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Silencing of endogenous retroviruses by heterochromatin

Abstract

Endogenous retroviruses (ERV) are an abundant class of repetitive elements in mammalian genomes. To ensure genomic stability, ERVs are largely transcriptionally silent. However, these elements also feature physiological roles in distinct developmental contexts, under which silencing needs to be partially relieved. ERV silencing is mediated through a heterochromatic structure, which is established by histone modification and DNA methylation machineries. This heterochromatic structure is largely refractory to transcriptional stimulation, however, challenges to the heterochromatic state, such as DNA replication, require re-establishment of the heterochromatic state in competition with transcriptional activators. In this review, we discuss the major pathways leading to efficient establishment of robust and inaccessible heterochromatin across ERVs.

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References

  1. Aravin AA, Sachidanandam R, Bourc’his D, Schaefer C, Pezic D, Fejes Toth K, Bestor T, Hannon GJ (2008) A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol Cell 31:785–799

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Aravin AA, Sachidanandam R, Girard A, Fejes-Toth K, Hannon GJ (2007) Developmentally regulated piRNA clusters implicate MILI in transposon control. Science 316:744–747

    CAS  Article  PubMed  Google Scholar 

  3. Bannert N, Kurth R (2004). Retroelements and the human genome: new perspectives on an old relation. Proc Natl Acad Sci USA 101 Suppl 2:14572–14579

    Article  PubMed  Google Scholar 

  4. Bannert N, Kurth R (2006) The evolutionary dynamics of human endogenous retroviral families. Annu Rev Genom Hum Genet 7:149–173

    CAS  Article  Google Scholar 

  5. Barau J, Teissandier A, Zamudio N, Roy S, Nalesso V, Hérault Y, Guillou F, Bourc’his D (2016) The DNA methyltransferase DNMT3C protects male germ cells from transposon activity. Science 354:909

    CAS  Article  PubMed  Google Scholar 

  6. Belancio VP, Roy-Engel AM, Deininger PL (2010) All y’all need to know ‘bout retroelements in cancer. Semin Cancer Biol 20:200–210

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Bierhoff H, Dammert MA, Brocks D, Dambacher S, Schotta G, Grummt I (2014) Quiescence-induced LncRNAs trigger H4K20 trimethylation and transcriptional silencing. Mol Cell 54:675–682

    CAS  Article  PubMed  Google Scholar 

  8. Bourc’his D, Bestor TH (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431:96–99

    Article  PubMed  Google Scholar 

  9. Bulut-Karslioglu A, De La Rosa-Velazquez IA, Ramirez F, Barenboim M, Onishi-Seebacher M, Arand J, Galan C, Winter GE, Engist B, Gerle B et al (2014) Suv39h-dependent H3K9me3 marks intact retrotransposons and silences LINE elements in mouse embryonic stem cells. Mol Cell 55:277–290

    CAS  Article  PubMed  Google Scholar 

  10. Bulut-Karslioglu A, Perrera V, Scaranaro M, de la Rosa-Velazquez IA, van de Nobelen S, Shukeir N, Popow J, Gerle B, Opravil S, Pagani M et al (2012) A transcription factor-based mechanism for mouse heterochromatin formation. Nat Struct Mol Biol 19:1023–1030

    CAS  Article  PubMed  Google Scholar 

  11. Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, Hein A, Rote NS, Cope LM, Snyder A et al (2015) Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162:974–986

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Coffin JM, Hughes SH, Varmus HE (1997). Retroviruses. Cold Spring Harbor Laboratory Press, NY

    Google Scholar 

  13. Collins PL, Kyle KE, Egawa T, Shinkai Y, Oltz EM (2015) The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes. Proc Natl Acad Sci USA 112:8367–8372

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Cordaux R, Batzer MA (2009) The impact of retrotransposons on human genome evolution. Nat Rev Genet 10:691–703

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Cordaux R, Hedges DJ, Herke SW, Batzer MA (2006) Estimating the retrotransposition rate of human Alu elements. Gene 373:134–137

    CAS  Article  PubMed  Google Scholar 

  16. Cubenas-Potts C, Matunis MJ (2013) SUMO: a multifaceted modifier of chromatin structure and function. Dev Cell 24:1–12

