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Characterization of DNA methylation and promoter activity of long terminal repeat elements of feline endogenous retrovirus RDRS C2a

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Abstract

Endogenous retroviruses (ERVs) are genomic elements derived from retroviral infections in ancestral germ lines. Most ERVs are inactivated by genetic or epigenetic mechanisms, such as DNA methylation. RD-114-virus-related sequence (RDRS) C2a is a feline endogenous retrovirus present in all domestic cats; however, its expression and function are not clearly known. DNA methylation at CpG dinucleotides is a hallmark of silenced ERVs. This study aimed to investigate whether long terminal repeats (LTRs) of RDRS C2a function as a gene regulatory region. The DNA methylation status of RDRS C2a was examined by bisulfite sequencing, and CpG sites in 5ʹ LTR of RDRS C2a were found hypomethylated, whereas those in 3ʹ LTR were hypermethylated in feline cells. Several transcription factor-binding sites were identified in LTRs of RDRS C2a. Luciferase assay suggested that 5ʹ LTR of RDRS C2a exhibited strong transcriptional activity, which was suppressed by in vitro DNA methylation. The study indicates that 5ʹ LTR of RDRS C2a possibly functions as a promoter for itself or neighboring genes.

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Fig. 1

Data availability

All data presented in this study are available from the corresponding author upon reasonable request.

References

  1. Coffin JM, Hughes SH, Varmus HE (1997) Retroviruses. Cold Spring Harbor Laboratory Press, New York

    Google Scholar 

  2. Lander ES, Linton LM, Birren B et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921. https://doi.org/10.1038/35057062

    Article  CAS  PubMed  Google Scholar 

  3. Chinwalla AT, Cook LL, Delehaunty KD et al (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420:520–563. https://doi.org/10.1038/nature01262

    Article  CAS  PubMed  Google Scholar 

  4. Gifford R, Tristem M (2003) The evolution, distribution and diversity of endogenous retroviruses. Virus Genes 26:291–315. https://doi.org/10.1023/A:1024455415443

    Article  CAS  PubMed  Google Scholar 

  5. Rowe HM, Trono D (2011) Dynamic control of endogenous retroviruses during development. Virology 411:273–287. https://doi.org/10.1016/j.virol.2010.12.007

    Article  CAS  PubMed  Google Scholar 

  6. Hutnick LK, Huang X, Loo TC et al (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. https://doi.org/10.1074/jbc.M110.125674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stoye JP (2012) Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nat Rev Microbiol 10:395–406. https://doi.org/10.1038/nrmicro2783

    Article  CAS  PubMed  Google Scholar 

  8. Yoder JA, Walsh CP, Bestor TH (1997) Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 13:335–340. https://doi.org/10.1016/S0168-9525(97)01181-5

    Article  CAS  PubMed  Google Scholar 

  9. Walsh CP, Chaillet JR, Bestor TH (1998) Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20:116–117. https://doi.org/10.1038/2413

    Article  CAS  PubMed  Google Scholar 

  10. Lavie L, Kitova M, Maldener E et al (2005) CpG methylation directly regulates transcriptional activity of the human endogenous retrovirus family HERV-K (HML-2). J Virol 79:876–883. https://doi.org/10.1128/JVI.79.2.876-883.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Matoušková M, Blažková J, Pajer P et al (2006) CpG methylation suppresses transcriptional activity of human syncytin-1 in non-placental tissues. Exp Cell Res 312:1011–1020. https://doi.org/10.1016/j.yexcr.2005.12.010

    Article  CAS  PubMed  Google Scholar 

  12. Gimenez J, Montgiraud C, Pichon JP et al (2010) Custom human endogenous retroviruses dedicated microarray identifies self-induced HERV-W family elements reactivated in testicular cancer upon methylation control. Nucleic Acids Res 38:2229–2246. https://doi.org/10.1093/nar/gkp1214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Arand J, Spieler D, Karius T et al (2012) In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet 8:e1002750. https://doi.org/10.1371/journal.pgen.1002750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chuong EB, Elde NC, Feschotte C (2017) Regulatory activities of transposable elements: from conflicts to benefits. Nat Rev Genet 18:71–86. https://doi.org/10.1038/nrg.2016.139

