF locus. We used purified bone marrow (BM) cells from 12 week old mice to assess their self-renewal capacity by methylcellulose-based medium serial replating assays to detect and quantify hematopoietic progenitors in colony-forming unit (CFU) experiments and long-term self-renewal. In parallel, Methyl DNA immunoprecipitation followed by deep-sequencing (MeDiP-seq) was performed in order to establish DNA methylation pattern and characterize PLZF induced DNA methylation regions (PLZF-DMR). Retrotransposon activity was determined by quantifying the expression of L1 retrotransposon mRNAs in mouse cells and by retrotransposon assay using a GFP-L1 reporter in human 293T cells. Validation and functions of PLZF genomic targets found in mouse cells were tested in KG1a CD34+ hematopoietic human cells by Chromatin immunoprecipitation (ChIP) and reporter gene assays using PLZF-DMR luciferase vectors containing L1 and also Alu and telomeric sequences targeted by PLZF. Results: We have created two PLZF functional mutants, PLZFON mutant constitutively binding DNA and PLZFOFF mutant unable to interact with DNA, and shown that PLZFOFF mice are infertile due to loss of germinal cells recapitulating the PLZF knock-out mouse model phenotype. In both PLZFOFF and PLZFON 12 week old mice the number of myeloid colonies decreased by 62% compared to PLZFWT and a total absence of self-renewal capacity at the 1st replating in PLZFOFF was noted. In BM cells, establishment of differential DNA methylation profiles by MEDIP-seq of PLZFOFF, PLZFON and PLZFWT mice allowed to identify more than 500 PLZF-DMRs. We found that primary PLZF genomic targets are repeat elements scattered throughout the genome (75% of all PLZF-DMRs). These repeat elements include retrotransposons (L1, 21.9%), Alu sequences (14.4%), retroviruses (22.1%) and sub-telomeric/telomeric regions (10%). We first investigated the impact of PLZF on L1 elements because of their involvment in genome instability, gene control and cancer through retrotransposition and methylation events: -a) L1 and PLZF interact through an 8bp conserved binding site; -b) PLZF binds to full length and truncated L1 DNA sequences, inducing DNA methylation and histone deacetylation propagation by recruiting of DNMT and HDAC proteins; L1 mRNA expression is increased PLZFOFF BM cells. Furthermore, in a retrotransposition assay using a GFP-L1 reporter in human cells we demonstrate that PLZF inhibits L1 retrotransposition and that PLZF-DMRs containing L1, Alu and telomeric sequences induce transcriptional repression by creating heterochromatin boundaries. Conclusions: These results, using unique mouse models of PLZF inactivation, with loss of HSC maintenance show that PLZF may be a guardian of genome integrity of long living hematopoietic cells by establishing DNA methylation patterning, associated with constitutive heterochromatin domains involved in retrotransposition silencing and centromere/telomere stability. Disclosures No relevant conflicts of interest to declare.

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Cook, Pamela R., Charles E. Jones, and Anthony V. Furano. "Phosphorylation of ORF1p is required for L1 retrotransposition." Proceedings of the National Academy of Sciences 112, no. 14 (March 23, 2015): 4298–303. http://dx.doi.org/10.1073/pnas.1416869112.

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Although members of the L1 (LINE-1) clade of non-LTR retrotransposons can be deleterious, the L1 clade has remained active in most mammals for ∼100 million years and generated almost 40% of the human genome. The details of L1–host interaction are largely unknown, however. Here we report that L1 activity requires phosphorylation of the protein encoded by the L1 ORF1 (ORF1p). Critical phospho-acceptor residues (two serines and two threonines) reside in four conserved proline-directed protein kinase (PDPK) target sites. The PDPK family includes mitogen-activated protein kinases and cyclin-dependent kinases. Mutation of any PDPK phospho-acceptor inhibits L1 retrotransposition. The phosphomimetic aspartic acid can restore activity at the two serine sites, but not at either threonine site, where it is strongly inhibitory. ORF1p also contains conserved PDPK docking sites, which promote specific interaction of PDPKs with their targets. As expected, mutations in these sites also inhibit L1 activity. PDPK mutations in ORF1p that inactivate L1 have no significant effect on the ability of ORF1p to anneal RNA in vitro, an important biochemical property of the protein. We show that phosphorylated PDPK sites in ORF1p are required for an interaction with the peptidyl prolyl isomerase 1 (Pin1), a critical component of PDPK-mediated regulation. Pin1 acts via isomerization of proline side chains at phosphorylated PDPK motifs, thereby affecting substrate conformation and activity. Our demonstration that L1 activity is dependent on and integrated with cellular phosphorylation regulatory cascades significantly increases our understanding of interactions between L1 and its host.

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Lu, J. Yuyang, Lei Chang, Tong Li, Ting Wang, Yafei Yin, Ge Zhan, Xue Han, et al. "Homotypic clustering of L1 and B1/Alu repeats compartmentalizes the 3D genome." Cell Research 31, no. 6 (January 29, 2021): 613–30. http://dx.doi.org/10.1038/s41422-020-00466-6.