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. de Koning AP, Gu W, Castoe TA, Batzer MA, Pollock DD (2011) Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet 7:e1002384

    Article  PubMed  PubMed Central  Google Scholar 

  18. Dewannieux M, Dupressoir A, Harper F, Pierron G, Heidmann T (2004) Identification of autonomous IAP LTR retrotransposons mobile in mammalian cells. Nat Genet 36:534–539

    CAS  Article  PubMed  Google Scholar 

  19. Doolittle WF, Sapienza C (1980) Selfish genes, the phenotype paradigm and genome evolution. Nature 284:601–603

    CAS  Article  PubMed  Google Scholar 

  20. Drane P, Ouararhni K, Depaux A, Shuaib M, Hamiche A (2010) The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev 24:1253–1265

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Ecco G, Cassano M, Kauzlaric A, Duc J, Coluccio A, Offner S, Imbeault M, Rowe HM, Turelli P, Trono D (2016) Transposable elements and their KRAB-ZFP controllers regulate gene expression in adult tissues. Dev Cell 36:611–623

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Elisaphenko EA, Kolesnikov NN, Shevchenko AI, Rogozin IB, Nesterova TB, Brockdorff N, Zakian SM (2008) A dual origin of the Xist gene from a protein-coding gene and a set of transposable elements. PloS One 3:e2521

    Article  PubMed  PubMed Central  Google Scholar 

  23. Elsasser SJ, Noh KM, Diaz N, Allis CD, Banaszynski LA (2015) Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells. Nature 522:240–244

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Eymery A, Liu Z, Ozonov EA, Stadler MB, Peters AHFM (2016) The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos. Development 143:2767

    CAS  Article  PubMed  Google Scholar 

  25. Fasching L, Kapopoulou A, Sachdeva R, Petri R, Jonsson ME, Manne C, Turelli P, Jern P, Cammas F, Trono D, et al (2015) TRIM28 represses transcription of endogenous retroviruses in neural progenitor cells. Cell Rep 10:20–28

    CAS  Article  PubMed  Google Scholar 

  26. Faulkner GJ, Kimura Y, Daub CO, Wani S, Plessy C, Irvine KM, Schroder K, Cloonan N, Steptoe AL, Lassmann T et al (2009) The regulated retrotransposon transcriptome of mammalian cells. Nat Genet 41:563–571

    CAS  Article  PubMed  Google Scholar 

  27. Feschotte C, Pritham EJ (2007) DNA transposons and the evolution of eukaryotic genomes. Annu Rev Genet 41:331–368

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Fort A, Hashimoto K, Yamada D, Salimullah M, Keya CA, Saxena A, Bonetti A, Voineagu I, Bertin N, Kratz A et al (2014) Deep transcriptome profiling of mammalian stem cells supports a regulatory role for retrotransposons in pluripotency maintenance. Nat Genet 46:558–566

    CAS  Article  PubMed  Google Scholar 

  29. Friedli M, Trono D (2015) The developmental control of transposable elements and the evolution of higher species. Annu Rev Cell Dev Biol 31:429–451

    CAS  Article  PubMed  Google Scholar 

  30. Gifford R, Tristem M (2003) The evolution, distribution and diversity of endogenous retroviruses. Virus Genes 26:291–315

    CAS  Article  PubMed  Google Scholar 

  31. Gifford WD, Pfaff SL, Macfarlan TS (2013) Transposable elements as genetic regulatory substrates in early development. Trends Cell Biol 23:218–226

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Göke J, Lu X, Chan Y-S, Ng H-H, Ly L-H, Sachs F, Szczerbinska I (2015) Dynamic transcription of distinct classes of endogenous retroviral elements marks specific populations of early human embryonic cells. Cell Stem Cell 16:135–141

    Article  PubMed  Google Scholar 

  33. Goldberg AD, Banaszynski LA, Noh KM, Lewis PW, Elsaesser SJ, Stadler S, Dewell S, Law M, Guo X, Li X et al (2010) Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140:678–691

