Skip to main content

Advertisement

SpringerLink
Log in

Integration site selection by retroviruses and transposable elements in eukaryotes

  • Review Article
  • Published:

From Nature Reviews Genetics

View current issue Sign up to alerts

Key Points

  • The non-random distribution of transposable elements (TEs) in eukaryotic genomes is the consequence of both TE integration site preferences and post-integration selection processes.

  • Next-generation sequencing approaches and experimentally induced de novo TE mobilization are pivotal for investigating the mechanisms of TE integration site preference.

  • Chromatin structure and spatial organization in the nucleus contribute to the efficiency and/or selectivity of TE integration.

  • Mobilization machineries are often tethered to specific chromatin states by a variety of host factors that determine the favoured insertion sites.

  • Target site preference is part of TE–host co-adaptation strategies that lead to TE repression or reactivation, which potentially results in rapid host adaptation or pathogenicity.

Abstract

Transposable elements and retroviruses are found in most genomes, can be pathogenic and are widely used as gene-delivery and functional genomics tools. Exploring whether these genetic elements target specific genomic sites for integration and how this preference is achieved is crucial to our understanding of genome evolution, somatic genome plasticity in cancer and ageing, host–parasite interactions and genome engineering applications. High-throughput profiling of integration sites by next-generation sequencing, combined with large-scale genomic data mining and cellular or biochemical approaches, has revealed that the insertions are usually non-random. The DNA sequence, chromatin and nuclear context, and cellular proteins cooperate in guiding integration in eukaryotic genomes, leading to a remarkable diversity of insertion site distribution and evolutionary strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1: Accumulation of transposable elements in genomes results from the balance between transposable element integration site preference and post-integration selection processes.
Figure 2: Principles of insertion profiling by deep sequencing.
Figure 3: Extended tethering scheme.
Figure 4: Models of the regulation of integration site selection.
Figure 5: Multiple factors influence integration site selection.

Similar content being viewed by others

References

  1. Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science 351, 1083–1087 (2016). This study experimentally demonstrates the importance of retroelements in rewiring a gene network crucial for innate immunity and antiviral defence during mammalian evolution.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Goodier, J. L. Retrotransposition in tumors and brains. Mob. DNA 5, 11 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Brodeur, G. M., Sandmeyer, S. B. & Olson, M. V. Consistent association between sigma elements and tRNA genes in yeast. Proc. Natl Acad. Sci. USA 80, 3292–3296 (1983).

    Article  CAS  PubMed  Google Scholar 

  4. Burke, W. D., Calalang, C. C. & Eickbush, T. H. The site-specific ribosomal insertion element type II of Bombyx mori (R2Bm) contains the coding sequence for a reverse transcriptase-like enzyme. Mol. Cell. Biol. 7, 2221–2230 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Xiong, Y. & Eickbush, T. H. The site-specific ribosomal DNA insertion element R1Bm belongs to a class of non-long-terminal-repeat retrotransposons. Mol. Cell. Biol. 8, 114–123 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schröder, A. R. et al. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110, 521–529 (2002).

    Article  PubMed  Google Scholar 

  7. Bushman, F. et al. Genome-wide analysis of retroviral DNA integration. Nat. Rev. Microbiol. 3, 848–858 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Hacein-Bey-Abina, S. et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302, 415–419 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Campos-Sánchez, R., Kapusta, A., Feschotte, C., Chiaromonte, F. & Makova, K. D. Genomic landscape of human, bat, and ex vivo DNA transposon integrations. Mol. Biol. Evol. 31, 1816–1832 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Quadrana, L. et al. The Arabidopsis thaliana mobilome and its impact at the species level. eLife 5, e15716 (2016). This work offers a population-scale and genome-wide analysis of TE distribution in A. thaliana genomes and shows how TE distribution affects adaptive responses to climate.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Wagstaff, B. J. et al. Rescuing Alu: recovery of new inserts shows LINE-1 preserves Alu activity through A-tail expansion. PLoS Genet. 8, e1002842 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Brady, T. et al. Integration target site selection by a resurrected human endogenous retrovirus. Genes Dev. 23, 633–642 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Heidmann, T., Heidmann, O. & Nicolas, J. F. An indicator gene to demonstrate intracellular transposition of defective retroviruses. Proc. Natl Acad. Sci. USA 85, 2219–2223 (1988).

    Article  CAS  PubMed  Google Scholar 

  15. Baller, J. A., Gao, J., Stamenova, R., Curcio, M. J. & Voytas, D. F. A nucleosomal surface defines an integration hotspot for the Saccharomyces cerevisiae Ty1 retrotransposon. Genome Res. 22, 704–713 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mularoni, L. et al. Retrotransposon Ty1 integration targets specifically positioned asymmetric nucleosomal DNA segments in tRNA hotspots. Genome Res. 22, 693–703 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. de Jong, J., Wessels, L. F. A., van Lohuizen, M., de Ridder, J. & Akhtar, W. Applications of DNA integrating elements: facing the bias bully. Mob. Genet. Elements 4, 1–6 (2014).

    Article  PubMed  Google Scholar 

  18. Li, X. et al. A resurrected mammalian hAT transposable element and a closely related insect element are highly active in human cell culture. Proc. Natl Acad. Sci. USA 110, E478–E487 (2013).

