Retrotransposons are "copy-and-paste" insertional mutagens that substantially contribute to mammalian genome content. Retrotransposons often carry long terminal repeats (LTRs) for retrovirus-like reverse transcription and integration into the genome. We report an extraordinary impact of a group of LTRs from the mammalian endogenous retrovirus-related ERVL retrotransposon class on gene expression in the germline and beyond. In mouse, we identified more than 800 LTRs from ORR1, MT, MT2, and MLT families, which resemble mobile gene-remodeling platforms that supply promoters and first exons. The LTR-mediated gene remodeling also extends to hamster, human, and bovine oocytes. The LTRs function in a stage-specific manner during the oocyte-to-embryo transition by activating transcription, altering protein-coding sequences, producing noncoding RNAs, and even supporting evolution of new protein-coding genes. These functions result, for example, in recycling processed pseudogenes into mRNAs or lncRNAs with regulatory roles. The functional potential of the studied LTRs is even higher, because we show that dormant LTR promoter activity can rescue loss of an essential upstream promoter. We also report a novel protein-coding gene evolution-D6Ertd527e-in which an MT LTR provided a promoter and the 5' exon with a functional start codon while the bulk of the protein-coding sequence evolved through a CAG repeat expansion. Altogether, ERVL LTRs provide molecular mechanisms for stochastically scanning, rewiring, and recycling genetic information on an extraordinary scale. ERVL LTRs thus offer means for a comprehensive survey of the genome's expression potential, tightly intertwining with gene expression and evolution in the germline.

Bioinformatics Group Division of Molecular Biology Department of Biology Faculty of Science University of Zagreb 10000 Zagreb Croatia

Department of Biology University of Pennsylvania Philadelphia Pennsylvania 19104 USA

Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences The University of Tokyo Kashiwa 277 8562 Japan

Department of Integrated Biosciences Graduate School of Frontier Sciences The University of Tokyo Kashiwa 277 8562 Japan

Institute of Molecular Genetics Academy of Sciences of the Czech Republic 142 20 Prague 4 Czech Republic

Zobrazit více v PubMed

Abe K, Yamamoto R, Franke V, Cao M, Suzuki Y, Suzuki MG, Vlahovicek K, Svoboda P, Schultz RM, Aoki F. 2015. The first murine zygotic transcription is promiscuous and uncoupled from splicing and 3′ processing. EMBO J 34: 1523–1537. PubMed PMC

Bénit L, De Parseval N, Casella JF, Callebaut I, Cordonnier A, Heidmann T. 1997. Cloning of a new murine endogenous retrovirus, MuERV-L, with strong similarity to the human HERV-L element and with a gag coding sequence closely related to the Fv1 restriction gene. J Virol 71: 5652–5657. PubMed PMC

Blum ES, Schwendeman AR, Shaham S. 2013. PolyQ disease: misfiring of a developmental cell death program? Trends Cell Biol 23: 168–174. PubMed PMC

Chen L, DeVries AL, Cheng CH. 1997a. Convergent evolution of antifreeze glycoproteins in Antarctic notothenioid fish and Arctic cod. Proc Natl Acad Sci 94: 3817–3822. PubMed PMC

Chen L, DeVries AL, Cheng CH. 1997b. Evolution of antifreeze glycoprotein gene from a trypsinogen gene in Antarctic notothenioid fish. Proc Natl Acad Sci 94: 3811–3816. PubMed PMC

Chew TG, Peaston A, Lim AK, Lorthongpanich C, Knowles BB, Solter D. 2013. A tudor domain protein SPINDLIN1 interacts with the mRNA-binding protein SERBP1 and is involved in mouse oocyte meiotic resumption. PLoS One 8: e69764. PubMed PMC

Chuong EB, Rumi MA, Soares MJ, Baker JC. 2013. Endogenous retroviruses function as species-specific enhancer elements in the placenta. Nat Genet 45: 325–329. PubMed PMC

Chuong EB, Elde NC, Feschotte C. 2016. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science 351: 1083–1087. PubMed PMC

Costas J. 2003. Molecular characterization of the recent intragenomic spread of the murine endogenous retrovirus MuERV-L. J Mol Evol 56: 181–186. PubMed

Craig NL, Chandler M, Gellert M, Lambowitz AM, Rice PA, Sandmeyer SB. 2015. Mobile DNA III. AMS Press, Washington, DC.