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Gonzalez-Sandoval A, Towbin, Benjamin D., Kalck V, Cabianca, Daphne S., Gaidatzis D, Hauer, Michael H., Geng L, Wang L, Yang T, Wang X et al (2015) Perinuclear anchoring of H3K9-methylated chromatin stabilizes induced cell fate in C. elegans embryos. Cell 163:1333–1347

    CAS  Article  PubMed  Google Scholar 

  35. Hancks DC, Kazazian HH (2012) Active human retrotransposons: variation and disease. Curr Opin Genet Dev 22:191–203

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. He Q, Kim H, Huang R, Lu W, Tang M, Shi F, Yang D, Zhang X, Huang J, Liu D, et al (2015) The Daxx/Atrx complex protects tandem repetitive elements during DNA hypomethylation by promoting H3K9 trimethylation. Cell Stem Cell 17:273–286

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Hutnick LK, Golshani P, Namihira M, Xue Z, Matynia A, Yang XW, Silva AJ, Schweizer FE, Fan G (2009) DNA hypomethylation restricted to the murine forebrain induces cortical degeneration and impairs postnatal neuronal maturation. Hum Mol Genet 18:2875–2888

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Hutnick LK, Huang X, Loo TC, Ma Z, Fan G (2010) Repression of retrotransposal elements in mouse embryonic stem cells is primarily mediated by a DNA methylation-independent mechanism. J Biol Chem 285:21082–21091

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Ivanov AV, Peng H, Yurchenko V, Yap KL, Negorev DG, Schultz DC, Psulkowski E, Fredericks WJ, White DE, Maul GG et al (2007) PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing. Mol Cell 28:823–837

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Jacobs FM, Greenberg D, Nguyen N, Haeussler M, Ewing AD, Katzman S, Paten B, Salama SR, Haussler D (2014) An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature 516:242–245

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Jern P, Coffin JM (2008) Effects of retroviruses on host genome function. Annu Rev Genet 42:709–732

    CAS  Article  PubMed  Google Scholar 

  42. Johnson WE (2015) Endogenous retroviruses in the genomics era. Annu Rev Virol 2:135–159

    CAS  Article  PubMed  Google Scholar 

  43. Karimi MM, Goyal P, Maksakova IA, Bilenky M, Leung D, Tang JX, Shinkai Y, Mager DL, Jones S, Hirst M et al (2011) DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs. Cell Stem Cell 8:676–687

    CAS  Article  PubMed  Google Scholar 

  44. Kelley DR, Hendrickson DG, Tenen D, Rinn JL (2014) Transposable elements modulate human RNA abundance and splicing via specific RNA-protein interactions. Genome Biol 15:537

    Article  PubMed  PubMed Central  Google Scholar 

  45. Kramerov DA, Vassetzky NS (2011) SINEs. Wiley Interdiscip Rev RNA 2:772–786

    CAS  Article  PubMed  Google Scholar 

  46. Kuramochi-Miyagawa S, Watanabe T, Gotoh K, Totoki Y, Toyoda A, Ikawa M, Asada N, Kojima K, Yamaguchi Y, Ijiri TW et al (2008) DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes Dev 22:908–917

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Consortium IHGS (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921

    CAS  Article  PubMed  Google Scholar 

  48. Lewis PW, Elsaesser SJ, Noh K-M, Stadler SC, Allis CD (2010) Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci USA 107:14075–14080

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Li J, Kannan M, Trivett AL, Liao H, Wu X, Akagi K, Symer DE (2014) An antisense promoter in mouse L1 retrotransposon open reading frame-1 initiates expression of diverse fusion transcripts and limits retrotransposition. Nucleic Acids Res 42:4546–4562

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Li W, Lee M-H, Henderson L, Tyagi R, Bachani M, Steiner J, Campanac E, Hoffman DA, von Geldern G, Johnson K et al (2015) Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med 7:307ra153–307ra153

    Article  PubMed  Google Scholar 

  51. Liu S, Brind’Amour J, Karimi MM, Shirane K, Bogutz A, Lefebvre L, Sasaki H, Shinkai Y, Lorincz MC (2014) Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells. Genes Dev 28:2041–2055

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Liu X, Gao Q, Li P, Zhao Q, Zhang J, Li J, Koseki H, Wong J (2013) UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi-methylated DNA and methylated H3K9. Nat Commun 4:1563

