• M. M. Popov V.N. Karazin Kharkiv National University, Kharkiv, Ukraine https://orcid.org/0000-0002-5759-9654
  • T. Yu Kolotova SI «Mechnikov Institute of Microbiology and Immunology of National Academy of Medical Sciences of Ukraine», Kharkiv, Ukraine
  • M. B. Davidenko SI «Mechnikov Institute of Microbiology and Immunology of National Academy of Medical Sciences of Ukraine», Kharkiv, Ukraine
Keywords: endogenous retroviruses, enhancer, promoter, lncRNA, regulatory networks, R-operon, mobile elements, genome evolution


Endogenous retroviruses (ERV) are the descendants of exogenous retroviruses that integrated into the germ cells genome, fixed and became inheritable. ERVs have evolved transcriptional enhancers and promoters that allow their replication in a wide range of tissue. Because ERVs comprise the regulatory elements it could be assume that ERVs capable to shape and reshape genomic regulatory networks by inserting their promoters and enhancers in new genomic loci upon retrotransposition. Thus retroransposition events can build new regulatory regions and lead to a new pattern of gene activation in the cell. In this review we summarize evidence which revealed that ERVs provide a plethora of novel gene regulatory elements, including tissue specific promoters and enhancers for protein-coding genes or long noncoding RNAs in a wide range of cell types. The accumulated findings support the hypothesis that the ERVs have rewired the gene regulatory networks and act as a major source of genomic regulatory innovation during evolution.


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Author Biographies

M. M. Popov, V.N. Karazin Kharkiv National University, Kharkiv, Ukraine

61022, Kharkiv, 4 Nauky Avenue

T. Yu Kolotova, SI «Mechnikov Institute of Microbiology and Immunology of National Academy of Medical Sciences of Ukraine», Kharkiv, Ukraine

14-16, Pushkinskaya St. 

M. B. Davidenko, SI «Mechnikov Institute of Microbiology and Immunology of National Academy of Medical Sciences of Ukraine», Kharkiv, Ukraine

14-16, Pushkinskaya St. 


Roossinck M. J. Move over bacteria! Viruses make their mark as mutualistic microbial symbionts // J. Virol. 2015. Vol. 89. P. 6532–6535.

Belyi V. A., Levine A. J., Skalka A. M. Unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes // PLoSPathog. 2010. Vol. 6. P. e1001030.

Belyi V. A., Levine A. J., Skalka A. M. Sequences from ancestral single-stranded DNA viruses in vertebrate genomes: The Parvoviridae and Circoviridae are more than 40 to 50 million years old // J. Virol. 2010. Vol. 84. P. 12458–12462.

Horie M., Honda T., Suzuki Y., Kobayashi Y., Daito T., Oshida T. [et al.] Endogenous non-retroviral RNA virus elements in mammalian genomes // Nature. 2010. Vol. 463. P. 84–87.

Gilbert C., Meik J. M., Dashevsky D., Card D. C., Castoe T. A., Schaack S. Endogenous hepadnaviruses, bornaviruses and circoviruses in snakes // Proc. Biol. Sci. 2014. Vol. 281.P. 20141122.

Taylor D. J., Leach R. W., Bruenn J. Filoviruses are ancient and integrated into mammalian genomes // BMC Evol. Biol. 2010.Vol. 10.P.193.

Feschotte C., Gilbert C. Endogenous viruses: Insights into viral evolution and impact on host biology // Nat. Rev. Genet. 2012. Vol. 13. P. 283–296.

Geuking M. B., Weber J., Dewannieux M., Gorelik E., Heidmann T., Hengartner H., Zinkernagel R. M., Hangartner L. Recombination of retrotransposon and exogenous RNA virus results in nonretroviralcDNAintegration // Science. 2009. Vol. 323. P. 393–396.

Bill C. A., Summers J. Genomic DNA double-strand breaks are targets for hepadnaviral DNA integration // Proc. Natl. Acad. Sci. USA. 2004. Vol. 101. P. 11135–11140.

Gilbert C., Cordaux R. Viruses as vectors of horizontal transfer of genetic material in eukaryotes // Curr. Opin.Virol.2017. Vol. 25. P. 16–22.

Shapiro J.A. Living Organisms Author Their Read-Write Genomes in Evolution // Biology (Basel). 2017. Vol. 6(4). P.pii: E42

Oliver K. R., Greene W. K. Transposable elements and viruses as factors in adaptation and evolution: an expansion and strengthening of the TE-Thrust hypothesis // Ecol. Evol. 2012. Vol. 2, N.11. P. 2912–2933.

