Abstract
Transposable elements (TEs) are insertional mutagens that contribute greatly to the plasticity of eukaryotic genomes, influencing the evolution and adaptation of species as well as physiology or disease in individuals. Measuring TE expression helps to understand not only when and where TE mobilization can occur but also how this process alters gene expression, chromatin accessibility or cellular signalling pathways. Although genome-wide gene expression assays such as RNA sequencing include transposon-derived transcripts, most computational analytical tools discard or misinterpret TE-derived reads. Emerging approaches are improving the identification of expressed TE loci and helping to discriminate TE transcripts that permit TE mobilization from chimeric gene–TE transcripts or pervasive transcription. Here we review the main challenges associated with the detection of TE expression, including mappability, insertional and internal sequence polymorphisms, and the diversity of the TE transcriptional landscape, as well as the different experimental and computational strategies to solve them.
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References
Chénais, B., Caruso, A., Hiard, S. & Casse, N. The impact of transposable elements on eukaryotic genomes: From genome size increase to genetic adaptation to stressful environments. Gene 509, 7–15 (2012).
Lisch, D. How important are transposons for plant evolution? Nat. Rev. Genet. 14, 49–61 (2013).
Faulkner, G. J. & Garcia-Perez, J. L. L1 Mosaicism in mammals: extent, effects, and evolution. Trends Genet. 33, 802–816 (2017).
Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory activities of transposable elements: from conflicts to benefits. Nat. Rev. Genet. 18, 71–86 (2017).
Payer, L. M. & Burns, K. H. Transposable elements in human genetic disease. Nat. Rev. Genet. 20, 760–772 (2019).
Tam, O. H., Ostrow, L. W. & Gale Hammell, M. Diseases of the nERVous system: retrotransposon activity in neurodegenerative disease. Mob. DNA 10, 32 (2019).
Sotero-Caio, C. G., Platt, R. N. II, Suh, A. & Ray, D. A. Evolution and diversity of transposable elements in vertebrate genomes. Genome Biol. Evol. 9, 161–177 (2017).
Cho, J. & Paszkowski, J. Regulation of rice root development by a retrotransposon acting as a microRNA sponge. eLife 6, 796 (2017).
Brattås, P. L. et al. TRIM28 controls a gene regulatory network based on endogenous retroviruses in human neural progenitor cells. Cell Rep. 18, 1–11 (2017).
Petri, R. et al. LINE-2 transposable elements are a source of functional human microRNAs and target sites. PLoS Genet. 15, e1008036 (2019).
Kashkush, K., Feldman, M. & Levy, A. A. Transcriptional activation of retrotransposons alters the expression of adjacent genes in wheat. Nat. Genet. 33, 102–106 (2003).
Percharde, M. et al. A LINE1-nucleolin partnership regulates early development and ESC identity. Cell 174, 391–405.e19 (2018).
Conte, C., Dastugue, B. & Vaury, C. Promoter competition as a mechanism of transcriptional interference mediated by retrotransposons. EMBO J. 21, 3908–3916 (2002).
Jachowicz, J. W. et al. LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. Nat. Genet. 49, 1502–1510 (2017).
Stetson, D. B., Ko, J. S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).
Aravin, A. A. et al. Double-stranded RNA-mediated silencing of genomic tandem repeats and transposable elements in the D. melanogaster germline. Curr. Biol. 11, 1017–1027 (2001).
De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019).
Goic, B. et al. RNA-mediated interference and reverse transcription control the persistence of RNA viruses in the insect model Drosophila. Nat. Immunol. 14, 396–403 (2013).
Bourgeois, Y. & Boissinot, S. On the population dynamics of junk: a review on the population genomics of transposable elements. Genes 10, 419–423 (2019).
Khan, H., Smit, A. & Boissinot, S. Molecular evolution and tempo of amplification of human LINE-1 retrotransposons since the origin of primates. Genome Res. 16, 78–87 (2006).
Huang, C. R. L., Burns, K. H. & Boeke, J. D. Active transposition in genomes. Annu. Rev. Genet. 46, 651–675 (2012).
Mills, R. E., Bennett, E. A., Iskow, R. C. & Devine, S. E. Which transposable elements are active in the human genome? Trends Genet. 23, 183–191 (2007).
Brouha, B. et al. Hot L1s account for the bulk of retrotransposition in the human population. Proc. Natl Acad. Sci. USA 100, 5280–5285 (2003).
Beck, C. R. et al. LINE-1 retrotransposition activity in human genomes. Cell 141, 1159–1170 (2010).
Tubio, J. M. C. et al. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science 345, 1251343 (2014).
Gardner, E. J. et al. The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology. Genome Res. 27, 1916–1929 (2017).
Rodriguez-Martin, B. et al. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nat. Genet. 52, 306–319 (2020). Tubio et al. (2014), Gardner et al. (2017) and Rodriguez-Martin et al. (2020) identify progenitor L1 elements active in humans from whole-genome sequencing using 3′ transductions and internal SNPs in L1 sequences.