    Article  PubMed  Google Scholar 

  19. Ji, H. et al. Hotspots for unselected Ty1 transposition events on yeast chromosome III are near tRNA genes and LTR sequences. Cell 73, 1007–1018 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Gilbert, N., Lutz, S. & Moran, J. V. Multiple fates of L1 retrotransposition intermediates in cultured human cells. Mol. Cell. Biol. 25, 7780–7795 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mitchell, R. S. et al. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol. 2, E234 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chatterjee, A. G. et al. Serial number tagging reveals a prominent sequence preference of retrotransposon integration. Nucleic Acids Res. 42, 8449–8460 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hickey, A. et al. Single-nucleotide-specific targeting of the Tf1 retrotransposon promoted by the DNA-binding protein Sap1 of Schizosaccharomyces pombe. Genetics 201, 905–924 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Philippe, C. et al. Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci. eLife 5, e13926 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Berry, C. C. et al. Estimating abundances of retroviral insertion sites from DNA fragment length data. Bioinformatics 28, 755–762 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hacein-Bey-Abina, S. et al. A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. N. Engl. J. Med. 371, 1407–1417 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Maldarelli, F. et al. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 345, 179–183 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cherry, J. M. et al. Saccharomyces Genome Database: the genomics resource of budding yeast. Nucleic Acids Res. 40, D700–D705 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

  30. Baller, J. A., Gao, J. & Voytas, D. F. Access to DNA establishes a secondary target site bias for the yeast retrotransposon Ty5. Proc. Natl Acad. Sci. USA 108, 20351–20356 (2011).

    Article  PubMed  Google Scholar 

  31. Ciuffi, A. et al. Methods for integration site distribution analyses in animal cell genomes. Methods 47, 261–268 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Gogol-Döring, A. et al. Genome-wide profiling reveals remarkable parallels between insertion site selection properties of the MLV retrovirus and the piggyBac transposon in primary human CD4+ T cells. Mol. Ther. 24, 592–606 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fungtammasan, A., Walsh, E., Chiaromonte, F., Eckert, K. A. & Makova, K. D. A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome? Genome Res. 22, 993–1005 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Devine, S. E. & Boeke, J. D. Integration of the yeast retrotransposon Ty1 is targeted to regions upstream of genes transcribed by RNA polymerase III. Genes Dev. 10, 620–633 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Gangadharan, S., Mularoni, L., Fain-Thornton, J., Wheelan, S. J. & Craig, N. L. DNA transposon Hermes inserts into DNA in nucleosome-free regions in vivo. Proc. Natl Acad. Sci. USA 107, 21966–21972 (2010).

    Article  PubMed  Google Scholar 

  36. Ciuffi, A. et al. A role for LEDGF/p75 in targeting HIV DNA integration. Nat. Med. 11, 1287–1289 (2005). This study demonstrates the role of the transcriptional coactivator LEDGF in directing HIV integration into actively transcribed genes by simultaneously binding the viral integrase and host chromatin.

    Article  CAS  PubMed  Google Scholar 

  37. Bridier-Nahmias, A. et al. Retrotransposons. An RNA polymerase III subunit determines sites of retrotransposon integration. Science 348, 585–588 (2015). This study solves the long-standing mystery of how the yeast Ty1 element targets Pol III-transcribed genes.

    Article  CAS  PubMed  Google Scholar 

  38. Jacobs, J. Z. et al. Arrested replication forks guide retrotransposon integration. Science 349, 1549–1553 (2015). References 23 and 38 show that an interaction between the Tf1 integrase and the host protein Sap1, which is involved in replication fork arrest, contributes to the efficiency and the selectivity of Tf1 integration near arrested replication forks and upstream of the promoters of Pol II-transcribed genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Feng, Q., Moran, J. V., Kazazian, H. H. & Boeke, J. D. Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell 87, 905–916 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Yang, J., Malik, H. S. & Eickbush, T. H. Identification of the endonuclease domain encoded by R2 and other site-specific, non-long terminal repeat retrotransposable elements. Proc. Natl Acad. Sci. USA 96, 7847–7852 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Christensen, S. M., Bibillo, A. & Eickbush, T. H. Role of the Bombyx mori R2 element N-terminal domain in the target-primed reverse transcription (TPRT) reaction. Nucleic Acids Res. 33, 6461–6468 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Thompson, B. K. & Christensen, S. M. Independently derived targeting of 28S rDNA by A- and D-clade R2 retrotransposons: plasticity of integration mechanism. Mob. Genet. Elements 1, 29–37 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shivram, H., Cawley, D. & Christensen, S. M. Targeting novel sites: the N-terminal DNA binding domain of non-LTR retrotransposons is an adaptable module that is implicated in changing site specificities. Mob. Genet. Elements 1, 169–178 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Takahashi, H. & Fujiwara, H. Transplantation of target site specificity by swapping the endonuclease domains of two LINEs. EMBO J. 21, 408–417 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yoshitake, K. & Fujiwara, H. Creation of a novel telomere-cutting endonuclease based on the EN domain of telomere-specific non-long terminal repeat retrotransposon, TRAS1. Mob. DNA 1, 13 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Osanai-Futahashi, M. & Fujiwara, H. Coevolution of telomeric repeats and telomeric repeat-specific non-LTR retrotransposons in insects. Mol. Biol. Evol. 28, 2983–2986 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Weichenrieder, O., Repanas, K. & Perrakis, A. Crystal structure of the targeting endonuclease of the human LINE-1 retrotransposon. Structure 12, 975–986 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Maita, N., Anzai, T., Aoyagi, H., Mizuno, H. & Fujiwara, H. Crystal structure of the endonuclease domain encoded by the telomere-specific long interspersed nuclear element, TRAS1. J. Biol. Chem. 279, 41067–41076 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Maita, N., Aoyagi, H., Osanai, M., Shirakawa, M. & Fujiwara, H. Characterization of the sequence specificity of the R1Bm endonuclease domain by structural and biochemical studies. Nucleic Acids Res. 35, 3918–3927 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Repanas, K. et al. Determinants for DNA target structure selectivity of the human LINE-1 retrotransposon endonuclease. Nucleic Acids Res. 35, 4914–4926 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fujiwara, H. Site-specific non-LTR retrotransposons. Microbiol. Spectr. 3, MDNA3-0001-201414 (2015).