Crichton JH, Dunican DS, Maclennan M, Meehan RR, Adams IR. 2014. Defending the genome from the enemy within: mechanisms of retrotransposon suppression in the mouse germline. Cell Mol Life Sci 71: 1581–1605. PubMed PMC

de Souza FS, Franchini LF, Rubinstein M. 2013. Exaptation of transposable elements into novel cis-regulatory elements: is the evidence always strong? Mol Biol Evol 30: 1239–1251. PubMed PMC

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. PubMed PMC

Ferrigno O, Virolle T, Djabari Z, Ortonne JP, White RJ, Aberdam D. 2001. Transposable B2 SINE elements can provide mobile RNA polymerase II promoters. Nat Genet 28: 77–81. PubMed

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

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. PubMed

Gerdes P, Richardson SR, Mager DL, Faulkner GJ. 2016. Transposable elements in the mammalian embryo: pioneers surviving through stealth and service. Genome Biol 17: 100. PubMed PMC

Göke J, Ng HH. 2016. CTRL+INSERT: retrotransposons and their contribution to regulation and innovation of the transcriptome. EMBO Rep 17: 1131–1144. PubMed PMC

Hancks DC, Kazazian HH Jr. 2012. Active human retrotransposons: variation and disease. Curr Opin Genet Dev 22: 191–203. PubMed PMC

Hubley R, Finn RD, Clements J, Eddy SR, Jones TA, Bao W, Smit AF, Wheeler TJ. 2016. The Dfam database of repetitive DNA families. Nucleic Acids Res 44: D81–D89. PubMed PMC

Karlic R, Ganesh S, Franke V, Svobodova E, Urbanova J, Suzuki Y, Aoki F, Vlahovicek K, Svoboda P. 2017. Long non-coding RNA exchange during oocyte-to-embryo transition in mice. DNA Res 10.1093/dnares/dsw058. PubMed DOI

Katzourakis A, Rambaut A, Pybus OG. 2005. The evolutionary dynamics of endogenous retroviruses. Trends Microbiol 13: 463–468. PubMed

Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D. 2002. The human genome browser at UCSC. Genome Res 12: 996–1006. PubMed PMC

Kigami D, Minami N, Takayama H, Imai H. 2003. MuERV-L is one of the earliest transcribed genes in mouse one-cell embryos. Biol Reprod 68: 651–654. PubMed

Lim AK, Lorthongpanich C, Chew TG, Tan CW, Shue YT, Balu S, Gounko N, Kuramochi-Miyagawa S, Matzuk MM, Chuma S, et al. 2013. The nuage mediates retrotransposon silencing in mouse primordial ovarian follicles. Development 140: 3819–3825. PubMed PMC

Lim CY, Knowles BB, Solter D, Messerschmidt DM. 2016. Epigenetic control of early mouse development. Curr Topics Dev Biol 120: 311–360. PubMed

Long M, Betran E, Thornton K, Wang W. 2003. The origin of new genes: glimpses from the young and old. Nat Rev Genet 4: 865–875. PubMed

Lynch VJ, Nnamani MC, Kapusta A, Brayer K, Plaza SL, Mazur EC, Emera D, Sheikh SZ, Grutzner F, Bauersachs S, et al. 2015. Ancient transposable elements transformed the uterine regulatory landscape and transcriptome during the evolution of mammalian pregnancy. Cell Rep 10: 551–561. PubMed PMC

Macfarlan TS, Gifford WD, Agarwal S, Driscoll S, Lettieri K, Wang J, Andrews SE, Franco L, Rosenfeld MG, Ren B, et al. 2011. Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A. Genes Dev 25: 594–607. PubMed PMC

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

Mager DL, Stoye JP. 2015. Mammalian endogenous retroviruses. Microbiol Spectr 3: MDNA3-0009-2014. PubMed

Maksakova IA, Romanish MT, Gagnier L, Dunn CA, van de Lagemaat LN, Mager DL. 2006. Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS Genet 2: e2. PubMed PMC

