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Epigenetic regulation and role of LINE-1 retrotransposon in embryogenesis

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Abstract

LINE-1 retrotransposon is the most common mobile genetic element in the genomes of various mammals, including humans. Its genes are represented by the greatest number of copies. For a long time, it has been considered that the presence of LINE-1 in genome reflects the limited ability of cells to eliminate it, and the retrotransposon activity is negative owing to the insertional mutagenesis. In recent years, the increased expression of LINE-1 retrotransposon and the activity of their encoded proteins observed in mammalian cells at different stages of development and, first of all, in early embryogenesis have been discussed in the literature. Is early embryogenesis the stage of development when the organism is more susceptible to the activity of retrotransposons, or does LINE-1 play some positive role in early embryonic development? This review is aimed at classifying the available data on the epigenetic regulation and the role of LINE-1 retrotransposon in embryogenesis of mammals. The link between the mechanisms of regulation of LINE-1 expression and the waves of epigenetic reprogramming is tracked in germ cells, during fertilization, and in blastocyst, as well as during the differentiation of embryonic and extraembryonic tissues.

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References

  1. Ostertag, E.M. and Kazazian, H.H., Biology of mammalian L1 retrotransposons, Annu. Rev. Genet., 2001, vol. 35, pp. 501–538. doi 10.1146/annurev.genet.35.102401.091032

    Article  CAS  PubMed  Google Scholar 

  2. Mukherjee, S., Mukhopadhyay, A., Banerjee, D., et al., Molecular pathology of haemophilia B: identification of five novel mutations including a LINE 1 insertion in Indian patients, Haemophilia, 2004, vol. 10, no. 3, pp. 259–263. doi 10.1111/j.1365-2516.2004. 00895.x

    Article  CAS  PubMed  Google Scholar 

  3. Brooks, M.B., Gu, W., Barnas, J.L., et al., A Line 1 insertion in the Factor IX gene segregates with mild hemophilia B in dogs, Mamm. Genome, 2003, vol. 14, no. 11, pp. 788–795. doi 10.1007/s00335-003-2290-z

    Article  CAS  PubMed  Google Scholar 

  4. Muhle, C., Zenker, M., Chuzhanova, N., and Schneider, H., Recurrent inversion with concomitant deletion and insertion events in the coagulation factor VIII gene suggests a new mechanism for X-chromosomal rearrangements causing hemophilia A, Hum. Mutat., 2007, vol. 28, no. 10, p. 1045. doi 10.1002/humu.9506

    Article  PubMed  Google Scholar 

  5. Feschotte, C., Transposable elements and the evolution of regulatory networks, Nat. Rev. Genet., 2008, vol. 9, no. 5, pp. 397–405. doi 10.1038/nrg2337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Goodier, J.L. and Kazazian, H.H., Retrotransposons revisited: the restraint and rehabilitation of parasites, Cell, 2008, vol. 135, no. 1, pp. 23–35. doi 10.1016/j.cell.2008.09.022

    Article  CAS  PubMed  Google Scholar 

  7. Faulkner, G.J., Kimura, Y., Daub, C.O., et al., The regulated retrotransposon transcriptome of mammalian cells, Nat. Genet., 2009, vol. 41, no. 5, pp. 563–571. doi 10.1038/ng.368

    Article  CAS  PubMed  Google Scholar 

  8. Jachowicz, J.W. and Torres-Padilla, M.E., LINEs in mice: features, families, and potential roles in early development, Chromosoma, 2015, vol. 125, no. 1, pp. 29–39. doi 10.1007/s00412-015-0520-2

    Article  PubMed  Google Scholar 

  9. Beck, C.R., Collier, P., Macfarlane, C., et al., LINE-1 retrotransposition activity in human genomes, Cell, 2010, vol. 141, no. 7, pp. 1159–1170. doi 10.1016/j.cell. 2010.05.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Iskow, R.C., McCabe, M.T., Mills, R.E., et al., Natural mutagenesis of human genomes by endogenous retrotransposons, Cell, 2010, vol. 141, no. 7, pp. 1253–1261. doi 10.1016/j.cell.2010.05.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Aschacher, T., Wolf, B., Enzmann, F., et al., LINE-1 induces hTERT and ensures telomere maintenance in tumour cell lines, Oncogene, 2015, vol. 35, no. 1, pp. 94–104. doi 10.1038/onc.2015.65