    Google Scholar 

  52. Monot, C. et al. The specificity and flexibility of L1 reverse transcription priming at imperfect T-tracts. PLoS Genet. 9, e1003499 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Viollet, S., Monot, C. & Cristofari, G. L1 retrotransposition: the snap-velcro model and its consequences. Mob. Genet. Elements 4, e28907 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Anzai, T., Osanai, M., Hamada, M. & Fujiwara, H. Functional roles of 3′-terminal structures of template RNA during in vivo retrotransposition of non-LTR retrotransposon, R1Bm. Nucleic Acids Res. 33, 1993–2002 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hickman, A. B. & Dyda, F. DNA transposition at work. Chem. Rev. 116, 12758–12784 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Fraser, M. J., Brusca, J. S., Smith, G. E. & Summers, M. D. Transposon-mediated mutagenesis of a baculovirus. Virology 145, 356–361 (1985).

    Article  CAS  PubMed  Google Scholar 

  57. Ivics, Z., Hackett, P. B. & Izsvák, Z. Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell 91, 501–510 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Vigdal, T. J., Kaufman, C. D., Izsvák, Z., Voytas, D. F. & Ivics, Z. Common physical properties of DNA affecting target site selection of Sleeping Beauty and other Tc1/mariner transposable elements. J. Mol. Biol. 323, 441–452 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Serrao, E., Ballandras-Colas, A., Cherepanov, P., Maertens, G. N. & Engelman, A. N. Key determinants of target DNA recognition by retroviral intasomes. Retrovirology 12, 39 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Maertens, G. N., Hare, S. & Cherepanov, P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468, 326–329 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Morris, E. R., Grey, H., McKenzie, G., Jones, A. C. & Richardson, J. M. A bend, flip and trap mechanism for transposon integration. eLife 5, e15537 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Serrao, E. et al. Integrase residues that determine nucleotide preferences at sites of HIV-1 integration: implications for the mechanism of target DNA binding. Nucleic Acids Res. 42, 5164–5176 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Aiyer, S. et al. Structural and sequencing analysis of local target DNA recognition by MLV integrase. Nucleic Acids Res. 43, 5647–5663 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Faye, B. et al. Functional characteristics of a highly specific integrase encoded by an LTR-retrotransposon. PLoS ONE 3, e3185 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Liao, G. C., Rehm, E. J. & Rubin, G. M. Insertion site preferences of the P transposable element in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 97, 3347–3351 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Holman, A. G. & Coffin, J. M. Symmetrical base preferences surrounding HIV-1, avian sarcoma/leukosis virus, and murine leukemia virus integration sites. Proc. Natl Acad. Sci. USA 102, 6103–6107 (2002).

    Article  CAS  Google Scholar 

  67. Linheiro, R. S. & Bergman, C. M. Testing the palindromic target site model for DNA transposon insertion using the Drosophila melanogaster P-element. Nucleic Acids Res. 36, 6199–6208 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Linheiro, R. S. & Bergman, C. M. Whole genome resequencing reveals natural target site preferences of transposable elements in Drosophila melanogaster. PLoS ONE 7, e30008 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wang, G. P., Ciuffi, A., Leipzig, J., Berry, C. C. & Bushman, F. D. HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res. 17, 1186–1194 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Maskell, D. P. et al. Structural basis for retroviral integration into nucleosomes. Nature 523, 366–369 (2015). This is the first study to solve the crystallographic structure of a retroviral integration complex bound to a nucleosome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yin, Z. et al. Crystal structure of the Rous sarcoma virus intasome. Nature 530, 362–366 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ballandras-Colas, A. et al. Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function. Nature 530, 358–361 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kirk, P. D., Huvet, M., Melamed, A., Maertens, G. N. & Bangham, C. R. Retroviruses integrate into a shared, non-palindromic DNA motif. Nat. Microbiol. 2, 16212 (2016).

    Article  CAS  PubMed  Google Scholar 

  74. Voigt, F. et al. Sleeping Beauty transposase structure allows rational design of hyperactive variants for genetic engineering. Nat. Commun. 7, 11126 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Pryciak, P. M. & Varmus, H. E. Nucleosomes, DNA-binding proteins, and DNA sequence modulate retroviral integration target site selection. Cell 69, 769–780 (1992).

    Article  CAS  PubMed  Google Scholar 

  76. Pruss, D., Bushman, F. D. & Wolffe, A. P. Human immunodeficiency virus integrase directs integration to sites of severe DNA distortion within the nucleosome core. Proc. Natl Acad. Sci. USA 91, 5913–5917 (1994).