Maksakova IA, Thompson PJ, Goyal P, Jones SJ, Singh PB, Karimi MM, Lorincz MC. 2013. Distinct roles of KAP1, HP1 and G9a/GLP in silencing of the two-cell-specific retrotransposon MERVL in mouse ES cells. Epigenet Chromatin 6: 15. PubMed PMC

McCarthy EM, McDonald JF. 2004. Long terminal repeat retrotransposons of Mus musculus. Genome Biol 5: R14. PubMed PMC

McLysaght A, Hurst LD. 2016. Open questions in the study of de novo genes: what, how and why. Nat Rev Genet 17: 567–578. PubMed

Mouse Genome Sequencing Consortium, Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, et al. 2002. Initial sequencing and comparative analysis of the mouse genome. Nature 420: 520–562. PubMed

Nagy A. 2003. Manipulating the mouse embryo: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

Nellaker C, Keane TM, Yalcin B, Wong K, Agam A, Belgard TG, Flint J, Adams DJ, Frankel WN, Ponting CP. 2012. The genomic landscape shaped by selection on transposable elements across 18 mouse strains. Genome Biol 13: R45. PubMed PMC

Nishihara H, Kobayashi N, Kimura-Yoshida C, Yan K, Bormuth O, Ding Q, Nakanishi A, Sasaki T, Hirakawa M, Sumiyama K, et al. 2016. Coordinately co-opted multiple transposable elements constitute an enhancer for wnt5a expression in the mammalian secondary palate. PLoS Genet 12: e1006380. PubMed PMC

Park SJ, Komata M, Inoue F, Yamada K, Nakai K, Ohsugi M, Shirahige K. 2013. Inferring the choreography of parental genomes during fertilization from ultralarge-scale whole-transcriptome analysis. Genes Dev 27: 2736–2748. PubMed PMC

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. PubMed

Pfeiffer MJ, Siatkowski M, Paudel Y, Balbach ST, Baeumer N, Crosetto N, Drexler HC, Fuellen G, Boiani M. 2011. Proteomic analysis of mouse oocytes reveals 28 candidate factors of the “reprogrammome”. J Proteome Res 10: 2140–2153. PubMed

Piao Y, Ko NT, Lim MK, Ko MS. 2001. Construction of long-transcript enriched cDNA libraries from submicrogram amounts of total RNAs by a universal PCR amplification method. Genome Res 11: 1553–1558. PubMed PMC

Ribet D, Louvet-Vallée S, Harper F, de Parseval N, Dewannieux M, Heidmann O, Pierron G, Maro B, Heidmann T. 2008. Murine endogenous retrovirus MuERV-L is the progenitor of the “orphan” ε viruslike particles of the early mouse embryo. J Virol 82: 1622–1625. PubMed PMC

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. PubMed

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. PubMed PMC

Schoorlemmer J, Pérez-Palacios R, Climent M, Guallar D, Muniesa P. 2014. Regulation of mouse retroelement MuERV-L/MERVL expression by REX1 and epigenetic control of stem cell potency. Front Oncol 4: 14. PubMed PMC

Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, Lopez R, McWilliam H, Remmert M, Söding J, et al. 2011. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7: 539. PubMed PMC

Smallwood SA, Tomizawa S, Krueger F, Ruf N, Carli N, Segonds-Pichon A, Sato S, Hata K, Andrews SR, Kelsey G. 2011. Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat Genet 43: 811–814. PubMed PMC

Smit AF. 1993. Identification of a new, abundant superfamily of mammalian LTR-transposons. Nucleic Acids Res 21: 1863–1872. PubMed PMC

Smit AFA, Hubley R, Green P. 2013–2015. RepeatMasker Open-4.0. http://www.repeatmasker.org/.