    Article  PubMed  Google Scholar 

  53. Lu X, Sachs F, Ramsay L, Jacques P-É, Göke J, Bourque G, Ng H-H (2014) The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity. Nat Struct Mol Biol 21:423–425

    CAS  Article  PubMed  Google Scholar 

  54. Macfarlan TS, Gifford WD, Driscoll S, Lettieri K, Rowe HM, Bonanomi D, Firth A, Singer O, Trono D, Pfaff SL (2012) ES cell potency fluctuates with endogenous retrovirus activity. Nature 487:57–63

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Maison C, Bailly D, Roche D, de Oca RM, Probst AV, Vassias I, Dingli F, Lombard B, Loew D, Quivy J-P et al (2011) SUMOylation promotes de novo targeting of HP1[alpha] to pericentric heterochromatin. Nat Genet 43:220–227

    CAS  Article  PubMed  Google Scholar 

  56. Maksakova IA, Goyal P, Bullwinkel J, Brown JP, Bilenky M, Mager DL, Singh PB, Lorincz MC (2011) H3K9me3-binding proteins are dispensable for SETDB1/H3K9me3-dependent retroviral silencing. Epigenet Chromatin 4:12–12

    CAS  Article  Google Scholar 

  57. Manakov SA, Pezic D, Marinov GK, Pastor WA, Sachidanandam R, Aravin AA (2015) MIWI2 and MILI have differential effects on piRNA biogenesis and DNA methylation. Cell Rep 12:1234–1243

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Matsui T, Leung D, Miyashita H, Maksakova IA, Miyachi H, Kimura H, Tachibana M, Lorincz MC, Shinkai Y (2010) Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464:927–931

    CAS  Article  PubMed  Google Scholar 

  59. Medstrand P, van de Lagemaat LN, Dunn CA, Landry JR, Svenback D, Mager DL (2005) Impact of transposable elements on the evolution of mammalian gene regulation. Cytogenet Genome Res 110:342–352

    CAS  Article  PubMed  Google Scholar 

  60. Mi S, Lee X, Li, X.-p., Veldman GM, Finnerty H, Racie L, LaVallie E, Tang X-Y, Edouard P, Howes S et al (2000) Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403:785–789

    CAS  Article  PubMed  Google Scholar 

  61. Müller-Ott K, Erdel F, Matveeva A, Mallm JP, Rademacher A, Hahn M, Bauer C, Zhang Q, Kaltofen S, Schotta G et al (2014) Specificity, propagation, and memory of pericentric heterochromatin. Mol Syst Biol 10:746

    Article  PubMed  PubMed Central  Google Scholar 

  62. Orgel LE, Crick FHC (1980) Selfish DNA: the ultimate parasite. Nature 284:604–607

    CAS  Article  PubMed  Google Scholar 

  63. Pasquarella A, Ebert A, Pereira de Almeida G, Hinterberger M, Kazerani M, Nuber A, Ellwart J, Klein L, Busslinger M, Schotta G (2016) Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro-B cells. Development 143:1788–1799

    CAS  Article  PubMed  Google Scholar 

  64. Pastor WA, Stroud H, Nee K, Liu W, Pezic D, Manakov S, Lee SA, Moissiard G, Zamudio N, Bourc’his D et al (2014) MORC1 represses transposable elements in the mouse male germline. Nat Commun 5:5795

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Peaston AE, Evsikov AV, Graber JH, de Vries WN, Holbrook AE, Solter D, Knowles BB (2004) Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos. Dev Cell 7:597–606

    CAS  Article  PubMed  Google Scholar 

  66. Politz JC, Scalzo D, Groudine M (2015) The redundancy of the mammalian heterochromatic compartment. Curr Opin Genet Dev 37:1–8

    Article  PubMed  Google Scholar 

  67. Ramírez MA, Pericuesta E, Fernandez-Gonzalez R, Moreira P, Pintado B, Gutierrez-Adan A (2006) Transcriptional and post-transcriptional regulation of retrotransposons IAP and MuERV-L affect pluripotency of mice ES cells. Reprod Biol Endocrinol 4:55–55