Deininger, P. L., Batzer, M. A., Hutchison, C. A. & Edgell, M. H. Master genes in mammalian repetitive DNA amplification. Trends Genet. 8, 307–311 (1992).
Jacobs, F. M. J. et al. An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature 516, 242–245 (2014).
Imbeault, M., Helleboid, P.-Y. & Trono, D. KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks. Nature 543, 550–554 (2017).
Sanchez-Luque, F. J. et al. LINE-1 evasion of epigenetic repression in humans. Mol. Cell 75, 590–604 (2019).
Boissinot, S., Entezam, A., Young, L., Munson, P. J. & Furano, A. V. The insertional history of an active family of L1 retrotransposons in humans. Genome Res. 14, 1221–1231 (2004).
Scott, E. C. et al. A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer. Genome Res. 26, 745–755 (2016). This study resequenced all non-reference L1 elements in a colon cancer case to identify internal diagnostic SNPs and subsequently which elements are expressed in the sample.
Chalopin, D., Naville, M., Plard, F., Galiana, D. & Volff, J.-N. Comparative analysis of transposable elements highlights mobilome diversity and evolution in vertebrates. Genome Biol. Evol. 7, 567–580 (2015).
Quadrana, L. et al. The Arabidopsis thaliana mobilome and its impact at the species level. eLife 5, e15716 (2016).
McCullers, T. J. & Steiniger, M. Transposable elements in Drosophila. Mob. Genet. Elem. 7, 1–18 (2017).
Vitte, C. & Panaud, O. LTR retrotransposons and flowering plant genome size: emergence of the increase/decrease model. Cytogenet. Genome Res. 110, 91–107 (2005).
Hawkins, J. S., Proulx, S. R., Rapp, R. A. & Wendel, J. F. Rapid DNA loss as a counterbalance to genome expansion through retrotransposon proliferation in plants. Proc. Natl Acad. Sci. USA 106, 17811–17816 (2009).
Kapusta, A., Suh, A. & Feschotte, C. Dynamics of genome size evolution in birds and mammals. Proc. Natl Acad. Sci. USA 114, E1460–E1469 (2017).
Goerner-Potvin, P. & Bourque, G. Computational tools to unmask transposable elements. Nat. Rev. Genet. 19, 688–704 (2018).
Vendrell-Mir, P. et al. A benchmark of transposon insertion detection tools using real data. Mob. DNA 10, 53 (2019).
O’Neill, K., Brocks, D. & Hammell, M. G. Mobile genomics: tools and techniques for tackling transposons. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 375, 20190345 (2020).
Sudmant, P. H. et al. An integrated map of structural variation in 2,504 human genomes. Nature 526, 75–81 (2015).
Ewing, A. D. & Kazazian, H. H. High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes. Genome Res. 20, 1262–1270 (2010).
Maksakova, I. A. et al. Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS Genet. 2, e2 (2006).
Zhang, Y., Maksakova, I. A., Gagnier, L., van de Lagemaat, L. N. & Mager, D. L. Genome-wide assessments reveal extremely high levels of polymorphism of two active families of mouse endogenous retroviral elements. PLoS Genet. 4, e1000007 (2008).
Nellåker, C. et al. The genomic landscape shaped by selection on transposable elements across 18 mouse strains. Genome Biol. 13, R45 (2012).
Richardson, S. R. et al. Heritable L1 retrotransposition in the mouse primordial germline and early embryo. Genome Res. 27, 1395–1405 (2017).
Carpentier, M.-C. et al. Retrotranspositional landscape of Asian rice revealed by 3000 genomes. Nat. Commun. 10, 24 (2019).
Feusier, J. et al. Pedigree-based estimation of human mobile element retrotransposition rates. Genome Res. 29, 1567–1577 (2019).
Rech, G. E. et al. Stress response, behavior, and development are shaped by transposable element-induced mutations in Drosophila. PLoS Genet. 15, e1007900 (2019).
González, J., Karasov, T. L., Messer, P. W. & Petrov, D. A. Genome-wide patterns of adaptation to temperate environments associated with transposable elements in Drosophila. PLoS Genet. 6, e1000905 (2010).
Payer, L. M. et al. Structural variants caused by Alu insertions are associated with risks for many human diseases. Proc. Natl Acad. Sci. USA 114, E3984–E3992 (2017).
Kazazian, H. H. Jr & Moran, J. V. Mobile DNA in health and disease. N. Engl. J. Med. 377, 361–370 (2017).
Seleme, M. D. C. et al. Extensive individual variation in L1 retrotransposition capability contributes to human genetic diversity. Proc. Natl Acad. Sci. USA 103, 6611–6616 (2006). Seleme et al. (2006) and Sanchez-Luque et al. (2019) show that a given L1 locus can exhibit internal sequence variation leading to differences in retrotransposition activity between individuals.
Swergold, G. D. Identification, characterization, and cell specificity of a human LINE-1 promoter. Mol. Cell. Biol. 10, 6718–6729 (1990).
Thompson, P. J., Macfarlan, T. S. & Lorincz, M. C. Long terminal repeats: from parasitic elements to building blocks of the transcriptional regulatory repertoire. Mol. Cell 62, 766–776 (2016).