    Article  CAS  PubMed  Google Scholar 

  77. Benleulmi, M. S. et al. Intasome architecture and chromatin density modulate retroviral integration into nucleosome. Retrovirology 12, 13 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Pasi, M. et al. DNA minicircles clarify the specific role of DNA structure on retroviral integration. Nucleic Acids Res. 44, 7830–7847 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Liu, S. et al. Mu transposon insertion sites and meiotic recombination events co-localize with epigenetic marks for open chromatin across the maize genome. PLoS Genet. 5, e1000733 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Naito, K. et al. Unexpected consequences of a sudden and massive transposon amplification on rice gene expression. Nature 461, 1130–1134 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Guo, Y. & Levin, H. L. High-throughput sequencing of retrotransposon integration provides a saturated profile of target activity in Schizosaccharomyces pombe. Genome Res. 20, 239–248 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lesbats, P. et al. Functional coupling between HIV-1 integrase and the SWI/SNF chromatin remodeling complex for efficient in vitro integration into stable nucleosomes. PLoS Pathog. 7, e1001280 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Naughtin, M. et al. DNA physical properties and nucleosome positions are major determinants of HIV-1 integrase selectivity. PLoS ONE 10, e0129427 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Bachman, N., Eby, Y. & Boeke, J. D. Local definition of Ty1 target preference by long terminal repeats and clustered tRNA genes. Genome Res. 14, 1232–1247 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Taganov, K. D. et al. Integrase-specific enhancement and suppression of retroviral DNA integration by compacted chromatin structure in vitro. J. Virol. 78, 5848–5855 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gelbart, M. E., Bachman, N., Delrow, J., Boeke, J. D. & Tsukiyama, T. Genome-wide identification of Isw2 chromatin-remodeling targets by localization of a catalytically inactive mutant. Genes Dev. 19, 942–954 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dang, V. D. & Levin, H. L. Nuclear import of the retrotransposon Tf1 is governed by a nuclear localization signal that possesses a unique requirement for the FXFG nuclear pore factor Nup124p. Mol. Cell. Biol. 20, 7798–7812 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lin, S. S., Nymark-McMahon, M. H., Yieh, L. & Sandmeyer, S. B. Integrase mediates nuclear localization of Ty3. Mol. Cell. Biol. 21, 7826–7838 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Katz, R. A. et al. Transduction of interphase cells by avian sarcoma virus. J. Virol. 76, 5422–5434 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. McLane, L. M., Pulliam, K. F., Devine, S. E. & Corbett, A. H. The Ty1 integrase protein can exploit the classical nuclear protein import machinery for entry into the nucleus. Nucleic Acids Res. 36, 4317–4326 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Andrake, M. D. et al. Nuclear import of avian sarcoma virus integrase is facilitated by host cell factors. Retrovirology 5, 73 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Levin, A., Loyter, A. & Bukrinsky, M. Strategies to inhibit viral protein nuclear import: HIV-1 as a target. Biochim. Biophys. Acta 1813, 1646–1653 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Lewinski, M. K. et al. Retroviral DNA integration: viral and cellular determinants of target-site selection. PLoS Pathog. 2, e60 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Schaller, T. et al. HIV-1 capsid–cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathog. 7, e1002439 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Koh, Y. et al. Differential effects of human immunodeficiency virus type 1 capsid and cellular factors nucleoporin 153 and LEDGF/p75 on the efficiency and specificity of viral DNA integration. J. Virol. 87, 648–658 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sowd, G. A. et al. A critical role for alternative polyadenylation factor CPSF6 in targeting HIV-1 integration to transcriptionally active chromatin. Proc. Natl Acad. Sci. USA 113, E1054–E1063 (2016).

    Article  CAS  PubMed  Google Scholar 

  97. Varadarajan, P. et al. The functionally conserved nucleoporins Nup124p from fission yeast and the human Nup153 mediate nuclear import and activity of the Tf1 retrotransposon and HIV-1 Vpr. Mol. Biol. Cell 16, 1823–1838 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Irwin, B. et al. Retroviruses and yeast retrotransposons use overlapping sets of host genes. Genome Res. 15, 641–654 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Curcio, M. J., Lutz, S. & Lesage, P. The Ty1 LTR-retrotransposon of budding yeast, Saccharomyces cerevisiae. Microbiol. Spectr. 3, MDNA3-0053-2014 (2015).

    PubMed  Google Scholar 

  100. Beliakova-Bethell, N. et al. Ty3 nuclear entry is initiated by viruslike particle docking on GLFG nucleoporins. J. Virol. 83, 11914–11925 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Albanese, A., Arosio, D., Terreni, M. & Cereseto, A. HIV-1 pre-integration complexes selectively target decondensed chromatin in the nuclear periphery. PLoS ONE 3, e2413 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Di Primio, C. et al. Single-cell imaging of HIV-1 provirus (SCIP). Proc. Natl Acad. Sci. USA 110, 5636–5641 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Burdick, R. C., Hu, W. S. & Pathak, V. K. Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes. Proc. Natl Acad. Sci. USA 110, E4780–E4789 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Marini, B. et al. Nuclear architecture dictates HIV-1 integration site selection. Nature 521, 227–231 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Vaquerizas, J. M. et al. Nuclear pore proteins nup153 and megator define transcriptionally active regions in the Drosophila genome. PLoS Genet. 6, e1000846 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lelek, M. et al. Chromatin organization at the nuclear pore favours HIV replication. Nat. Commun. 6, 6483 (2015). References 104 and 106 show that HIV preferentially integrates into actively transcribed genes located near the NPC and demonstrate the contribution of the nucleoporin TPR in this process.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sandmeyer, S. B., Hansen, L. J. & Chalker, D. L. Integration specificity of retrotransposons and retroviruses. Annu. Rev. Genet. 24, 491–518 (1990).

    Article  CAS  PubMed  Google Scholar 

  108. Zou, S., Ke, N., Kim, J. M. & Voytas, D. F. The Saccharomyces retrotransposon Ty5 integrates preferentially into regions of silent chromatin at the telomeres and mating loci. Genes Dev. 10, 634–645 (1996).