Oliver K. R., Greene W. K. Mobile DNA and the TE-Thrust hypothesis: Supporting evidence from the primates // Mob. DNA.2011. Vol. 2. P. 8.

De Koning A. P., Gu W., Castoe T. A., Batzer M. A., Pollock D. D. Repetitive elements may comprise over two-thirds of the human genome // PLoS Genet. 2011. Vol. 7. P. e1002384.

Rowe H. M., Trono D. Dynamic control of endogenous retroviruses during development // Virology. 2011. Vol. 411. P. 273–287.

Tarlinton R. E., Meers J., Young P. R. Retroviral invasion of the koala genome // Nature. 2006. Vol. 442. P.79–81.

Lander E. S., Linton L. M., Birren B., Nusbaum C., Zody M. C., Baldwin J. et al. Initial sequencing and analysis of the human genome // Nature. 2001. Vol. 409. P. 860–921.

Friedli M., Trono D. The developmental control of transposable elements and the evolution of higher species // Annu. Rev. Cell. Dev. Biol. 2015. Vol. 31. P. 429-451.

Kapitonov V. V., Jurka J. The long terminal repeat of an endogenous retrovirus induces alternative splicing and encodes an additional carboxy-terminal sequence in the human leptin receptor // J. Mol. Evol. 1999. Vol. 48. P. 248 – 251.

Mager D. L., Hunter D. G., Schertzer M., Freeman J. D. Endogenous retroviruses provide the primary polyadenylation signal for two new human genes (HHLA2 and HHLA3) // Genomics. 1999. Vol. 59. P. 255–263.

Manghera M., Douville R. N. Endogenous retrovirus-K promoter: a landing strip for inflammatory transcription factors? // Retrovirology. 2013. Vol.10. P. 16.

Sundaram V., Choudhary M. N., Pehrsson E., Xing X., Fiore C., Pandey M., Maricque B., Udawatta M., Ngo D., Chen Y., Paguntalan A., Ray T., Hughes A., Cohen B. A., Wang T. Functional cis-regulatory modules encoded by mouse-specific endogenous retrovirus // Nat. Commun. 2017. Vol. 8. P.4550.

Thurman R. E., Rynes E., Humbert R., Vierstra J., Maurano M. T., Haugen E., Sheffield N. C., Stergachis A. B., Wang H., Vernot B., et al. The accessible chromatin landscape of the human genome // Nature. 2012. Vol. 489. P. 75– 82.

Jacques P. É., Jeyakani J., Bourque G. The majority of primate-specific regulatory sequences are derived from transposable elements // PLoS Genet. 2013. Vol. 9, N 5. P. e1003504.

Xie M., Hong C., Zhang B., Lowdon R.F., Xing X., Li D., Zhou X., Lee H. J., Maire C. L., Ligon K. L., Gascard P., Sigaroudinia M., Tlsty T. D., Kadlecek T., Weiss A., O'Geen H., Farnham P. J., Madden P. A., Mungall A. J., Tam A., Kamoh B., Cho S., Moore R., Hirst M., Marra M. A., Costello J. F., Wang T. DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape // Nat. Genet. 2013. Vol.45. P. 836-841.

Garazha A., Ivanova A., Suntsova M., Malakhova G., Roumiantsev S., Zhavoronkov A., Buzdin A. New bioinformatic tool for quick identification of functionally relevant endogenous retroviral inserts in human genome // Cell Cycle. 2015. Vol. 14. P. 1476–1484.

Ito J., Sugimoto R., Nakaoka H., Yamada S., Kimura T., Hayano T. et al. Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses // PLoS Genet. 2017. Vol. 13. P. e1006883.

Sundaram V., Cheng Y., Ma Z., Li D., Xing X., Edge P., Snyder M. P., Wang T. Widespread contribution of transposable elements to the innovation of gene regulatory networks // Genome Research. 2014. Vol. 24. P. 1963–1976.

Kunarso G., Chia N. Y., Jeyakani J., Hwang C., Lu X., Chan Y. S., Ng H. H., Bourque G. Transposable elements have rewired the core regulatory network of human embryonic stem cells // Nat. Genet. 2010. Vol. 42 (7). P. 631–634.