    Article  PubMed  Google Scholar 

  12. Guo, F., Yan, L., Guo, H., et al., The transcriptome and DNA methylome landscapes of human primordial germ cells, Cell, 2015, vol. 161, no. 6, pp. 1437–1452. doi 10.1016/j.cell.2015.05.015

    Article  CAS  PubMed  Google Scholar 

  13. Mathias, S.L., Scott, A.F., Kazazian, H.H., et al., Reverse transcriptase encoded by a human transposable element, Science, 1991, vol. 254, no. 5039, pp. 1808–1810. doi 10.1126/science.1722352

    Article  CAS  PubMed  Google Scholar 

  14. Fedorov, A., Regulation of mammalian LINE1 retrotransposon transcription, Cell Tiss. Biol., 2009, vol. 3, no. 1, p 1. doi 10.1134/S1990519X09010015

    Article  Google Scholar 

  15. Martin, S.L., Nucleic acid chaperone properties of ORF1p from the non-LTR retrotransposon, LINE-1, RNA Biol., 2010, vol. 7, no. 6, pp. 706–711. doi 10.4161/rna.7.6.13766

    Article  CAS  PubMed  Google Scholar 

  16. An, W., Dai, L., Niewiadomska, A.M., et al., Characterization of a synthetic human LINE-1 retrotransposon ORFeus-Hs, Mob. DNA, 2011, vol. 2, no. 1, p. 2. doi 10.1186/1759-8753-2-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dai, L., Huang, Q., and Boeke, J.D., Effect of reverse transcriptase inhibitors on LINE-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition, BMC Biochem., 2011, vol. 12, p. 18. doi 10.1186/1471-2091-12-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dewannieux, M. and Heidmann, T., LINEs, SINEs and processed pseudogenes: parasitic strategies for genome modeling, Cytogenet. Genome Res., 2005, vol. 110, nos. 1–4, pp. 35–48. doi 10.1159/000084936

    Article  CAS  PubMed  Google Scholar 

  19. Doucet, A.J., Hulme, A.E., Sahinovic, E., et al., Characterization of LINE-1 ribonucleoprotein particles, PLoS Genet., 2010, vol. 6, no. 10. doi 10.1371/journal. pgen.1001150

  20. Aravin, A.A., Sachidanandam, R., Bourc’his, D., et al., A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice, Mol. Cell, 2008, vol. 31, no. 6, pp. 785–799. doi 10.1016/j.molcel.2008.09.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Aravin, A.A., van der Heijden, G.W., Castaneda, J. et al., Cytoplasmic compartmentalization of the fetal piRNA pathway in mice, PLoS Genet., 2009, vol. 5, no. 12. e1000764. doi 10.1371/journal.pgen.1000764

    Article  Google Scholar 

  22. Smith, Z.D., Chan, M.M., Mikkelsen, T.S., et al., A unique regulatory phase of DNA methylation in the early mammalian embryo, Nature, 2012, vol. 484, no. 7394, pp. 339–344. doi 10.1038/nature10960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Malki, S., van der Heijden, G.W., O’Donnell, K.A., et al., A role for retrotransposon LINE-1 in fetal oocyte attrition in mice, Dev. Cell, 2014, vol. 29, no. 5, pp. 521–533. doi 10.1016/j.devcel.2014.04.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Luo, Y.B., Zhang, L., Lin, Z.L., et al., Distinct subcellular localization and potential role of LINE1-ORF1P in meiotic oocytes, Histochem. Cell Biol., 2015, vol. 145, no. 1, pp. 93–104. doi 10.1007/s00418-015-1369-4

    Article  PubMed  Google Scholar 

  25. Aravin, A.A., Sachidanandam, R., Girard, A., et al., Developmentally regulated piRNA clusters implicate MILI in transposon control, Science, 2007, vol. 316, no. 5825, pp. 744–747. doi 10.1126/science.1142612