    Article  CAS  PubMed  Google Scholar 

  109. De Rijck, J., Bartholomeeusen, K., Ceulemans, H., Debyser, Z. & Gijsbers, R. High-resolution profiling of the LEDGF/p75 chromatin interaction in the ENCODE region. Nucleic Acids Res. 38, 6135–6147 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Qi, X. et al. Retrotransposon profiling of RNA polymerase III initiation sites. Genome Res. 22, 681–692 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. De Rijck, J. et al. The BET family of proteins targets moloney murine leukemia virus integration near transcription start sites. Cell Rep. 5, 886–894 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sharma, A. et al. BET proteins promote efficient murine leukemia virus integration at transcription start sites. Proc. Natl Acad. Sci. USA 110, 12036–12041 (2013).

    Article  PubMed  Google Scholar 

  113. Zhu, Y., Dai, J., Fuerst, P. G. & Voytas, D. F. Controlling integration specificity of a yeast retrotransposon. Proc. Natl Acad. Sci. USA 100, 5891–5895 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Ferris, A. L. et al. Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration. Proc. Natl Acad. Sci. USA 107, 3135–3140 (2010).

    Article  PubMed  Google Scholar 

  115. Gijsbers, R. et al. LEDGF hybrids efficiently retarget lentiviral integration into heterochromatin. Mol. Ther. 18, 552–560 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Silvers, R. M. et al. Modification of integration site preferences of an HIV-1-based vector by expression of a novel synthetic protein. Hum. Gene Ther. 21, 337–349 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gai, X. & Voytas, D. F. A single amino acid change in the yeast retrotransposon Ty5 abolishes targeting to silent chromatin. Mol. Cell 1, 1051–1055 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. Xie, W. et al. Targeting of the yeast Ty5 retrotransposon to silent chromatin is mediated by interactions between integrase and Sir4p. Mol. Cell. Biol. 21, 6606–6614 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kirchner, J., Connolly, C. M. & Sandmeyer, S. B. Requirement of RNA polymerase III transcription factors for in vitro position-specific integration of a retroviruslike element. Science 267, 1488–1491 (1995).

    Article  CAS  PubMed  Google Scholar 

  120. Qi, X. & Sandmeyer, S. In vitro targeting of strand transfer by the Ty3 retroelement integrase. J. Biol. Chem. 287, 18589–18595 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Aye, M., Dildine, S. L., Claypool, J. A., Jourdain, S. & Sandmeyer, S. B. A truncation mutant of the 95-kilodalton subunit of transcription factor IIIC reveals asymmetry in Ty3 integration. Mol. Cell. Biol. 21, 7839–7851 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Cheung, S. et al. Ty1 integrase interacts with RNA polymerase III-specific subcomplexes to promote insertion of Ty1 elements upstream of polymerase (Pol) III-transcribed genes. J. Biol. Chem. 291, 6396–6411 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Gao, X., Hou, Y., Ebina, H., Levin, H. L. & Voytas, D. F. Chromodomains direct integration of retrotransposons to heterochromatin. Genome Res. 18, 359–369 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Cherepanov, P. et al. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J. Biol. Chem. 278, 372–381 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Llano, M. et al. An essential role for LEDGF/p75 in HIV integration. Science 314, 461–464 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Shun, M.-C. et al. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 21, 1767–1778 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Engelman, A. & Cherepanov, P. The lentiviral integrase binding protein LEDGF/p75 and HIV-1 replication. PLoS Pathog. 4, e1000046 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Singh, P. K. et al. LEDGF/p75 interacts with mRNA splicing factors and targets HIV-1 integration to highly spliced genes. Genes Dev. 29, 2287–2297 (2015). This study makes the important discovery that HIV integrase directs integration into highly spliced genes by interacting with splicing factors, thus highlighting the cooperation between multiple tethering factors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Morchikh, M. et al. TOX4 and NOVA1 proteins are partners of the LEDGF PWWP domain and affect HIV-1 replication. PLoS ONE 8, e81217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Eidahl, J. O. et al. Structural basis for high-affinity binding of LEDGF PWWP to mononucleosomes. Nucleic Acids Res. 41, 3924–3936 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Gupta, S. S. et al. Bromo- and extraterminal domain chromatin regulators serve as cofactors for murine leukemia virus integration. J. Virol. 87, 12721–12736 (2013). References 111, 112 and 131 indicate that BET proteins interact with MLV integrase and mediate MLV integration at transcription start sites.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Larue, R. C. et al. Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes. Nucleic Acids Res. 42, 4868–4881 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. De Ravin, S. S. et al. Enhancers are major targets for murine leukemia virus vector integration. J. Virol. 88, 4504–4513 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. LaFave, M. C. et al. MLV integration site selection is driven by strong enhancers and active promoters. Nucleic Acids Res. 42, 4257–4269 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Tobaly-Tapiero, J. et al. Chromatin tethering of incoming foamy virus by the structural Gag protein. Traffic 9, 1717–1727 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Hocum, J. D. et al. Retargeted foamy virus vectors integrate less frequently near proto-oncogenes. Sci. Rep. 6, 36610 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Elis, E., Ehrlich, M., Prizan-Ravid, A., Laham-Karam, N. & Bacharach, E. p12 tethers the murine leukemia virus pre-integration complex to mitotic chromosomes. PLoS Pathog. 8, e1003103 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wight, D. J. et al. The gammaretroviral p12 protein has multiple domains that function during the early stages of replication. Retrovirology 9, 83 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Schneider, W. M. et al. Viral DNA tethering domains complement replication-defective mutations in the p12 protein of MuLV Gag. Proc. Natl Acad. Sci. USA 110, 9487–9492 (2013).