Djebali S., Davis C. A., Merkel A., Dobin A., Lassmann T., Mortazavi A., et al. Landscape of transcription in human cells // Nature. 2012. Vol. 489. P. 101–108.

Haase K., Mosch A., Frishman D. Differential expression analysis of human endogenous retroviruses based on ENCODE RNA-seq data // BMC Med. Genomics. 2015. Vol.8. P.71.

Goke, J., Lu X., Chan Y. S., Ng H. H., Ly L. H., Sachs F., Szczerbinska I. Dynamic transcription of distinct classes of endogenous retroviral elements marks specific populations of early human embryonic cells // Cell Stem Cell. 2015. Vol. 16. P. 135–141.

Attig J., Young G. R., Stoye J. P., Kassiotis G., Physiological and Pathological Transcriptional Activation of Endogenous Retroelements Assessed by RNA-Sequencing of B Lymphocytes // Front. Microbiol. 2017. Vol.8. P.2489.

Ting C. N., Rosenberg M. P., Snow C. M., Samuelson L. C., Meisler M. H. Endogenous retroviral sequences are required for tissue-specific expression of a human salivary amylase gene // Genes Dev. 1992. Vol. 6. P. 1457–1465.

Dunn C. A., Medstrand P., Mager D. L. An endogenous retroviral long terminal repeat is the dominant promoter for human beta1,3-galactosyltransferase 5 in the colon // Proc. Natl. Acad. Sci. U. S. A. 2003. Vol.100. P.12841–12846.

Emera D., Casola C,; Lynch V. J., Wildman D. E., Agnew D., Wagner G. P. Convergent evolution of endometrial prolactin expression in primates, mice, and elephants through the independent recruitment of transposable elements // Mol. Biol. Evol. 2012. Vol.29. P. 239–247.

Romanish M. T., Lock W. M., van de Lagemaat L. N., Dunn C. A., Mager D. L. Repeated recruitment of LTR retrotransposons as promoters by the anti-apoptotic locus NAIP during mammalian evolution // PLoS Genet. 2007. Vol. 3. P. e10.

Upton K. R., Faulkner G. J. Blood from ‗junk‘: the LTR chimeric transcript Pu.2 promotes erythropoiesis // Mob. DNA. 2014. Vol. 5. P. 15.

Pi W., Zhu X., Wu M., Wang Y., Fulzele S., Eroglu A., Ling J., Tuan D. Long-range function of an intergenicretrotransposon // Proc. Natl. Acad. Sci. U S A. 2010. Vol. 107 (29). P. 12992–12997. 40. Hu T., Zhu X., Pi W., Yu M., Shi H., Tuan D. Hypermethylated LTR retrotransposon exhibits enhancer activity // Epigenetics. 2017. Vol. 12. P. 226–237.

Franchini L. F., López-Leal R., Nasif S., Beati P., Gelman D. M., Low M. J., de Souza F. J., Rubinstein M. Convergent evolution of two mammalian neuronal enhancers by sequential exaptation of unrelated retroposons // Proc. Natl. Acad. Sci. U S A. 2011. Vol. 108.P.15270–15275.

Lam D. D., de Souza F. S., Nasif S., Yamashita M., López-Leal R., Otero-Corchon V., Meece K., Sampath H., Mercer A. J., Wardlaw S. L., Rubinstein M., Low M. J. Partially redundant enhancers cooperatively maintain Mammalian pomc expression above a critical functional threshold // PLoS Genet. 2015. Vol. 11. P. e1004935.

Suntsova M., Gogvadze E. V., Salozhin S., Gaifullin N., Eroshkin F., Dmitriev S. E., et al. Humanspecific endogenous retroviral insert serves as an enhancer for the schizophrenia-linked gene PRODH // Proc. Natl. Acad. Sci. U S A. 2013. Vol. 110. P. 19472–19477.

Nishihara H., Kobayashi N., Kimura-Yoshida C., Yan K., Bormuth O., Ding Q., Nakanishi A., Sasaki T., Hirakawa M., Sumiyama K., Furuta Y., Tarabykin V., Matsuo I., Okada N. Coordinately Co-opted Multiple Transposable Elements Constitute an Enhancer for wnt5a Expression in the Mammalian Secondary Palate // PLoS Genet. 2016. Vol. 12. P. e1006380.