    Article  CAS  PubMed  Google Scholar 

  15. Reeves RH, O’Brien SJ (1984) Molecular genetic characterization of the RD-114 gene family of endogenous feline retroviral sequences. J Virol 52:164–171. https://doi.org/10.1128/jvi.52.1.164-171.1984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Reeves RH, Nash WG, O’Brien SJ (1985) Genetic mapping of endogenous RD-114 retroviral sequences of domestic cats. J Virol 56:303–306. https://doi.org/10.1128/jvi.56.1.303-306.1985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shimode S, Nakagawa S, Miyazawa T (2015) Multiple invasions of an infectious retrovirus in cat genomes. Sci Rep 5:8164. https://doi.org/10.1038/srep08164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Buzdin A, Kovalskaya-Alexandrova E, Gogvadze E et al (2006) At least 50% of human-specific HERV-K (HML-2) long terminal repeats serve in vivo as active promoters for host nonrepetitive DNA transcription. J Virol 80:10752–10762. https://doi.org/10.1128/JVI.00871-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chuong EB, Rumi MA, Soares MJ et al (2013) Endogenous retroviruses function as species-specific enhancer elements in the placenta. Nat Genet 45:325–329. https://doi.org/10.1038/ng.2553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Suntsova M, Gogvadze EV, Salozhin S et al (2013) Human-specific endogenous retroviral insert serves as an enhancer for the schizophrenia-linked gene PRODH. Proc Natl Acad Sci USA 110:19472–19477. https://doi.org/10.1073/pnas.1318172110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Suntsova M, Garazha A, Ivanova A et al (2015) Molecular functions of human endogenous retroviruses in health and disease. Cell Mol Life Sci 72:3653–3675. https://doi.org/10.1007/s00018-015-1947-6

    Article  CAS  PubMed  Google Scholar 

  22. Schumann GG, Gogvadze EV, Osanai-Futahashi M et al (2010) Unique functions of repetitive transcriptomes. Int Rev Cell Mol Biol 285:115–188. https://doi.org/10.1016/B978-0-12-381047-2.00003-7

    Article  CAS  PubMed  Google Scholar 

  23. Young JM, Whiddon JL, Yao Z et al (2013) DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis. PLoS Genet 9:e1003947. https://doi.org/10.1371/journal.pgen.1003947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9:465–476. https://doi.org/10.1038/nrg2341

    Article  CAS  PubMed  Google Scholar 

  25. Li G, Hillier LW, Grahn RA et al (2016) A high-resolution SNP array-based linkage map anchors a new domestic cat draft genome assembly and provides detailed patterns of recombination. Genes Genomes Genet 6:1607–1616. https://doi.org/10.1534/g3.116.028746

    Article  Google Scholar 

  26. Buckley RM, Davis BW, Brashear WA et al (2020) A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism. PLoS Genet 16:e1008926. https://doi.org/10.1371/journal.pgen.1008926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang W, Schoenebeck JJ (2020) The ninth life of the cat reference genome Felis_catus. PLoS Genet 16:e1009045. https://doi.org/10.1371/journal.pgen.1009045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Isobe S, Matsumoto Y, Chung C et al (2020) AnAms1.0: a high-quality chromosome-scale assembly of a domestic cat Felis catus of American Shorthair breed. bioRxiv. https://doi.org/10.1101/2020.05.19.103788

    Article  Google Scholar 

  29. Li LC, Dahiya R (2002) MethPrimer: designing primers for methylation PCRs. Bioinformatics 18:1427–1431. https://doi.org/10.1093/bioinformatics/18.11.1427

    Article  CAS  PubMed  Google Scholar 

  30. Kumaki Y, Oda M, Okano M (2008) QUMA: quantification tool for methylation analysis. Nucleic Acids Res 36:W170-175. https://doi.org/10.1093/nar/gkn294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tsunoda T, Takagi T (1999) Estimating transcription factor bindability on DNA. Bioinformatics 15:622–630. https://doi.org/10.1093/bioinformatics/15.7.622

    Article  CAS  PubMed  Google Scholar 

  32. Alexandrov A, Martzen MR, Phizicky EM (2002) Two proteins that form a complex are required for 7-methylguanosine modification of yeast tRNA. RNA 8:1253–1266. https://doi.org/10.1017/s1355838202024019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kawasaki J, Nishigaki K (2018) Tracking the continuous evolutionary processes of an endogenous retrovirus of the domestic cat: ERV-DC10. Viruses 10:179. https://doi.org/10.3390/v10040179

    Article  CAS  PubMed Central  Google Scholar 

  34. Anai Y, Ochi H, Watanabe S et al (2012) Infectious endogenous retroviruses in cats and emergence of recombinant viruses. J Virol 86:8634–8644. https://doi.org/10.1128/JVI.00280-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Johnson WE, Eizirik E, Pecon-Slattery J et al (2006) The late miocene radiation of modern Felidae: a genetic assessment. Science 311:73–77. https://doi.org/10.1126/science.1122277