    Article  PubMed  Google Scholar 

  140. Rashkova, S., Karam, S. E., Kellum, R. & Pardue, M. L. Gag proteins of the two Drosophila telomeric retrotransposons are targeted to chromosome ends. J. Cell Biol. 159, 397–402 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Fuller, A. M., Cook, E. G. & Kelley, K. J. Gag proteins of Drosophila telomeric retrotransposons: collaborative targeting to chromosome ends. Genetics 184, 629–636 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Zhang, L., Beaucher, M., Cheng, Y. & Rong, Y. S. Coordination of transposon expression with DNA replication in the targeting of telomeric retrotransposons in Drosophila. EMBO J. 33, 1148–1158 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Matsumoto, T., Takahashi, H. & Fujiwara, H. Targeted nuclear import of open reading frame 1 protein is required for in vivo retrotransposition of a telomere-specific non-long terminal repeat retrotransposon, SART1. Mol. Cell. Biol. 24, 105–122 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Chung, T., Siol, O., Dingermann, T. & Winckler, T. Protein interactions involved in tRNA gene-specific integration of Dictyostelium discoideum non-long terminal repeat retrotransposon TRE5-A. Mol. Cell. Biol. 27, 8492–8501 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Siol, O. et al. Role of RNA polymerase III transcription factors in the selection of integration sites by the Dictyostelium non-long terminal repeat retrotransposon TRE5-A. Mol. Cell. Biol. 26, 8242–8251 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Schrijvers, R. et al. HRP-2 determines HIV-1 integration site selection in LEDGF/p75 depleted cells. Retrovirology 9, 84 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wang, H. et al. HRP2 determines the efficiency and specificity of HIV-1 integration in LEDGF/p75 knockout cells but does not contribute to the antiviral activity of a potent LEDGF/p75-binding site integrase inhibitor. Nucleic Acids Res. 40, 11518–11530 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Chin, C. R. et al. Direct visualization of HIV-1 replication intermediates shows that capsid and CPSF6 modulate HIV-1 intra-nuclear invasion and integration. Cell Rep. 13, 1717–1731 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Leem, Y.-E. et al. Retrotransposon Tf1 is targeted to Pol II promoters by transcription activators. Mol. Cell 30, 98–107 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Majumdar, A., Chatterjee, A. G., Ripmaster, T. L. & Levin, H. L. Determinants that specify the integration pattern of retrotransposon Tf1 in the fbp1 promoter of Schizosaccharomyces pombe. J. Virol. 85, 519–529 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Ho, K. L. et al. A role for the budding yeast separase, Esp1, in Ty1 element retrotransposition. PLoS Genet. 11, e1005109 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Mok, H.-P. & Lever, A. M. Chromatin, gene silencing and HIV latency. Genome Biol. 8, 228 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Scott, E. C. et al. A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer. Genome Res. 26, 745–755 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Deininger, P. et al. A comprehensive approach to expression of L1 loci. Nucleic Acids Res. http://dx.doi.org/10.1093/nar/gkw1067 (2016). References 24, 154 and 155 provide genome-wide evidence that only a limited subset of L1 elements are transcriptionally active, some being polymorphic among individuals, and that these loci are regulated in a cell type-specific manner.

  156. 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).

    Article  CAS  PubMed  Google Scholar 

  157. Beck, C. R. et al. LINE-1 retrotransposition activity in human genomes. Cell 141, 1159–1170 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Tubio, J. M. et al. Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science 345, 1251343 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory activities of transposable elements: from conflicts to benefits. Nat. Rev. Genet. 18, 71–86 (2017).

    Article  CAS  PubMed  Google Scholar 

  160. Curcio, M. J. & Garfinkel, D. J. Single-step selection for Ty1 element retrotransposition. Proc. Natl Acad. Sci. USA 88, 936–940 (1991).

    Article  CAS  PubMed  Google Scholar 

  161. Bryk, M. et al. Transcriptional silencing of Ty1 elements in the RDN1 locus of yeast. Genes Dev. 11, 255–269 (1997).

    Article  CAS  PubMed  Google Scholar 

  162. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zamudio, N. & Bourc'his, D. Transposable elements in the mammalian germline: a comfortable niche or a deadly trap? Heredity (Edinb.) 105, 92–104 (2010).

    Article  CAS  Google Scholar 

  164. Quadrana, L. & Colot, V. Plant transgenerational epigenetics. Annu. Rev. Genet. 50, 467–491 (2016).

    Article  CAS  PubMed  Google Scholar 

  165. Holoch, D. & Moazed, D. RNA-mediated epigenetic regulation of gene expression. Nat. Rev. Genet. 16, 71–84 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Sigman, M. J. & Slotkin, R. K. The first rule of plant transposable element silencing: location, location, location. Plant Cell 28, 304–313 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kinsey, P. T. & Sandmeyer, S. B. Ty3 transposes in mating populations of yeast: a novel transposition assay for Ty3. Genetics 139, 81–94 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Ke, N., Irwin, P. A. & Voytas, D. F. The pheromone response pathway activates transcription of Ty5 retrotransposons located within silent chromatin of Saccharomyces cerevisiae. EMBO J. 16, 6272–6280 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Grandbastien, M. A. LTR retrotransposons, handy hitchhikers of plant regulation and stress response. Biochim. Biophys. Acta 1849, 403–416 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Deeks, S. G. et al. Towards an HIV cure: a global scientific strategy. Nat. Rev. Immunol. 12, 607–614 (2012).