Derrien T., Johnson, R., Bussotti, G., Tanzer, A., Djebali S., Tilgner H., Guernec G., Martin D., Merkel A., Knowles D. G., et al. The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression // Genome Res. 2012. Vol. 22. P. 1775–1789.

Pennisi E. ENCODE project writes eulogy for junk DNA // Science. 2012. Vol. 337. P. 1159.

Fang S., Zhang L., Guo J., Niu Y., Wu Y., Li H., Zhao L., Li X., Teng X., Sun X., Sun L., Zhang M. Q., Chen R., Zhao Y.,NONCODEV5: a comprehensive annotation database for long non-coding RNAs // Nucleic Acids Res. 2018. Vol. 46, D1. P. D308-D314.

Liu S.J., Nowakowski T. J., Pollen A. A., Lui J. H., Horlbeck M. A., Attenello F. J., He D., Weissman J. S., Kriegstein A. R., Diaz A. A., Lim D.A., et al. Single-cell analysis of long non-coding RNAs in the developing human neocortex // Genome Biol. 2016. Vol. 17.P. 67.

Kelley D., Rinn J. Transposable elements reveal a stem cell-specific class of long noncoding RNAs // Genome Biol. 2012. Vol. 13. P. R107.

Kapusta A., Kronenberg Z., Lynch V. J., Zhuo X., Ramsay L., Bourque G., Yandell M., Feschotte C. Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs // PLoS Genetics 9. 2013. P. e1003470.

Werner M. A., Sullivan R. N., Shah R. D., Nadadur A. T., Grzybowski V., Galat I. P., Moskowitz A. J. Ruthenburg. Chromatin-enriched lncRNAs can act as cell-type specific activators of proximal gene transcription // Nat. Struct. Mol. Biol. 2017. Vol. 24. P. 596–603.

Wang X., Ai G., Zhang C., Cui L., Wang J., Li H., Zhang J., Ye Z. Expression and diversification analysis reveals transposable elements play important roles in the origin of Lycopersicon-specific lncRNAs in tomato // New Phytol. 2016. Vol. 209. P. 1442–1455.

Faulkner G. J., Kimura Y., Daub C. O., Wani S., Plessy C., Irvine K. M., Schroder K., Cloonan N., Steptoe A. L., Lassmann T., Waki K., Hornig N., Arakawa T., Takahashi H., Kawai J., Forrest A. R. R., Suzuki H., Hayashizaki Y., Hume D. A., Orlando V., Grimmond S. M., Carninci P. The regulated retrotransposontranscriptome of mammalian cells // Nat. Genet. 2009. Vol. 41. P. 563–571. 54. Peaston A. E. Evsikov A. V., Graber J. H., de Vries W. N., Holbrook A. E., Solter D., Knowles B. B. Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos // Dev Cell. 2004. Vol. 7. P. 597–606.

Macfarlan T. S., Gifford W. D., Driscoll S., Lettieri K., Rowe H. M., Bonanomi D., Firth A., Singer O., Trono D., Pfaff S. L. Embryonic stem cell potency fluctuates with endogenous retrovirus activity // Nature. 2012. Vol. 487. P. 57–63.

Ge S. X. Exploratory bioinformatics investigation reveals importance of ―junk‖ DNA in early embryo development // BMC Genom. 2017. Vol. 18. P. 200–489.

Flemr M., Malik R., Franke V., Nejepinska J., Sedlacek R., Vlahovicek K., Svoboda P. A retrotransposondriven dicer isoform directs endogenous small interfering RNA production in mouse oocytes // Cell. 2013. Vol. 155. P. 807–816.

Fuentes D. R., Swigut T., Wysocka J. Systematic perturbation of retroviral LTRs reveals widespread longrange effects on human gene regulation // Elife. 2018. Vol.7. P. e35989.

Yasuhiko Y., Hirabayashi Y., Ono R. LTRs of Endogenous Retroviruses as a Source of Tbx6 Binding Sites // Front Chem. 2017. Vol. 5.P. 34.

Chuong E., Rumi M. A., Soares M. J., Baker J. C. Endogenous retroviruses function as species-specific enhancer elements in the placenta // Nat. Genet. 2013. Vol. 45. P. 325–329.

Trizzino M., Park Y., Holsbach-Beltrame M., Aracena K., Mika K., Caliskan M., Perry G. H., Lynch V. J., Brown C. D. Transposable elements are the primary source of novelty in primate gene regulation // Genome Res. 2017. Vol. 27. P. 1623–1633.