Mighell, A. J., Markham, A. F. & Robinson, P. A. Alu sequences. FEBS Lett. 417, 1–5 (1997).
Hancks, D. C., Ewing, A. D., Chen, J. E., Tokunaga, K. & Kazazian, H. H. Exon-trapping mediated by the human retrotransposon SVA. Genome Res. 19, 1983–1991 (2009).
Honigman, A., Bar-Shira, A., Silberberg, H. & Panet, A. Generation of a uniform 3’ end RNA of murine leukemia virus. J. Virol. 53, 330–334 (1985).
Dombroski, B. A., Mathias, S. L., Nanthakumar, E., Scott, A. F. & Kazazian, H. H. Isolation of an active human transposable element. Science 254, 1805–1808 (1991).
Conti, A. et al. Identification of RNA polymerase III-transcribed Alu loci by computational screening of RNA-Seq data. Nucleic Acids Res. 43, 817–835 (2014).
Holmes, S. E., Dombroski, B. A., Krebs, C. M., Boehm, C. D. & Kazazian, H. H. A new retrotransposable human L1 element from the LRE2 locus on chromosome 1q produces a chimaeric insertion. Nat. Genet. 7, 143–148 (1994).
Moran, J. V., DeBerardinis, R. J. & Kazazian, H. H. Exon shuffling by L1 retrotransposition. Science 283, 1530–1534 (1999).
McKerrow, W. & Fenyö, D. L1EM: A tool for accurate locus specific LINE-1 RNA quantification. Bioinformatics 544, 115 (2019).
Pickeral, O. K., Makałowski, W., Boguski, M. S. & Boeke, J. D. Frequent human genomic DNA transduction driven by LINE-1 retrotransposition. Genome Res. 10, 411–415 (2000).
Goodier, J. L., Ostertag, E. M. & Kazazian, H. H. Transduction of 3’-flanking sequences is common in L1 retrotransposition. Hum. Mol. Genet. 9, 653–657 (2000).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Evrony, G. D. et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151, 483–496 (2012).
Damert, A. et al. 5’-Transducing SVA retrotransposon groups spread efficiently throughout the human genome. Genome Res. 19, 1992–2008 (2009).
Eickbush, D. G. & Eickbush, T. H. R2 retrotransposons encode a self-cleaving ribozyme for processing from an rRNA cotranscript. Mol. Cell. Biol. 30, 3142–3150 (2010).
Perepelitsa-Belancio, V. & Deininger, P. RNA truncation by premature polyadenylation attenuates human mobile element activity. Nat. Genet. 35, 363–366 (2003).
Schrom, E.-M., Moschall, R., Schuch, A. & Bodem, J. Regulation of retroviral polyadenylation. Adv. Virus Res. 85, 1–24 (2013).
Belancio, V. P., Hedges, D. J. & Deininger, P. LINE-1 RNA splicing and influences on mammalian gene expression. Nucleic Acids Res. 34, 1512–1521 (2006).
Teixeira, F. K. et al. PiRNA-mediated regulation of transposon alternative splicing in the soma and germ line. Nature 552, 268–272 (2017).
Kines, K. J., Sokolowski, M., DeHaro, D. L., Christian, C. M. & Belancio, V. P. Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci. Nucleic Acids Res. 42, 10488–10502 (2014).
Saha, A. et al. A trans-dominant form of Gag restricts Ty1 retrotransposition and mediates copy number control. J. Virol. 89, 3922–3938 (2015).
Speek, M. Antisense promoter of human L1 retrotransposon drives transcription of adjacent cellular genes. Mol. Cell. Biol. 21, 1973–1985 (2001).
Cruickshanks, H. A. & Tufarelli, C. Isolation of cancer-specific chimeric transcripts induced by hypomethylation of the LINE-1 antisense promoter. Genomics 94, 397–406 (2009).
Weber, B., Kimhi, S., Howard, G., Eden, A. & Lyko, F. Demethylation of a LINE-1 antisense promoter in the cMet locus impairs Met signalling through induction of illegitimate transcription. Oncogene 29, 5775–5784 (2010).
Li, J. et al. An antisense promoter in mouse L1 retrotransposon open reading frame-1 initiates expression of diverse fusion transcripts and limits retrotransposition. Nucleic Acids Res. 42, 4546–4562 (2014).
Denli, A. M. et al. Primate-specific ORF0 contributes to retrotransposon-mediated diversity. Cell 163, 583–593 (2015). This is first study to use mass spectrometry data on a large scale to identify unknown TE chimeric proteins.
Russo, J., Harrington, A. W. & Steiniger, M. Antisense transcription of retrotransposons in Drosophila: an origin of endogenous small interfering RNA precursors. Genetics 202, 107–121 (2016).
Harrington, A. W. & Steiniger, M. Bioinformatic analyses of sense and antisense expression from terminal inverted repeat transposons in Drosophila somatic cells. FLY 10, 1–10 (2016).
Zingler, N. et al. Analysis of 5' junctions of human LINE-1 and Alu retrotransposons suggests an alternative model for 5'-end attachment requiring microhomology-mediated end-joining. Genome Res. 15, 780–789 (2005).
