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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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
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
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
Bannert N, Kurth R (2006) The evolutionary dynamics of human endogenous retroviral families. Annu Rev Genom Hum Genet 7:149–173
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
Belancio VP, Roy-Engel AM, Deininger PL (2010) All y’all need to know ‘bout retroelements in cancer. Semin Cancer Biol 20:200–210
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
Bourc’his D, Bestor TH (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431:96–99
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
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
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
Coffin JM, Hughes SH, Varmus HE (1997). Retroviruses. Cold Spring Harbor Laboratory Press, NY
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
Cordaux R, Batzer MA (2009) The impact of retrotransposons on human genome evolution. Nat Rev Genet 10:691–703
Cordaux R, Hedges DJ, Herke SW, Batzer MA (2006) Estimating the retrotransposition rate of human Alu elements. Gene 373:134–137
Cubenas-Potts C, Matunis MJ (2013) SUMO: a multifaceted modifier of chromatin structure and function. Dev Cell 24:1–12
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
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
Doolittle WF, Sapienza C (1980) Selfish genes, the phenotype paradigm and genome evolution. Nature 284:601–603
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
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
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
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
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
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
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
Feschotte C, Pritham EJ (2007) DNA transposons and the evolution of eukaryotic genomes. Annu Rev Genet 41:331–368
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
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
Gifford R, Tristem M (2003) The evolution, distribution and diversity of endogenous retroviruses. Virus Genes 26:291–315
Gifford WD, Pfaff SL, Macfarlan TS (2013) Transposable elements as genetic regulatory substrates in early development. Trends Cell Biol 23:218–226
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
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
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
Hancks DC, Kazazian HH (2012) Active human retrotransposons: variation and disease. Curr Opin Genet Dev 22:191–203
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
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
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
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
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
Jern P, Coffin JM (2008) Effects of retroviruses on host genome function. Annu Rev Genet 42:709–732
Johnson WE (2015) Endogenous retroviruses in the genomics era. Annu Rev Virol 2:135–159
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
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
Kramerov DA, Vassetzky NS (2011) SINEs. Wiley Interdiscip Rev RNA 2:772–786
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Orgel LE, Crick FHC (1980) Selfish DNA: the ultimate parasite. Nature 284:604–607
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
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
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
Politz JC, Scalzo D, Groudine M (2015) The redundancy of the mammalian heterochromatic compartment. Curr Opin Genet Dev 37:1–8
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
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
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
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
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
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
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
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
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
Slokar G, Hasler G (2015) Human endogenous retroviruses as pathogenic factors in the development of schizophrenia. Front Psychiatry 6:183
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
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
Stocking C, Kozak CA (2008) Murine endogenous retroviruses. Cell Mol Life Sci CMLS 65:3383–3398
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
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
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
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
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
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
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
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
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
Volkman HE, Stetson DB (2014) The enemy within: endogenous retroelements and autoimmune disease. Nature Immunol 15:415–422
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
Walsh CP, Chaillet JR, Bestor TH (1998) Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20:116–117
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
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
Werner A (2013) Biological functions of natural antisense transcripts. BMC Biol 11:31
Wolf D, Goff SP (2009) Embryonic stem cells use ZFP809 to silence retroviral DNAs. Nature 458:1201–1204
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
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
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
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
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Work in the lab of G.S. was funded by Deutsche Forschungsgemeinschaft (SFB 1064 and SPP1923).
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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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DOI: https://doi.org/10.1007/s00018-017-2454-8