    Article  PubMed  PubMed Central  Google Scholar 

  68. Rebollo R, Karimi MM, Bilenky M, Gagnier L, Miceli-Royer K, Zhang Y, Goyal P, Keane TM, Jones S, Hirst M et al (2011) Retrotransposon-induced heterochromatin spreading in the mouse revealed by insertional polymorphisms. PLoS Genet 7:e1002301

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. Rebollo R, Romanish MT, Mager DL (2012) Transposable elements: an abundant and natural source of regulatory sequences for host genes. Annu Rev Genet 46:21–42

    CAS  Article  PubMed  Google Scholar 

  70. Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, Han H, Liang G, Jones PA, Pugh TJ et al (2015) DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162:961–973

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Rowe HM, Jakobsson J, Mesnard D, Rougemont J, Reynard S, Aktas T, Maillard PV, Layard-Liesching H, Verp S, Marquis J et al (2010) KAP1 controls endogenous retroviruses in embryonic stem cells. Nature 463:237–240

    CAS  Article  PubMed  Google Scholar 

  72. Rowe HM, Kapopoulou A, Corsinotti A, Fasching L, Macfarlan TS, Tarabay Y, Viville S, Jakobsson J, Pfaff SL, Trono D (2013) TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells. Genome Res 23:452–461

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Sadic D, Schmidt K, Groh S, Kondofersky I, Ellwart J, Fuchs C, Theis FJ, Schotta G (2015) Atrx promotes heterochromatin formation at retrotransposons. EMBO Rep 16:836–850

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ, 3rd (2002) SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev 16:919–932

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. Sharif J, Endo TA, Nakayama M, Karimi MM, Shimada M, Katsuyama K, Goyal P, Brind’Amour J, Sun M-A, Sun Z et al (2016) Activation of endogenous retroviruses in dnmt1(−/−) ESCs involves disruption of SETDB1-mediated repression by NP95 binding to hemimethylated DNA. Cell Stem Cell 19:81–94

    CAS  Article  PubMed  Google Scholar 

  76. Slokar G, Hasler G (2015) Human endogenous retroviruses as pathogenic factors in the development of schizophrenia. Front Psychiatry 6:183

    PubMed  Google Scholar 

  77. Solovei I, Wang AS, Thanisch K, Schmidt CS, Krebs S, Zwerger M, Cohen TV, Devys D, Foisner R, Peichl L et al (2013) LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell 152:584–598

    CAS  Article  PubMed  Google Scholar 

  78. Stein P, Rozhkov NV, Li F, Cárdenas FL, Davydenk O, Vandivier LE, Gregory BD, Hannon GJ, Schultz RM (2015) Essential role for endogenous siRNAs during meiosis in mouse oocytes. PLoS Genet 11:e1005013

    Article  PubMed  PubMed Central  Google Scholar 

  79. Stocking C, Kozak CA (2008) Murine endogenous retroviruses. Cell Mol Life Sci CMLS 65:3383–3398

    CAS  Article  PubMed  Google Scholar 

  80. Tan SL, Nishi M, Ohtsuka T, Matsui T, Takemoto K, Kamio-Miura A, Aburatani H, Shinkai Y, Kageyama R (2012) Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development. Development 139:3806–3816

    CAS  Article  PubMed  Google Scholar 

  81. Tan X, Xu X, Elkenani M, Smorag L, Zechner U, Nolte J, Engel W, Pantakani DV (2013) Zfp819, a novel KRAB-zinc finger protein, interacts with KAP1 and functions in genomic integrity maintenance of mouse embryonic stem cells. Stem Cell Res 11:1045–1059

    CAS  Article  PubMed  Google Scholar 

  82. Tanskanen JA, Sabot F, Vicient C, Schulman AH (2007) Life without GAG: the BARE-2 retrotransposon as a parasite’s parasite. Gene 390:166–174

    CAS  Article  PubMed  Google Scholar 

  83. Theunissen TW, Friedli M, He Y, Planet E, O’Neil RC, Markoulaki S, Pontis J, Wang H, Iouranova A, Imbeault M et al (2016) molecular criteria for defining the naive human pluripotent state. Cell Stem Cell 19:502–515