    Article  CAS  PubMed  Google Scholar 

  171. Jordan, A., Bisgrove, D. & Verdin, E. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J. 22, 1868–1877 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Lewinski, M. K. et al. Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription. J. Virol. 79, 6610–6619 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Sherrill-Mix, S. et al. HIV latency and integration site placement in five cell-based models. Retrovirology 10, 90 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Manson McManamy, M. E., Hakre, S., Verdin, E. M. & Margolis, D. M. Therapy for latent HIV-1 infection: the role of histone deacetylase inhibitors. Antivir. Chem. Chemother. 23, 145–149 (2014).

    Article  CAS  PubMed  Google Scholar 

  175. Lusic, M. & Giacca, M. Regulation of HIV-1 latency by chromatin structure and nuclear architecture. J. Mol. Biol. 427, 688–694 (2015).

    Article  CAS  PubMed  Google Scholar 

  176. Koiwa, T. et al. 5′-long terminal repeat-selective CpG methylation of latent human T-cell leukemia virus type 1 provirus in vitro and in vivo. J. Virol. 76, 9389–9397 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Taniguchi, Y. et al. Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms. Retrovirology 2, 64 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Rafati, H., Moshkin, Y., Mahmoudi, T., Parra, M. & Hakre, S. New transcription regulatory mechanisms of latent HIV LTR. Retrovirology 9, O3 (2012).

    Article  PubMed Central  Google Scholar 

  179. Gérard, A. et al. The integrase cofactor LEDGF/p75 associates with Iws1 and Spt6 for postintegration silencing of HIV-1 gene expression in latently infected cells. Cell Host Microbe 17, 107–117 (2015).

    Article  CAS  PubMed  Google Scholar 

  180. Wagner, T. A. et al. HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 345, 570–573 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Sandmeyer, S., Patterson, K. & Bilanchone, V. Ty3, a position-specific retrotransposon in budding yeast. Microbiol. Spectr. 3, MDNA3-0057-2014 (2015).

    PubMed  Google Scholar 

  182. Spaller, T., Kling, E., Glöckner, G., Hillmann, F. & Winckler, T. Convergent evolution of tRNA gene targeting preferences in compact genomes. Mob. DNA 7, 17 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Guo, Y., Singh, P. K. & Levin, H. L. A long terminal repeat retrotransposon of Schizosaccharomyces japonicus integrates upstream of RNA Pol III transcribed genes. Mob. DNA 6, 19 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Pardue, M. L. & DeBaryshe, P. G. Retrotransposons that maintain chromosome ends. Proc. Natl Acad. Sci. USA 108, 20317–20324 (2011).

    Article  PubMed  Google Scholar 

  185. Kasper, D. M., Gardner, K. E. & Reinke, V. Homeland security in the C. elegans germ line: insights into the biogenesis and function of piRNAs. Epigenetics 9, 62–74 (2014).

    Article  CAS  PubMed  Google Scholar 

  186. Molla-Herman, A., Vallés, A. M., Ganem-Elbaz, C., Antoniewski, C. & Huynh, J. R. tRNA processing defects induce replication stress and Chk2-dependent disruption of piRNA transcription. EMBO J. 34, 3009–3027 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. McClintock, B. The significance of responses of the genome to challenge. Science 226, 792–801 (1984).

    Article  CAS  PubMed  Google Scholar 

  188. Morillon, A., Springer, M. & Lesage, P. Activation of the Kss1 invasive-filamentous growth pathway induces Ty1 transcription and retrotransposition in Saccharomyces cerevisiae. Mol. Cell. Biol. 20, 5766–5776 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Todeschini, A.-L., Morillon, A., Springer, M. & Lesage, P. Severe adenine starvation activates Ty1 transcription and retrotransposition in Saccharomyces cerevisiae. Mol. Cell. Biol. 25, 7459–7472 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Feng, G., Leem, Y.-E. & Levin, H. L. Transposon integration enhances expression of stress response genes. Nucleic Acids Res. 41, 775–789 (2013).

    Article  CAS  PubMed  Google Scholar 

  191. Capy, P., Gasperi, G., Biémont, C. & Bazin, C. Stress and transposable elements: co-evolution or useful parasites? Heredity (Edinb.) 85, 101–106 (2000).

    Article  CAS  Google Scholar 

  192. Sehgal, A., Lee, C.-Y. S. & Espenshade, P. J. SREBP controls oxygen-dependent mobilization of retrotransposons in fission yeast. PLoS Genet. 3, e131 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Dai, J., Xie, W., Brady, T. L., Gao, J. & Voytas, D. F. Phosphorylation regulates integration of the yeast Ty5 retrotransposon into heterochromatin. Mol. Cell 27, 289–299 (2007). This work provides the first indication that the host can control target specificity in response to stress by regulating the interaction between an integration complex and its tethering factor.

    Article  CAS  PubMed  Google Scholar 

  194. Brown, C. A., Murray, A. W. & Verstrepen, K. J. Rapid expansion and functional divergence of subtelomeric gene families in yeasts. Curr. Biol. 20, 895–903 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Zou, S., Kim, J. M. & Voytas, D. F. The Saccharomyces retrotransposon Ty5 influences the organization of chromosome ends. Nucleic Acids Res. 24, 4825–4831 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Biasco, L., Baricordi, C. & Aiuti, A. Retroviral integrations in gene therapy trials. Mol. Ther. 20, 709–716 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Cavazzana-Calvo, M. et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288, 669–672 (2000).

    Article  CAS  PubMed  Google Scholar 

  198. Erlwein, O. & McClure, M. O. Progress and prospects: foamy virus vectors enter a new age. Gene Ther. 17, 1423–1429 (2010).

    Article  CAS  PubMed  Google Scholar 

  199. Copeland, N. G. & Jenkins, N. A. Harnessing transposons for cancer gene discovery. Nat. Rev. Cancer 10, 696–706 (2010).