    Article  CAS  PubMed  Google Scholar 

  36. O’Brien SJ, Johnson WE (2007) The evolution of cats. Sci Am 297:68–75

    Article  Google Scholar 

  37. Elbarbary RA, Lucas BA, Maquat LE (2016) Retrotransposons as regulators of gene expression. Science 351:aac7247. https://doi.org/10.1126/science.aac7247

    Article  PubMed  PubMed Central  Google Scholar 

  38. Wu X, Li Y, Crise B et al (2003) Transcription start regions in the human genome are favored targets for MLV integration. Science 300:1749–1751. https://doi.org/10.1126/science.1083413

    Article  CAS  PubMed  Google Scholar 

  39. Trobridge GD, Miller DG, Jacobs MA et al (2006) Foamy virus vector integration sites in normal human cells. Proc Natl Acad Sci USA 103:1498–1503. https://doi.org/10.1073/pnas.0510046103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. LaFave MC, Varshney GK, Gildea DE et al (2014) MLV integration site selection is driven by strong enhancers and active promoters. Nucleic Acids Res 42:4257–4269. https://doi.org/10.1093/nar/gkt1399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. De Ravin SS, Su L, Theobald N et al (2014) Enhancers are major targets for murine leukemia virus vector integration. J Virol 88:4504–4513. https://doi.org/10.1128/JVI.00011-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sultana T, Zamborlini A, Cristofari G et al (2017) Integration site selection by retroviruses and transposable elements in eukaryotes. Nat Rev Genet 18:292–308. https://doi.org/10.1038/nrg.2017.7

    Article  CAS  PubMed  Google Scholar 

  43. Poletti V, Mavilio F (2018) Interactions between retroviruses and the host cell genome. Mol Ther Methods Clin Dev 8:31–41. https://doi.org/10.1016/j.omtm.2017.10.001

    Article  CAS  PubMed  Google Scholar 

  44. Malicorne S, Vernochet C, Cornelis G et al (2006) Genome-wide screening of retroviral envelope genes in the nine-banded armadillo (Dasypus novemcinctus, Xenarthra) reveals an unfixed chimeric endogenous betaretrovirus using the ASCT2 receptor. J Virol 90:8132–8149. https://doi.org/10.1128/JVI.00483-16

    Article  CAS  Google Scholar 

  45. Malfavon-Borja R, Feschotte C (2015) Fighting fire with fire: endogenous retrovirus envelopes as restriction factors. J Virol 89:4047–4050. https://doi.org/10.1128/JVI.03653-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cosby RL, Judd J, Zhang R et al (2021) Recurrent evolution of vertebrate transcription factors by transposase capture. Science 371:eabc6405. https://doi.org/10.1126/science.abc6405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Niman HL, Stephenson JR, Gardner MB et al (1977) RD-114 and feline leukaemia virus genome expression in natural lymphomas of domestic cats. Nature 266:357–360. https://doi.org/10.1038/266357a0

    Article  CAS  PubMed  Google Scholar 

  48. Niman HL, Gardner MB, Stephenson JR et al (1977) Endogenous RD-114 virus genome expression in malignant tissues of domestic cats. J Virol 23:578–586. https://doi.org/10.1128/jvi.23.3.578-586.1977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are grateful to Dr. Takayuki Miyazawa (Kyoto University, Kyoto, Japan) and Dr. Hiroshi Ochiai (Hiroshima University, Hiroshima, Japan) for providing helpful advice and Editage (www.editage.com) for English language editing. This work was supported by JSPS KAKENHI (Grant Numbers JP16K21129 and JP20K15692).

Funding

This work was supported by JSPS KAKENHI (Grant Numbers JP16K21129 and JP20K15692).

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Authors and Affiliations

  1. Genome Editing Innovation Center, Hiroshima University, 3-10-23 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-0046, Japan

    Sayumi Shimode

  2. Graduate School of Integrated Sciences for Life, Hiroshima University, 1-4-4 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8528, Japan

    Takashi Yamamoto

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  1. Sayumi Shimode
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  2. Takashi Yamamoto
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SS performed the experiments and analyzed the data. SS and TY wrote and reviewed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Sayumi Shimode.

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Shimode, S., Yamamoto, T. Characterization of DNA methylation and promoter activity of long terminal repeat elements of feline endogenous retrovirus RDRS C2a. Virus Genes 58, 70–74 (2022). https://doi.org/10.1007/s11262-021-01878-1

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