    Article  CAS  PubMed  Google Scholar 

  26. Heyn, H., Ferreira, H.J., Bassas, L., et al., Epigenetic disruption of the PIWI pathway in human spermatogenic disorders, PLoS One, 2012, vol. 7, no. 10. e47892. doi 10.1371/journal.pone.0047892

    Article  Google Scholar 

  27. Gasior, S.L., Wakeman, T.P., Xu, B., and Deininger, P.L., The human LINE-1 retrotransposon creates DNA dou ble-strand breaks, J. Mol. Biol., 2006, vol. 357, no. 5, pp. 1383–1393. doi 10.1016/j.jmb.2006.01.089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Vitullo, P., Sciamanna, I., Baiocchi, M., et al., LINE-1 retrotransposon copies are amplified during murine early embryo development, Mol. Reprod. Dev., 2012, vol. 79, no. 2, p. 118–127. doi 10.1002/mrd.22003

    Article  CAS  PubMed  Google Scholar 

  29. Tian, M., Bao, H., Martin, F.L., et al., Association of DNA methylation and mitochondrial DNA copy number with human semen quality, Biol. Reprod., 2014, vol. 91, no. 4, p. 101. doi 10.1095/biolreprod.114.122465

    Article  PubMed  Google Scholar 

  30. Houshdaran, S., Cortessis, V.K., Siegmund, K., et al., Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm, PLoS One, 2007, vol. 2, no. 12. e1289. doi 10.1371/journal.pone.0001289

    Article  Google Scholar 

  31. Evsikov, A.V., de Vries, W.N., Peaston, A.E., et al., Systems biology of the 2-cell mouse embryo, Cytogenet. Genome Res., 2004, vol. 105, nos. 2–4, pp. 240–250. doi 10.1159/000078195

    Article  CAS  PubMed  Google Scholar 

  32. Peaston, A.E., Evsikov, A.V., Graber, J.H., et al., Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos, Dev. Cell, 2004, vol. 7, no. 4, pp. 597–606. doi 10.1016/j.devcel.2004.09.004

    Article  CAS  PubMed  Google Scholar 

  33. Peaston, A.E., Knowles, B.B., and Hutchison, K.W., Genome plasticity in the mouse oocyte and early embryo, Biochem. Soc. Trans., 2007, vol. 35, no. 3, pp. 618–622. doi 10.1042/BST0350618

    Article  CAS  PubMed  Google Scholar 

  34. Fadloun, A., Le Gras, S., Jost, B., et al., Chromatin signatures and retrotransposon profiling in mouse embryos reveal regulation of LINE-1 by RNA, Nat. Struct. Mol. Biol., 2013, vol. 20, no. 3, pp. 332–338. doi 10.1038/nsmb.2495

    Article  CAS  PubMed  Google Scholar 

  35. Brouha, B., Meischl, C., Ostertag, E., et al., Evidence consistent with human L1 retrotransposition in maternal meiosis I, Am. J. Hum. Genet., 2002, vol. 71, no. 2, pp. 327–336. doi 10.1086/341722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Garcia-Perez, J.L., Marchetto, M.C., Muotri, A.R., et al., LINE-1 retrotransposition in human embryonic stem cells, Hum. Mol. Genet., 2007, vol. 16, no. 13, pp. 1569–1577. doi 10.1093/hmg/ddm105

    Article  CAS  PubMed  Google Scholar 

  37. Kano, H., Godoy, I., Courtney, C., et al., L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism, Genes Dev., 2009, vol. 23, no. 11, pp. 1303–1312. doi 10.1101/gad.1803909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ostertag, E.M., DeBerardinis, R.J., Goodier, J.L., et al., A mouse model of human L1 retrotransposition, Nat. Genet., 2002, vol. 32, no. 4, pp. 655–660. doi 10.1038/ng1022

    Article  CAS  PubMed  Google Scholar 

  39. van den Hurk, J.A., Meij, I.C., Seleme, M.C., et al., L1 retrotransposition can occur early in human embryonic development, Hum. Mol. Genet., 2007, vol. 16, no. 13, pp. 1587–1592. doi 10.1093/hmg/ddm108