Chuong E.B., Elde N.C., Feschotte C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses // Science. 2016. Vol. 351(6277). P.1083–1087.

Davis M. P., Carrieri C., Saini H. K., van Dongen S., Leonardi T., Bussotti G., Monahan J. M., Auchynnikava T., Bitetti A., Rappsilber J., Allshire R. C., Shkumatava A., O'Carroll D., Enright A. J. Transposon-driven transcription is a conserved feature of vertebrate spermatogenesis and transcript evolution // EMBO Rep. 2017. Vol. 18. P. 1231–1247.

Chishima T., Iwakiri J., Hamada M. Identification of Transposable Elements Contributing to TissueSpecific Expression of Long Non-Coding RNAs // Genes (Basel). 2018. Vol.9. P. E23.

Hu T., Pi W., Zhu X., Yu M., Ha H., Shi H., Choi J. H., Tuan D. Long non-coding RNAs transcribed by ERV-9 LTR retrotransposon act in cis to modulate long-range LTR enhancer function // Nucleic Acids Res. 2017. Vol.45. P.4479-4492.

Muotri A.R. Chu V. T., Marchetto M. C., Deng W., Moran J. V., Gage F. H. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition // Nature. 2005. Vol. 435. P. 903–910.

Upton K. R., Gerhardt D. J., Jesuadian J. S., Richardson S. R., Sánchez-Luque F. J., Bodea G. O., Ewing A. D., Salvador-Palomeque C., van der Knaap M. S., Brennan P. M., Vanderver A., Faulkner G. J. Ubiquitous L1 mosaicism in hippocampal neurons // Cell. 2015. Vol. 161. P. 228–239.

Newman A. G., Bessa P., Tarabykin V., Singh P. B. Activity-DEPendent Transposition // EMBO Rep. 2017. Vol. 18. P. 346–348.

Tang S.-J. A Model of DNA Repeat-Assembled Mitotic Chromosomal Skeleton // Genes. 2011. Vol. 2. P. 661–670.

Tang S. J. A Model of Repetitive-DNA-Organized Chromatin Network of Interphase Chromosomes // Genes. 2012. Vol. 3. P. 167–175.

Cournac A., Koszul R., Mozziconacci J. The 3D folding of metazoan genomes correlates with the association of similar repetitive elements // Nucleic Acids Res. 2016. Vol. 44. P. 245–255. 72. Nishikawa J., Ohyama T. Selective association between nucleosomes with identical DNA sequences // Nucleic Acids Res. 2013. Vol. 41. P. 1544–1554.

Tang S.-J. The R-Operon: A Model of Repetitive DNA-Organized Transcriptional Compartmentation of Eukaryotic Chromosomes for Coordinated Gene Expression// Genes (Basel). 2016. Vol. 7. P. E16.

Patel B., Kang Y., Cui K., Litt M., Riberio M. S., et al. Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia // Leukemia. 2014. Vol. 28. P. 349–361.

Markenscoff-Papadimitriou E., Allen W. E., Colquitt B. M., Goh T., Murphy K. K., et al. Enhancer interaction networks as a means for singular olfactory receptor expression // Cell. 2014. Vol. 159. P. 543– 557.

Williams A., Spilianakis C. G., Flavell R. A. Interchromosomal association and gene regulation in trans // Trends Genet. 2010. Vol. 26. P. 188–197.

Li G., Ruan X., Auerbach R., Sandhu K., Zheng M., Wang P., Poh H., Goh Y., Lim J., Zhang J. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation // Cell. 2012. Vol. 148. P. 84–98.

LoM. Y., Rival-Gervier S., Pasceri P.,Ellis J. Rapid transcriptional pulsing dynamics of high expressing retroviral transgenes in embryonic stem cells // PLoS One. 2012. Vol. 7.P. e37130.

Schlesinger S., Meshorer E., Goff S. P. Asynchronous transcriptional silencing of individual retroviral genomes in embryonic cells // Retrovirology. 2014. Vol. 11. P. 31.

How to Cite
Popov, M., Kolotova, T., & Davidenko, M. (2019). ENDOGENOUS RETROVIRUSES AS GENETIC MODULES THAT SHAPE THE GENOME REGULATORY NETWORKS DURING EVOLUTION. The Journal of V. N. Karazin Kharkiv National University, Series "Medicine", (36), 80-95. Retrieved from https://periodicals.karazin.ua/medicine/article/view/12194