Suzuki, J. et al. Genetic evidence that the non-homologous end-joining repair pathway is involved in LINE retrotransposition. PLoS Genet. 5, e1000461 (2009).
Larson, P. A. et al. Spliced integrated retrotransposed element (SpIRE) formation in the human genome. PLoS Biol. 16, e2003067 (2018).
Penzkofer, T. et al. L1Base 2 - more retrotransposition-active LINE-1s, more mammalian genomes. Nucleic Acids Res. 45, D68–D73 (2017).
Wirth, T., Glöggler, K., Baumruker, T., Schmidt, M. & Horak, I. Family of middle repetitive DNA sequences in the mouse genome with structural features of solitary retroviral long terminal repeats. Proc. Natl Acad. Sci. USA 80, 3327–3330 (1983).
Mager, D. L. & Goodchild, N. L. Homologous recombination between the LTRs of a human retrovirus-like element causes a 5-kb deletion in two siblings. Am. J. Hum. Genet. 45, 848–854 (1989).
Vitte, C. & Panaud, O. Formation of solo-LTRs through unequal homologous recombination counterbalances amplifications of LTR retrotransposons in rice Oryza sativa L. Mol. Biol. Evol. 20, 528–540 (2003).
Cossu, R. M. et al. LTR Retrotransposons show low levels of unequal recombination and high rates of intraelement gene conversion in large plant genomes. Genome Biol. Evol. 9, 3449–3462 (2017).
Rebollo, R., Farivar, S. & Mager, D. L. C-GATE - catalogue of genes affected by transposable elements. Mob. DNA 3, 9 (2012).
Kelley, D. & Rinn, J. Transposable elements reveal a stem cell-specific class of long noncoding RNAs. Genome Biol. 13, R107 (2012).
Kapusta, A. et al. Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs. PLoS Genet. 9, e1003470 (2013). Kapusta et al. (2013) and Kelley and Rinn (2012) discovered that a large fraction of lncRNA derives from TEs in vertebrates.
Lu, X. et al. The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity. Nat. Struct. Mol. Biol. 21, 423–425 (2014).
Wang, J. et al. Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells. Nature 516, 405–409 (2014).
Izsvák, Z., Wang, J., Singh, M., Mager, D. L. & Hurst, L. D. Pluripotency and the endogenous retrovirus HERVH: conflict or serendipity? BioEssays 38, 109–117 (2015).
Deininger, P. et al. A comprehensive approach to expression of L1 loci. Nucleic Acids Res. 45, e31 (2017).
Navarro, F. C. P. et al. TeXP: Deconvolving the effects of pervasive and autonomous transcription of transposable elements. PLoS Comput. Biol. 15, e1007293 (2019).
Jensen, T. H., Jacquier, A. & Libri, D. Dealing with pervasive transcription. Mol. Cell 52, 473–484 (2013).
Lee, H., Zhang, Z. & Krause, H. M. Long noncoding RNAs and repetitive elements: junk or intimate evolutionary partners? Trends Genet. 35, 892–902 (2019).
Kim, T.-K., Hemberg, M. & Gray, J. M. Enhancer RNAs: a class of long noncoding RNAs synthesized at enhancers. Cold Spring Harb. Perspect. Biol. 7, a018622 (2015).
Wassenegger, M., Heimes, S., Riedel, L. & Sänger, H. L. RNA-directed de novo methylation of genomic sequences in plants. Cell 76, 567–576 (1994).
Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).
Yang, N. & Kazazian, H. H. L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nat. Struct. Mol. Biol. 13, 763–771 (2006).
Slotkin, R. K. et al. Epigenetic reprogramming and small RNA silencing of transposable elements in pollen. Cell 136, 1451–1454 (2009).
Heras, S. R. et al. The Microprocessor controls the activity of mammalian retrotransposons. Nat. Struct. Mol. Biol. 20, 1173–1181 (2013).
Cuerda-Gil, D. & Slotkin, R. K. Non-canonical RNA-directed DNA methylation. Nat. Plants 2, 567–568 (2016).
van de Lagemaat, L. N., Medstrand, P. & Mager, D. L. Multiple effects govern endogenous retrovirus survival patterns in human gene introns. Genome Biol. 7, R86 (2006).
Berrens, R. V. et al. An endosiRNA-based repression mechanism counteracts transposon activation during global DNA demethylation in embryonic stem cells. Stem Cell 21, 694–703.e7 (2017).
Gong, C., Tang, Y. & Maquat, L. E. mRNA-mRNA duplexes that autoelicit Staufen1-mediated mRNA decay. Nat. Struct. Mol. Biol. 20, 1214–1222 (2013).
Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015).
Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015).
Skowronski, J. & Singer, M. F. Expression of a cytoplasmic LINE-1 transcript is regulated in a human teratocarcinoma cell line. Proc. Natl Acad. Sci. USA 82, 6050–6054 (1985).