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. Thompson PJ, Dulberg V, Moon K-M, Foster LJ, Chen C, Karimi MM, Lorincz MC (2015) hnRNP K coordinates transcriptional silencing by SETDB1 in embryonic stem cells. PLoS Genet 11:e1004933

    Article  PubMed  PubMed Central  Google Scholar 

  85. Thompson PJ, Macfarlan TS, Lorincz MC (2016) Long terminal repeats: from parasitic elements to building blocks of the transcriptional regulatory repertoire. Mol Cell 62:766–776

  86. Uchimura Y, Ichimura T, Uwada J, Tachibana T, Sugahara S, Nakao M, Saitoh H (2006) Involvement of SUMO Modification in MBD1- and MCAF1-mediated Heterochromatin Formation. J Biol Chem 281:23180–23190

    CAS  Article  PubMed  Google Scholar 

  87. Udugama MM, Chang FT, Chan FL, Tang MC, Pickett HAR, McGhie JD, Mayne L, Collas P, Mann JR, Wong LH (2015) Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres. Nucleic Acids Res 43:10227–10237

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Veselovska L, Smallwood SA, Saadeh H, Stewart KR, Krueger F, Maupetit-Méhouas S, Arnaud P, Tomizawa, S.-i., Andrews S, Kelsey G (2015) Deep sequencing and de novo assembly of the mouse oocyte transcriptome define the contribution of transcription to the DNA methylation landscape. Genome Biol 16:209

    Article  PubMed  PubMed Central  Google Scholar 

  89. Volkman HE, Stetson DB (2014) The enemy within: endogenous retroelements and autoimmune disease. Nature Immunol 15:415–422

    CAS  Article  Google Scholar 

  90. Voon HP, Hughes JR, Rode C, De La R-V, Inti A, Jenuwein T, Feil R, Higgs DR Gibbons RJ (2015) ATRX plays a key role in maintaining silencing at interstitial heterochromatic loci and imprinted genes. Cell Rep 11:405–418

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. Walsh CP, Chaillet JR, Bestor TH (1998) Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20:116–117

    CAS  Article  PubMed  Google Scholar 

  92. Watanabe T, Totoki Y, Toyoda A, Kaneda M, Kuramochi-Miyagawa S, Obata Y, Chiba H, Kohara Y, Kono T, Nakano T et al (2008) Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453:539–543

    CAS  Article  PubMed  Google Scholar 

  93. Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Lander ES (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420:520–562

    CAS  Article  PubMed  Google Scholar 

  94. Werner A (2013) Biological functions of natural antisense transcripts. BMC Biol 11:31

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. Wolf D, Goff SP (2009) Embryonic stem cells use ZFP809 to silence retroviral DNAs. Nature 458:1201–1204

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. Wolf G, Yang P, Fuchtbauer AC, Fuchtbauer EM, Silva AM, Park C, Wu W, Nielsen AL, Pedersen FS, Macfarlan TS (2015) The KRAB zinc finger protein ZFP809 is required to initiate epigenetic silencing of endogenous retroviruses. Genes Dev 29:538–554

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. Yang BX, El Farran CA, Guo HC, Yu T, Fang HT, Wang HF, Schlesinger S, Seah YF, Goh GY, Neo SP et al (2015) Systematic identification of factors for provirus silencing in embryonic stem cells. Cell 163:230–245

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. Yang N, Kazazian HH (2006) L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nat Struct Mol Biol 13:763–771

    CAS  Article  PubMed  Google Scholar 

  99. Young GR, Eksmond U, Salcedo R, Alexopoulou L, Stoye JP, Kassiotis G (2012) Resurrection of endogenous retroviruses in antibody-deficient mice. Nature 491:774–778

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Work in the lab of G.S. was funded by Deutsche Forschungsgemeinschaft (SFB 1064 and SPP1923).

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Correspondence to Gunnar Schotta.

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Groh, S., Schotta, G. Silencing of endogenous retroviruses by heterochromatin. Cell. Mol. Life Sci. 74, 2055–2065 (2017). https://doi.org/10.1007/s00018-017-2454-8

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Keywords

  • ERV restriction
  • Setdb1
  • Trim28
  • Daxx
  • Atrx
  • H3K9me3
  • Retrotransposons
  • Transposable elements
  • TEs