    Article  CAS  PubMed  Google Scholar 

  200. Narayanavari, S. A., Chilkunda, S. S., Ivics, Z. & Izsvák, Z. Sleeping Beauty transposition: from biology to applications. Crit. Rev. Biochem. Mol. Biol. 52, 18–44 (2016).

    Article  CAS  PubMed  Google Scholar 

  201. Craigie, R. Targeting HIV-1 DNA integration by swapping tethers. Proc. Natl Acad. Sci. USA 107, 2735–2736 (2010).

    Article  PubMed  Google Scholar 

  202. El Ashkar, S. et al. BET-independent MLV-based vectors target away from promoters and regulatory elements. Mol. Ther. Nucleic Acids 3, e179 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Owens, J. B. et al. Transcription activator like effector (TALE)-directed piggyBac transposition in human cells. Nucleic Acids Res. 41, 9197–9207 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Ammar, I., Izsvák, Z. & Ivics, Z. The Sleeping Beauty transposon toolbox. Methods Mol. Biol. 859, 229–240 (2012).

    Article  CAS  PubMed  Google Scholar 

  205. Ballandras-Colas, A. et al. A supramolecular assembly mediates lentiviral DNA integration. Science 355, 93–95 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Passos, D. O. et al. Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome. Science 355, 89–92 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Schmidt, M. et al. High-resolution insertion-site analysis by linear amplification-mediated PCR (LAM-PCR). Nat. Methods 4, 1051–1057 (2007).

    Article  CAS  PubMed  Google Scholar 

  208. Ray, D. A. & Batzer, M. A. Reading TE leaves: new approaches to the identification of transposable element insertions. Genome Res. 21, 813–820 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Upton, K. R. et al. Ubiquitous L1 mosaicism in hippocampal neurons. Cell 161, 228–239 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Streva, V. A. et al. Sequencing, identification and mapping of primed L1 elements (SIMPLE) reveals significant variation in full length L1 elements between individuals. BMC Genomics 16, 220 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors apologize to 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 M. Lavigne, A. Doucet and J. Recht for critical reading of the manuscript. This work was supported by grants to G.C. from the Fondation ARC pour la Recherche sur le Cancer (Projet Fondation ARC, 20141201838); the Fondation pour la Recherche Médicale (FRM; DEP20131128533); the French Government (Agence Nationale Recherche (ANR)) through 'Investments for the Future' (LABEX SIGNALIFE, ANR-11- LABX-0028-01) and through the generic call project RETROMET (ANR-16-CE12-0020); the Cancéropôle Provence-Alpes-Côte d'Azur (Projet Emergence), Centre National de la Recherche Scientifique (CNRS; GDR 3546); and the University Hospital Federation (FHU) OncoAge. T.S. was supported by a joint Erasmus Mundus Mobility with Asia fellowship between Université Côte d'Azur, France, and University of Dhaka, Bangladesh. The work of P.L. is supported by intramural funding from CNRS, the Université Paris Diderot and the Institut National de la Santé et de la Recherche Médicale, and by grants from the Canceropôle Ile de France (2015–1 EMERG-24), Fondation ARC pour la Recherche sur le Cancer (PJA 20151203412), the ANR through the initiatives d'excellence (Idex ANR-11-IDEX-0005-02), the Labex Who am I? ANR11-LABX-0071) and the generic call project NiCiTy (ANR-13-BSV3-0012). The work of A.Z. is supported by intramural funding from Conservatoire National des Arts et Métiers, France.

Author information

Author notes

  1. Tania Sultana and Alessia Zamborlini: These authors contributed equally to this work.

Authors and Affiliations

  1. Université Côte d'Azur, INSERM, CNRS, IRCAN, 28 Ave de Valombrose, 06107, Nice Cedex 02, France

    Tania Sultana & Gael Cristofari

  2. Sorbonne Paris Cité, Université Paris Diderot, Institut National de la Santé et de la Recherche Médicale U944, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7212, Institut Universitaire d'Hématologie, Hôpital St. Louis, 1 Ave Claude Vellefaux, Paris, 75010, France

    Alessia Zamborlini & Pascale Lesage

  3. Laboratoire Pathologie et Virologie Moléculaire, Conservatoire National des Arts et Métiers, 292 Rue Saint-Martin, Paris, 75003, France

    Alessia Zamborlini

Authors
  1. Tania Sultana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessia Zamborlini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gael Cristofari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pascale Lesage
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Gael Cristofari or Pascale Lesage.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information S1 (table) (PDF 136 kb)

PowerPoint slides

Glossary

Cis-regulatory sequences

Sequences within a DNA or RNA molecule that regulate transactions involving the same nucleic acid (for example, transcription, splicing, polyadenylation, translation, degradation, replication and recombination).

Selection

A process by which biological and environmental constraints eliminate — or favour the reproduction of — organisms or cells with a given phenotype.

Tropism

In the context of this Review, the propensity of a transposable element to target specific genomic regions. The term can also refer to the preferred cell type or tissue of an infectious microorganism.

Accessions

Strains from a plant variety that has been propagated from seeds collected from a single individual in the wild. Accessions are typically given the name of the location from which the seeds were collected.

Euchromatic

A term that describes a type of chromatin that is less tightly packed and is enriched in transcribed genes.

Closed mitosis

A cell division in which the nuclear envelope stays intact.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sultana, T., Zamborlini, A., Cristofari, G. et al. Integration site selection by retroviruses and transposable elements in eukaryotes. Nat Rev Genet 18, 292–308 (2017). https://doi.org/10.1038/nrg.2017.7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg.2017.7

  • Springer Nature Limited

This article is cited by

Search

Navigation