Belancio, V. P., Roy-Engel, A. M., Pochampally, R. R. & Deininger, P. Somatic expression of LINE-1 elements in human tissues. Nucleic Acids Res. 38, 3909–3922 (2010). Together with Deininger et al. (2017), this work shows that most of the L1 RNA detected in somatic cells is not unit-length RNA but is rather truncated L1 RNA or derives from co-transcription or pervasive transcription.
Morillon, A., Bénard, L., Springer, M. & Lesage, P. Differential effects of chromatin and Gcn4 on the 50-fold range of expression among individual yeast Ty1 retrotransposons. Mol. Cell. Biol. 22, 2078–2088 (2002).
Slotkin, R. K. & Martienssen, R. Transposable elements and the epigenetic regulation of the genome. Nat. Rev. Genet. 8, 272–285 (2007).
Pizarro, J. G. & Cristofari, G. Post-transcriptional control of LINE-1 retrotransposition by cellular host factors in somatic cells. Front. Cell Dev. Biol. 4, 14 (2016).
Goodier, J. L. Restricting retrotransposons: a review. Mob. DNA 7, 344 (2016).
Schorn, A. J., Gutbrod, M. J., LeBlanc, C. & Martienssen, R. LTR-retrotransposon control by tRNA-derived small RNAs. Cell 170, 61–71.e11 (2017).
Hohjoh, H. & Singer, M. F. Cytoplasmic ribonucleoprotein complexes containing human LINE-1 protein and RNA. EMBO J. 15, 630–639 (1996).
Biczysko, W., Pienkowski, M., Solter, D. & Koprowski, H. Virus particles in early mouse embryos. J. Natl Cancer Inst. 51, 1041–1050 (1973).
Kulpa, D. A. & Moran, J. V. Ribonucleoprotein particle formation is necessary but not sufficient for LINE-1 retrotransposition. Hum. Mol. Genet. 14, 3237–3248 (2005).
Grow, E. J. et al. Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature 522, 221–225 (2015).
Seifarth, W. et al. Comprehensive analysis of human endogenous retrovirus transcriptional activity in human tissues with a retrovirus-specific microarray. J. Virol. 79, 341–352 (2005).
Picault, N. et al. Identification of an active LTR retrotransposon in rice. Plant. J. 58, 754–765 (2009).
Horard, B. et al. Global analysis of DNA methylation and transcription of human repetitive sequences. Epigenetics 4, 339–350 (2009).
Reichmann, J. et al. Microarray analysis of LTR retrotransposon silencing identifies Hdac1 as a regulator of retrotransposon expression in mouse embryonic stem cells. PLoS Comput. Biol. 8, e1002486 (2012).
Gnanakkan, V. P. et al. TE-array–a high throughput tool to study transposon transcription. BMC Genomics 14, 869 (2013).
Faulkner, G. J. et al. A rescue strategy for multimapping short sequence tags refines surveys of transcriptional activity by CAGE. Genomics 91, 281–288 (2008).
Chung, N. et al. Transcriptome analyses of tumor-adjacent somatic tissues reveal genes co-expressed with transposable elements. Mob. DNA 10, 15 (2019). Chung et al. (2019) and McKerrow and Fenyö (2019) propose strategies based on the EM algorithm to discriminate and quantify TE transcript types.
Sexton, C. E. & Han, M. V. Paired-end mappability of transposable elements in the human genome. Mob. DNA 10, 29 (2019).
Teissandier, A., Servant, N., Barillot, E. & Bourc’his, D. Tools and best practices for retrotransposon analysis using high-throughput sequencing data. Mob. DNA 10, 52 (2019).
Bao, W., Kojima, K. K. & Kohany, O. Repbase update, a database of repetitive elements in eukaryotic genomes. Mob. DNA 6, 11 (2015).
Lerat, E., Fablet, M., Modolo, L., Lopez-Maestre, H. & Vieira, C. TEtools facilitates big data expression analysis of transposable elements and reveals an antagonism between their activity and that of piRNA genes. Nucleic Acids Res. 45, 1–12 (2017).
Romero-Soriano, V. et al. Transposable element misregulation is linked to the divergence between parental piRNA pathways in Drosophila hybrids. Genome Biol. Evol. 9, 1450–1470 (2017).
Zeng, Z. et al. Genome-wide DNA methylation and transcriptomic profiles in the lifestyle strategies and asexual development of the forest fungal pathogen Heterobasidion parviporum. Epigenetics 14, 16–40 (2019).
Song, H. et al. Rapid evolution of piRNA pathway and its transposon targets in Japanese flounder (Paralichthys olivaceus). Comp. Biochem. Physiol. Part. D Genomics Proteom. 31, 100609 (2019).
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
Trapnell, C., Pachter, L. & Salzberg, S. L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009).
Dobin, A. et al. STAR - ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
Criscione, S. W., Zhang, Y., Thompson, W., Sedivy, J. M. & Neretti, N. Transcriptional landscape of repetitive elements in normal and cancer human cells. BMC Genomics 15, 583 (2014).
Yang, W. R., Ardeljan, D., Pacyna, C. N., Payer, L. M. & Burns, K. H. SQuIRE reveals locus-specific regulation of interspersed repeat expression. Nucleic Acids Res. 47, e27 (2019).