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AbstractOrganization of the genome into euchromatin and heterochromatin appears to be evolutionarily conserved and relatively stable during lineage differentiation. In an effort to unravel the basic principle underlying genome folding, here we focus on the genome itself and report a fundamental role for L1 (LINE1 or LINE-1) and B1/Alu retrotransposons, the most abundant subclasses of repetitive sequences, in chromatin compartmentalization. We find that homotypic clustering of L1 and B1/Alu demarcates the genome into grossly exclusive domains, and characterizes and predicts Hi-C compartments. Spatial segregation of L1-rich sequences in the nuclear and nucleolar peripheries and B1/Alu-rich sequences in the nuclear interior is conserved in mouse and human cells and occurs dynamically during the cell cycle. In addition, de novo establishment of L1 and B1 nuclear segregation is coincident with the formation of higher-order chromatin structures during early embryogenesis and appears to be critically regulated by L1 and B1 transcripts. Importantly, depletion of L1 transcripts in embryonic stem cells drastically weakens homotypic repeat contacts and compartmental strength, and disrupts the nuclear segregation of L1- or B1-rich chromosomal sequences at genome-wide and individual sites. Mechanistically, nuclear co-localization and liquid droplet formation of L1 repeat DNA and RNA with heterochromatin protein HP1α suggest a phase-separation mechanism by which L1 promotes heterochromatin compartmentalization. Taken together, we propose a genetically encoded model in which L1 and B1/Alu repeats blueprint chromatin macrostructure. Our model explains the robustness of genome folding into a common conserved core, on which dynamic gene regulation is overlaid across cells.

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Tristan-Ramos, Pablo, Santiago Morell, Laura Sanchez, Belen Toledo, Jose L. Garcia-Perez, and Sara R. Heras. "sRNA/L1 retrotransposition: using siRNAs and miRNAs to expand the applications of the cell culture-based LINE-1 retrotransposition assay." Philosophical Transactions of the Royal Society B: Biological Sciences 375, no. 1795 (February 10, 2020): 20190346. http://dx.doi.org/10.1098/rstb.2019.0346.

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The cell culture-based retrotransposition reporter assay has been (and is) an essential tool for the study of vertebrate Long INterspersed Elements (LINEs). Developed more than 20 years ago, this assay has been instrumental in characterizing the role of LINE-encoded proteins in retrotransposition, understanding how ribonucleoprotein particles are formed, how host factors regulate LINE mobilization, etc. Moreover, variations of the conventional assay have been developed to investigate the biology of other currently active human retrotransposons, such as Alu and SVA. Here, we describe a protocol that allows combination of the conventional cell culture-based LINE-1 retrotransposition reporter assay with short interfering RNAs (siRNAs) and microRNA (miRNAs) mimics or inhibitors, which has allowed us to uncover specific miRNAs and host factors that regulate retrotransposition. The protocol described here is highly reproducible, quantitative, robust and flexible, and allows the study of several small RNA classes and various retrotransposons. To illustrate its utility, here we show that siRNAs to Fanconi anaemia proteins (FANC-A and FANC-C) and an inhibitor of miRNA-20 upregulate and downregulate human L1 retrotransposition, respectively. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

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Macfarlane, Catriona M., Pamela Collier, Raheleh Rahbari, Christine R. Beck, John F. Wagstaff, Samantha Igoe, John V. Moran, and Richard M. Badge. "Transduction-Specific ATLAS Reveals a Cohort of Highly Active L1 Retrotransposons in Human Populations." Human Mutation 34, no. 7 (April 23, 2013): 974–85. http://dx.doi.org/10.1002/humu.22327.

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Ukadike, Kennedy C., and Tomas Mustelin. "Implications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus." Journal of Clinical Medicine 10, no. 4 (February 19, 2021): 856. http://dx.doi.org/10.3390/jcm10040856.

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Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A hypothesis that combines several of these factors proposes that genomic elements, the L1 retrotransposons, are instrumental in SLE pathogenesis. L1 retroelements are transcriptionally activated in SLE and produce two proteins, ORF1p and ORF2p, which are immunogenic and can drive type I interferon (IFN) production by producing DNA species that activate cytosolic DNA sensors. In addition, these two proteins reside in RNA-rich macromolecular assemblies that also contain well-known SLE autoantigens like Ro60. We surmise that cells expressing L1 will exhibit all the hallmarks of cells infected by a virus, resulting in a cellular and humoral immune response similar to those in chronic viral infections. However, unlike exogenous viruses, L1 retroelements cannot be eliminated from the host genome. Hence, dysregulated L1 will cause a chronic, but perhaps episodic, challenge for the immune system. The clinical and immunological features of SLE can be at least partly explained by this model. Here we review the support for, and the gaps in, this hypothesis of SLE and its potential for new diagnostic, prognostic, and therapeutic options in SLE.

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Jacobs, Frank M. J., David Greenberg, Ngan Nguyen, Maximilian Haeussler, Adam D. Ewing, Sol Katzman, Benedict Paten, Sofie R. Salama, and David Haussler. "An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons." Nature 516, no. 7530 (September 28, 2014): 242–45. http://dx.doi.org/10.1038/nature13760.

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Journal articles on the topic 'L1 retrotransposons'

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