    Article  PubMed  Google Scholar 

  40. van den Hurk, J.A., van de Pol, D.J., Wissinger, B., et al., Novel types of mutation in the choroideremia (CHM) gene: a full-length L1 insertion and an intronic mutation activating a cryptic exon, Hum. Genet., 2003, vol. 113, no. 3, pp. 268–275. doi 10.1007/s00439-003- 0970-0

    Article  PubMed  Google Scholar 

  41. Li, J., Kannan, M., Trivett, A.L., 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., 2014, vol. 42, no. 7, pp. 4546–4562. doi 10.1093/nar/gku091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Beraldi, R., Pittoggi, C., Sciamanna, I., et al., Expression of LINE-1 retroposons is essential for murine preimplantation development, Mol. Reprod. Dev., 2006, vol. 73, no. 3, pp. 279–287. doi 10.1002/mrd.20423

    Article  CAS  PubMed  Google Scholar 

  43. Kigami, D., Minami, N., Takayama, H., and Imai, H., MuERV-L is one of the earliest transcribed genes in mouse one-cell embryos, Biol. Reprod., 2003, vol. 68, no. 2, pp. 651–654. doi 10.1095/biolreprod.102. 007906

    Article  CAS  PubMed  Google Scholar 

  44. Mangiacasale, R., Pittoggi, C., Sciamanna, I., et al., Exposure of normal and transformed cells to nevirapine, a reverse transcriptase inhibitor, reduces cell growth and promotes differentiation, Oncogene, 2003, vol. 22, no. 18, pp. 2750–2761. doi 10.1038/sj.onc. 1206354

    CAS  Google Scholar 

  45. Sciamanna, I., Landriscina, M., Pittoggi, C., et al., Inhibition of endogenous reverse transcriptase antagonizes human tumor growth, Oncogene, 2005, vol. 24, no. 24, pp. 3923–3931. doi 10.1038/sj.onc.1208562

    Article  CAS  PubMed  Google Scholar 

  46. Hall, L.L., Carone, D.M., Gomez, A.V., et al., Stable C0T-1 repeat RNA is abundant and is associated with euchromatic interphase chromosomes, Cell, 2014, vol. 156, no. 5, pp. 907–919. doi 10.1016/j.cell.2014.01.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lyon, M.F., X-chromosome inactivation: a repeat hypothesis, Cytogenet. Cell Genet., 1998, vol. 80, nos. 1–4, pp. 133–137. doi 10.1159/000014969

    Article  CAS  PubMed  Google Scholar 

  48. Lyon, M.F., LINE-1 elements and X chromosome inactivation: a function for “junk” DNA?, Proc. Natl. Acad. Sci. U.S.A., 2000, vol. 97, no. 12, pp. 6248–6249. doi 10.1073/pnas.97.12.6248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Waterston, R.H., Lindblad-Toh, K., Birney, E., et al., Initial sequencing and comparative analysis of the mouse genome, Nature, 2002, vol. 420, nos. 6915, pp. 520–562. doi 10.1038/nature01262

    Article  CAS  PubMed  Google Scholar 

  50. Boyle, A.L., Ballard, S.G., and Ward, D.C., Differential distribution of long and short interspersed element sequences in the mouse genome: chromosome karyotyping by fluorescence in situ hybridization, Proc. Natl. Acad. Sci. U.S.A., 1990, vol. 87, no. 19, pp. 7757–7761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bailey, J.A., Carrel, L., Chakravarti, A., and Eichler, E.E., Molecular evidence for a relationship between LINE-1 elements and X chromosome inactivation: the Lyon repeat hypothesis, Proc. Natl. Acad. Sci. U.S.A., 2000, vol. 97, no. 12, pp. 6634–6639. doi 10.1073/pnas. 97.12.6634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mikkelsen, T.S., Wakefield, M.J., Aken, B., et al., Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences, Nature, 2007, vol. 447, no. 7141, pp. 167–177. doi 10.1038/nature05805

    Article  CAS  PubMed  Google Scholar 

  53. Abrusan, G., Giordano, J., and Warburton, P.E., Analysis of transposon interruptions suggests selection for L1 elements on the X chromosome, PLoS Genet., 2008, vol. 4, no. 8. e1000172. doi 10.1371/journal.pgen. 1000172