Sookdeo A, Hepp CM, McClure MA, Boissinot S. 2013. Revisiting the evolution of mouse LINE-1 in the genomic era. Mobile DNA 4: 3. PubMed PMC

Sundaram V, Cheng Y, Ma Z, Li D, Xing X, Edge P, Snyder MP, Wang T. 2014. Widespread contribution of transposable elements to the innovation of gene regulatory networks. Genome Res 24: 1963–1976. PubMed PMC

Sved J, Bird A. 1990. The expected equilibrium of the CpG dinucleotide in vertebrate genomes under a mutation model. Proc Natl Acad Sci 87: 4692–4696. PubMed PMC

Svoboda P, Stein P, Anger M, Bernstein E, Hannon GJ, Schultz RM. 2004. RNAi and expression of retrotransposons MuERV-L and IAP in preimplantation mouse embryos. Dev Biol 269: 276–285. PubMed

Svoboda P, Franke V, Schultz RM. 2015. Sculpting the transcriptome during the oocyte-to-embryo transition in mouse. Curr Topics Dev Biol 113: 305–349. PubMed

Tam OH, Aravin AA, Stein P, Girard A, Murchison EP, Cheloufi S, Hodges E, Anger M, Sachidanandam R, Schultz RM, et al. 2008. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453: 534–538. PubMed PMC

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. PubMed PMC

van de Lagemaat LN, Medstrand P, Mager DL. 2006. Multiple effects govern endogenous retrovirus survival patterns in human gene introns. Genome Biol 7: R86. PubMed PMC

van de Sluis B, Voncken JW. 2011. Transgene design. Methods Mol Biol 693: 89–101. PubMed PMC

Veselovska L, Smallwood SA, Saadeh H, Stewart KR, Krueger F, Maupetit-Mehouas S, Arnaud P, Tomizawa S, 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. PubMed PMC

Veyrunes F, Britton-Davidian J, Robinson TJ, Calvet E, Denys C, Chevret P. 2005. Molecular phylogeny of the African pygmy mice, subgenus Nannomys (Rodentia, Murinae, Mus): implications for chromosomal evolution. Mol Phylogenet Evol 36: 358–369. PubMed

Wang S, Kou Z, Jing Z, Zhang Y, Guo X, Dong M, Wilmut I, Gao S. 2010. Proteome of mouse oocytes at different developmental stages. Proc Natl Acad Sci 107: 17639–17644. PubMed PMC

Wang B, Pfeiffer MJ, Drexler HC, Fuellen G, Boiani M. 2016. Proteomic analysis of mouse oocytes identifies PRMT7 as a reprogramming factor that replaces SOX2 in the induction of pluripotent stem cells. J Proteome Res 10.1021/acs.jproteome.5b01083. PubMed DOI

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. PubMed

Weber M, Hellmann I, Stadler MB, Ramos L, Pääbo S, Rebhan M, Schübeler D. 2007. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 39: 457–466. PubMed

Wolf G, Greenberg D, Macfarlan TS. 2015. Spotting the enemy within: Targeted silencing of foreign DNA in mammalian genomes by the Krüppel-associated box zinc finger protein family. Mobile DNA 6: 17. PubMed PMC

Xie D, Chen CC, Ptaszek LM, Xiao S, Cao X, Fang F, Ng HH, Lewin HA, Cowan C, Zhong S. 2010. Rewirable gene regulatory networks in the preimplantation embryonic development of three mammalian species. Genome Res 20: 804–815. PubMed PMC

Functional canonical RNAi in mice expressing a truncated Dicer isoform and long dsRNA

Expression analysis suggests that DNMT3L is required for oocyte de novo DNA methylation only in Muridae and Cricetidae rodents

De novo emergence, existence, and demise of a protein-coding gene in murids

Formation of spermatogonia and fertile oocytes in golden hamsters requires piRNAs

CRISPR-Induced Expression of N-Terminally Truncated Dicer in Mouse Cells

MicroRNA dilution during oocyte growth disables the microRNA pathway in mammalian oocytes

The most abundant maternal lncRNA Sirena1 acts post-transcriptionally and impacts mitochondrial distribution

Restricted and non-essential redundancy of RNAi and piRNA pathways in mouse oocytes

Splicing of long non-coding RNAs primarily depends on polypyrimidine tract and 5' splice-site sequences due to weak interactions with SR proteins

Role of Cnot6l in maternal mRNA turnover

The oocyte-to-embryo transition in mouse: past, present, and future