Valdebenito-Maturana, B. & Riadi, G. TEcandidates: prediction of genomic origin of expressed transposable elements using RNA-seq data. Bioinformatics 34, 3915–3916 (2018).
Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinforma. 12, 323 (2011).
Jin, Y., Tam, O. H., Paniagua, E. & Hammell, M. TEtranscripts: a package for including transposable elements in differential expression analysis of RNA-seq datasets. Bioinformatics 31, 3593–3599 (2015). TEtranscripts is the first application of the EM algorithm to TE RNA-seq analyses, and one of the most popular software packages dedicated to this task since its release.
Bendall, M. L. et al. Telescope: characterization of the retrotranscriptome by accurate estimation of transposable element expression. PLoS Comput. Biol. 15, e1006453 (2019).
Bray, N. L., Pimentel, H., Melsted, P. & Pachter, L. Near-optimal probabilistic RNA-seq quantification. Nat. Biotechnol. 34, 525–527 (2016).
Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017).
Jeong, H.-H., Yalamanchili, H. K., Guo, C., Shulman, J. M. & Liu, Z. An ultra-fast and scalable quantification pipeline for transposable elements from next generation sequencing data. Pac. Symp. Biocomput. 23, 168–179 (2018).
Kong, Y. et al. Transposable element expression in tumors is associated with immune infiltration and increased antigenicity. Nat. Commun. 10, 5228 (2019).
Philippe, C. et al. Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci. eLife 5, 166 (2016). This study proposes the first strategy to profile the expression of reference and non-reference L1 elements at the locus level by integrating targeted resequencing of L1 elements (ATLAS sequencing), RNA-seq data and ChIP–seq data.
Ewing, A. D. Transposable element detection from whole genome sequence data. Mob. DNA 6, 24 (2015).
Mir, A. A., Philippe, C. & Cristofari, G. euL1db: the European database of L1HS retrotransposon insertions in humans. Nucleic Acids Res. 43, D43–D47 (2015).
Tokuyama, M. et al. ERVmap analysis reveals genome-wide transcription of human endogenous retroviruses. Proc. Natl Acad. Sci. USA 115, 12565–12572 (2018).
Ansaloni, F., Scarpato, M., Di Schiavi, E., Gustincich, S. & Sanges, R. Exploratory analysis of transposable elements expression in the C. elegans early embryo. BMC Bioinforma. 20, 484 (2019).
Kaul, T., Morales, M. E., Sartor, A. O., Belancio, V. P. & Deininger, P. Comparative analysis on the expression of L1 loci using various RNA-Seq preparations. Mob. DNA 11, 860 (2020).
Faulkner, G. J. et al. The regulated retrotransposon transcriptome of mammalian cells. Nat. Genet. 41, 563–571 (2009). This article offers the first genome-wide description of TE transcription across multiple tissues using CAGE data from the PHANTOM project.
Brocks, D. et al. DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats. Nat. Genet. 49, 1052–1060 (2017).Brocks et al. (2017), Roulois et al. (2015) and Chiappinelli et al. (2015) reveal mechanisms by which the reactivation of TE with drugs targeting epigenetic pathways can kill cancer cells.
Batut, P., Dobin, A., Plessy, C., Carninci, P. & Gingeras, T. R. High-fidelity promoter profiling reveals widespread alternative promoter usage and transposon-driven developmental gene expression. Genome Res. 23, 169–180 (2013).
Rangwala, S. H., Zhang, L. & Kazazian, H. H. Many LINE1 elements contribute to the transcriptome of human somatic cells. Genome Biol. 10, R100 (2009).
Macia, A. et al. Epigenetic control of retrotransposon expression in human embryonic stem cells. Mol. Cell. Biol. 31, 300–316 (2011).
Lock, F. E. et al. Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma. Proc. Natl Acad. Sci. USA 111, E3534–E3543 (2014).
Morgan, H. D., Sutherland, H. G., Martin, D. I. & Whitelaw, E. Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet. 23, 314–318 (1999).
Wheelan, S. J., Aizawa, Y., Han, J. S. & Boeke, J. D. Gene-breaking: a new paradigm for human retrotransposon-mediated gene evolution. Genome Res. 15, 1073–1078 (2005).
Shen, S. et al. Widespread establishment and regulatory impact of Alu exons in human genes. Proc. Natl Acad. Sci. USA 108, 2837–2842 (2011).
Butelli, E. et al. Retrotransposons control fruit-specific, cold-dependent accumulation of anthocyanins in blood oranges. Plant. Cell 24, 1242–1255 (2012).
Ong-Abdullah, M. et al. Loss of Karma transposon methylation underlies the mantled somaclonal variant of oil palm. Nature 525, 533–537 (2015).
Barau, J. et al. The DNA methyltransferase DNMT3C protects male germ cells from transposon activity. Science 354, 909–912 (2016).
Attig, J. et al. LTR retroelement expansion of the human cancer transcriptome and immunopeptidome revealed by de novo transcript assembly. Genome Res. 29, 1578–1590 (2019).