    Article  Google Scholar 

  54. Allen, E., Horvath, S., Tong, F., et al., High concentrations of long interspersed nuclear element sequence distinguish monoallelically expressed genes, Proc. Natl. Acad. Sci. U.S.A., 2003, vol. 100, no. 17, pp. 9940–9945. doi 10.1073/pnas.1737401100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Paco, A., Adega, F., and Chaves, R., LINE-1 retrotransposons: from ‘parasite’ sequences to functional elements, J. Appl. Genet., 2014. doi 10.1007/s13353-014-0241-x

    Google Scholar 

  56. Chow, J.C., Ciaudo, C., Fazzari, M.J., et al., LINE-1 activity in facultative heterochromatin formation during X chromosome inactivation, Cell, 2010, vol. 141, no. 6, pp. 956–969. doi 10.1016/j.cell.2010.04.042

    Article  CAS  PubMed  Google Scholar 

  57. Rosser, J.M., and An, W., L1 expression and regulation in humans and rodents, Front. Biosci., 2012, vol. 4, pp. 2203–2225. 10.2741

    Article  Google Scholar 

  58. Vasil’ev, S.A., Tolmacheva, E.N., Kashevarova, A.A., et al., Methylation status of LINE-1 retrotransposon in chromosomal mosaicism during early stages of human embryonic development, Mol. Biol. (Moscow), 2015, vol. 49, no. 1, pp. 144–152. doi 10.7868/S0026898414060196

    Article  Google Scholar 

  59. Price, E.M., Cotton, A.M., Penaherrera, M.S., et al., Different measures of “genome-wide” DNA methylation exhibit unique properties in placental and somatic tissues, Epigenetics, 2012, vol. 7, no. 6, pp. 652–663. doi 10.4161/epi.20221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. He, Z.M., Li, J., Hwa, Y.L., et al., Transition of LINE-1 DNA methylation status and altered expression in first and third trimester placentas, PLoS One, 2014, vol. 9, no. 5. e96994. doi 10.1371/journal.pone.0096994

    Article  Google Scholar 

  61. Mi, S., Lee, X., Li, X., et al., Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis, Nature, 2000, vol. 403, no. 6771, pp. 785–789. doi 10.1038/35001608

    Article  CAS  PubMed  Google Scholar 

  62. Sugimoto, J., Sugimoto, M., Bernstein, H., et al., A novel human endogenous retroviral protein inhibits cell–cell fusion, Sci. Rep., 2013, vol. 3, p. 1462. doi 10.1038/srep01462

    PubMed  PubMed Central  Google Scholar 

  63. Yin, L.J., Zhang, Y., Lv, P.P., et al., Insufficient maintenance DNA methylation is associated with abnormal embryonic development, BMC Med., 2012, vol. 10, p. 26. doi 10.1186/1741-7015-10-26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Perrin, D., Ballestar, E., Fraga, M.F., et al., Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta, Oncogene, 2007, vol. 26, no. 17, pp. 2518–2524. doi 10.1038/sj.onc.1210039

    Article  CAS  PubMed  Google Scholar 

  65. Tolmacheva, E.N., Kashevarova, A.A., Skryabin, N.A., and Lebedev, I.N., Epigenetic effects of trisomy 16 in human placenta, Mol. Biol. (Moscow), 2013, vol. 47, no. 3, pp. 373–381. doi 10.7868/S002689841303018X

    Article  CAS  Google Scholar 

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  1. Institute of Medical Genetics, Tomsk National Research Center, Russian Academy of Sciences, Tomsk, 634050, Russia

    S. A. Vasilyev, E. N. Tolmacheva & I. N. Lebedev

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Original Russian Text © S.A. Vasilyev, E.N. Tolmacheva, I.N. Lebedev, 2016, published in Genetika, 2016, Vol. 52, No. 12, pp. 1349–1357.

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Vasilyev, S.A., Tolmacheva, E.N. & Lebedev, I.N. Epigenetic regulation and role of LINE-1 retrotransposon in embryogenesis. Russ J Genet 52, 1219–1226 (2016). https://doi.org/10.1134/S1022795416120152

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