Jang, H. S. et al. Transposable elements drive widespread expression of oncogenes in human cancers. Nat. Genet. 51, 611–617 (2019). Attig et al. (2019) and Jang et al. (2019) provides a systematic review of tumour-specific transcripts and antigens derived from TEs.
Nigumann, P., Redik, K., Mätlik, K. & Speek, M. Many human genes are transcribed from the antisense promoter of L1 retrotransposon. Genomics 79, 628–634 (2002).
Peaston, A. E. et al. Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos. Dev. Cell 7, 597–606 (2004).
Lipatov, M., Lenkov, K., Petrov, D. A. & Bergman, C. M. Paucity of chimeric gene-transposable element transcripts in the Drosophila melanogaster genome. BMC Biol. 3, 24 (2005).
Ha, H.-S. et al. Identification and characterization of transposable element-mediated chimeric transcripts from porcine Refseq and EST databases. Genes. Genom. 34, 409–414 (2012).
Criscione, S. W. et al. Genome-wide characterization of human L1 antisense promoter-driven transcripts. BMC Genomics 17, 463 (2016).
Pinson, M.-E., Pogorelcnik, R., Court, F., Arnaud, P. & Vaurs-Barrière, C. CLIFinder: identification of LINE-1 chimeric transcripts in RNA-seq data. Bioinformatics 34, 688–690 (2017).
Babaian, A. et al. LIONS: analysis suite for detecting and quantifying transposable element initiated transcription from RNA-seq. Bioinformatics 35, 3839–3841 (2019).
Wang, T. et al. A novel analytical strategy to identify fusion transcripts between repetitive elements and protein coding-exons using RNA-Seq. PLoS One 11, e0159028 (2016).
Larrosa, R., Arroyo, M., Bautista, R., López-Rodríguez, C. M. & Claros, M. G. NearTrans can identify correlated expression changes between retrotransposons and surrounding genes in human cancer. Bioinforma. Biomed. Eng. 10813, 373–382 (2018).
Karakülah, G., Arslan, N., Yandin, C. & Suner, A. TEffectR: an R package for studying the potential effects of transposable elements on gene expression with linear regression model. PeerJ 7, e8192 (2019).
Decker, C. J. et al. dsRNA-Seq: identification of viral infection by purifying and sequencing dsRNA. Viruses 11, 943 (2019).
Castel, S. E. & Martienssen, R. A. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat. Rev. Genet. 14, 100–112 (2013).
Johnson, N. R., Yeoh, J. M., Coruh, C. & Axtell, M. J. Improved placement of multi-mapping small RNAs. G3 6, 2103–2111 (2016).
Bousios, A., Gaut, B. S. & Darzentas, N. Considerations and complications of mapping small RNA high-throughput data to transposable elements. Mob. DNA 8, 3 (2017).
Garrison, E. et al. Variation graph toolkit improves read mapping by representing genetic variation in the reference. Nat. Biotechnol. 36, 875–879 (2018).
Rakocevic, G. et al. Fast and accurate genomic analyses using genome graphs. Nat. Genet. 51, 354–362 (2019).
Kim, D., Paggi, J. M., Park, C., Bennett, C. & Salzberg, S. L. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat. Biotechnol. 37, 907–915 (2019).
Sherman, R. M. & Salzberg, S. L. Pan-genomics in the human genome era. Nat. Rev. Genet. 21, 243–254 (2020).
Maringer, K. et al. Proteomics informed by transcriptomics for characterising active transposable elements and genome annotation in Aedes aegypti. BMC Genomics 18, 101 (2017).
Davidson, A. D., Matthews, D. A. & Maringer, K. Proteomics technique opens new frontiers in mobilome research. Mob. Genet. Elem. 7, 1–9 (2017).
Ardeljan, D. et al. LINE-1 ORF2p expression is nearly imperceptible in human cancers. Mob. DNA 11, 1–19 (2019).
Brocks, D., Chomsky, E., Mukamel, Z., Lifshitz, A. & Tanay, A. Single cell analysis reveals dynamics of transposable element transcription following epigenetic de-repression. BioRxiv https://doi.org/10.1101/462853 (2019).
Shahid, S. & Slotkin, R. K. The current revolution in transposable element biology enabled by long reads. Curr. Opin. Genet. Dev. 54, 49–56 (2020).
Jiang, F. et al. Long-read direct RNA sequencing by 5’-cap capturing reveals the impact of Piwi on the widespread exonization of transposable elements in locusts. RNA Biol. 16, 950–959 (2019). This study provides the first use of direct RNA-seq by Oxford Nanopore technology to characterize the impact of TE transcription on the transcriptome of a non-model organism.
Debladis, E., Llauro, C., Carpentier, M.-C., Mirouze, M. & Panaud, O. Detection of active transposable elements in Arabidopsis thaliana using Oxford Nanopore sequencing technology. BMC Genomics 18, 537 (2017).
Zhou, W. et al. Identification and characterization of occult human-specific LINE-1 insertions using long-read sequencing technology. Nucleic Acids Res. 409, 860 (2019).
Wu, T. P. et al. DNA methylation on N6-adenine in mammalian embryonic stem cells. Nature 532, 329–333 (2016).
Simpson, J. T. et al. Detecting DNA cytosine methylation using nanopore sequencing. Nat. Methods 14, 407–410 (2017).
Liu, Q. et al. Detection of DNA base modifications by deep recurrent neural network on Oxford Nanopore sequencing data. Nat. Commun. 10, 2449 (2019).
Liu, Q., Georgieva, D. C., Egli, D. & Wang, K. NanoMod: a computational tool to detect DNA modifications using Nanopore long-read sequencing data. BMC Genomics 20, 78 (2019).
Kutter, C., Jern, P. & Suh, A. Bridging gaps in transposable element research with single-molecule and single-cell technologies. Mob. DNA 9, 34 (2018).
Salk, J. J., Schmitt, M. W. & Loeb, L. A. Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat. Rev. Genet. 19, 269–285 (2018).
Slotkin, R. K. The case for not masking away repetitive DNA. Mob. DNA 9, 15 (2018).
Finnegan, D. J. Eukaryotic transposable elements and genome evolution. Trends Genet. 5, 103–107 (1989).
Wicker, T. et al. A unified classification system for eukaryotic transposable elements. Nat. Rev. Genet. 8, 973–982 (2007).
Piégu, B., Bire, S., Arensburger, P. & Bigot, Y. A survey of transposable element classification systems–a call for a fundamental update to meet the challenge of their diversity and complexity. Mol. Phylogenet. Evol. 86, 90–109 (2015).
Curcio, M. J. & Derbyshire, K. M. The outs and ins of transposition: from mu to kangaroo. Nat. Rev. Mol. Cell Biol. 4, 865–877 (2003).
Hubley, R. et al. The Dfam database of repetitive DNA families. Nucleic Acids Res. 44, D81–D89 (2016).
Amselem, J. et al. RepetDB: a unified resource for transposable element references. Mob. DNA 10, 6–8 (2019).
Herquel, B. et al. Trim24-repressed VL30 retrotransposons regulate gene expression by producing noncoding RNA. Nat. Struct. Mol. Biol. 20, 339–346 (2013).
Fadloun, A. et al. Chromatin signatures and retrotransposon profiling in mouse embryos reveal regulation of LINE-1 by RNA. Nat. Struct. Mol. Biol. 20, 332–338 (2013).
Derrien, T. et al. Fast computation and applications of genome mappability. PLoS One 7, e30377 (2012).
Karimzadeh, M., Ernst, C., Kundaje, A. & Hoffman, M. M. Umap and Bismap: quantifying genome and methylome mappability. Nucleic Acids Res. 46, e120 (2018).
Acknowledgements
The authors apologize to the many colleagues who have made significant contributions to the field but whose work could not be cited or discussed owing to space limitations. The authors are grateful to P. A. Defossez and A. Doucet for critical reading of the manuscript. This work was supported by grants to G.C. from the Fondation pour la Recherche Médicale (DEQ20180339170), the Agence Nationale de la Recherche (LABEX SIGNALIFE, ANR-11-LABX-0028-01; RetroMet, ANR-16-CE12-0020; ImpacTE, ANR-19-CE12-0032), the Canceropôle Provence–Alpes–Côte d’Azur, the French National Cancer Institute (INCa) and the Provence–Alpes–Côte d’Azur Region, CNRS (GDR 3546), and the University Hospital Federation (FHU) OncoAge.
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G.C. is an unpaid associate editor of the journal Mobile DNA (Springer Nature). S.L. declares no competing interests.
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Glossary
- Autonomous TE unit transcription
-
TE transcription driven by its own internal promoter.
- Chimeric transcripts
-
Transcripts containing both TE and non-TE (typically a gene) sequences.
- Co-transcription
-
Intronic TE expression through the expression of its surrounding gene without the implication of the promoter activity of the TE. Synonymous with ‘readthrough transcription’.
- Polymorphic
-
A term often used for TE insertional polymorphisms, whereby a TE insertion can be present or absent at a given locus or allele in a subset of individuals from the same species.
- Positive selection
-
A type of natural selection that promotes the spread of a beneficial trait or genetic variant within a given population.
- Long terminal repeat (LTR) retrotransposons
-
A class of retrotransposons that contains two long repeated sequences in direct orientation at both ends.
- TE unit-length transcripts
-
Full-length TE transcripts that can serve as a template for reverse transcription to produce a new intact copy.
- Pervasive transcription
-
Transcription of regions well beyond the boundaries of known genes.
- Multimappers
-
Sequencing reads that map ambiguously at multiple locations in the reference genome.
- Unimappers
-
Sequencing reads that can map non-ambiguously to a single location in the reference genome.
- k-mers
-
Short sequences with a length of k bases.
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Lanciano, S., Cristofari, G. Measuring and interpreting transposable element expression. Nat Rev Genet 21, 721–736 (2020). https://doi.org/10.1038/s41576-020-0251-y
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DOI: https://doi.org/10.1038/s41576-020-0251-y
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