Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Decoding the impact of nuclear organization on antigenic variation in parasites

Nature Microbiology volume 8, pages 1408–1418 (2023)Cite this article

Subjects

Abstract

Antigenic variation as a strategy to evade the host adaptive immune response has evolved in divergent pathogens. Antigenic variation involves restricted, and often mutually exclusive, expression of dominant antigens and a periodic switch in antigen expression during infection. In eukaryotes, nuclear compartmentalization, including three-dimensional folding of the genome and physical separation of proteins in compartments or condensates, regulates mutually exclusive gene expression and chromosomal translocations. In this Review, we discuss the impact of nuclear organization on antigenic variation in the protozoan pathogens Trypanosoma brucei and Plasmodium falciparum. In particular, we highlight the relevance of nuclear organization in both mutually exclusive antigen expression and genome stability, which underlie antigenic variation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Distribution of antigen-coding genes in T. brucei and P. falciparum.
Fig. 2: A switch in antigen isoform expression can be mediated by a change in transcriptional activity or a DNA recombination event.
Fig. 3: Nuclear organization of a P. falciparum ring and a T. brucei bloodstream form.

References

  1. Janeway, C., Travers, P., Walport, M. & Schlomchik, M. Immunobiology 5th edn (Elsevier España, 2001).

  2. Gupta, S., Ferguson, N. & Anderson, R. Chaos, persistence, and evolution of strain structure in antigenically diverse infectious agents. Science 280, 912–915 (1998).

    CAS  PubMed  Google Scholar 

  3. Deitsch, K. W., Lukehart, S. A. & Stringer, J. R. Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens. Nat. Rev. Microbiol. 7, 493–503 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Wisniewski-Dyé, F. & Vial, L. Phase and antigenic variation mediated by genome modifications. Antonie Van Leeuwenhoek 94, 493–515 (2008).

    PubMed  Google Scholar 

  5. Petrova, V. N. & Russell, C. A. The evolution of seasonal influenza viruses. Nat. Rev. Microbiol. 16, 47–60 (2018).

    CAS  PubMed  Google Scholar 

  6. Prucca, C. G., Rivero, F. D. & Lujan, H. D. Regulation of antigenic variation in Giardia lamblia. Annu. Rev. Microbiol. 65, 611–630 (2011).

    CAS  PubMed  Google Scholar 

  7. Al-Khedery, B. & Allred, D. R. Antigenic variation in Babesia bovis occurs through segmental gene conversion of the ves multigene family, within a bidirectional locus of active transcription. Mol. Microbiol. 59, 402–414 (2006).

    CAS  PubMed  Google Scholar 

  8. Schwede, A., Jones, N., Engstler, M. & Carrington, M. The VSG C-terminal domain is inaccessible to antibodies on live trypanosomes. Mol. Biochem. Parasitol. 175, 201–204 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Mugnier, M. R., Cross, G. A. & Papavasiliou, F. N. The in vivo dynamics of antigenic variation in Trypanosoma brucei. Science 347, 1470–1473 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Ramey-Butler, K., Ullu, E., Kolev, N. G. & Tschudi, C. Synchronous expression of individual metacyclic variant surface glycoprotein genes in Trypanosoma brucei. Mol. Biochem. Parasitol. 200, 1–4 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Barry, J. D. et al. VSG gene control and infectivity strategy of metacyclic stage Trypanosoma brucei. Mol. Biochem. Parasitol. 91, 93–105 (1998).

    CAS  PubMed  Google Scholar 

  12. Hutchinson, S. et al. The establishment of variant surface glycoprotein monoallelic expression revealed by single-cell RNA-seq of Trypanosoma brucei in the tsetse fly salivary glands. PLoS Pathog. 17, e1009904 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Scherf, A., Lopez-Rubio, J. J. & Riviere, L. Antigenic variation in Plasmodium falciparum. Annu. Rev. Microbiol. 62, 445–470 (2008).

    CAS  PubMed  Google Scholar 

  14. Kyes, S. A., Rowe, J. A., Kriek, N. & Newbold, C. I. Rifins: a second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum. Proc. Natl Acad. Sci. USA 96, 9333–9338 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Niang, M., Yan Yam, X. & Preiser, P. R. The Plasmodium falciparum STEVOR multigene family mediates antigenic variation of the infected erythrocyte. PLoS Pathog. 5, e1000307 (2009).

    PubMed  PubMed Central  Google Scholar 

  16. Miller, L. H., Baruch, D. I., Marsh, K. & Doumbo, O. K. The pathogenic basis of malaria. Nature 415, 673–679 (2002).

    CAS  PubMed  Google Scholar 

  17. Real, E., Nardella, F., Scherf, A. & Mancio-Silva, L. Repurposing of Plasmodium falciparum var genes beyond the blood stage. Curr. Opin. Microbiol. 70, 102207 (2022).

    CAS  PubMed  Google Scholar 

  18. Jerkovic, I. & Cavalli, G. Understanding 3D genome organization by multidisciplinary methods. Nat. Rev. Mol. Cell Biol. 22, 511–528 (2021).

    CAS  PubMed  Google Scholar 

  19. Cosentino, R. O., Brink, B. G. & Siegel, T. N. Allele-specific assembly of a eukaryotic genome corrects apparent frameshifts and reveals a lack of nonsense-mediated mRNA decay. NAR Genom. Bioinform. 3, lqab082 (2021).

    PubMed  PubMed Central  Google Scholar 

  20. Wickstead, B., Ersfeld, K. & Gull, K. The small chromosomes of Trypanosoma brucei involved in antigenic variation are constructed around repetitive palindromes. Genome Res. 14, 1014–1024 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Lopez-Rubio, J. J. et al. 5′ flanking region of var genes nucleate histone modification patterns linked to phenotypic inheritance of virulence traits in malaria parasites. Mol. Microbiol. 66, 1296–1305 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Perez-Toledo, K. et al. Plasmodium falciparum heterochromatin protein 1 binds to tri-methylated histone 3 lysine 9 and is linked to mutually exclusive expression of var genes. Nucleic Acids Res. 37, 2596–2606 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Gardner, M. J. et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498–511 (2002).

    CAS  PubMed  Google Scholar 

  24. Figueiredo, L. M., Freitas-Junior, L. H., Bottius, E., Olivo-Marin, J. C. & Scherf, A. A central role for Plasmodium falciparum subtelomeric regions in spatial positioning and telomere length regulation. EMBO J. 21, 815–824 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Otto, T. D. et al. Long read assemblies of geographically dispersed Plasmodium falciparum isolates reveal highly structured subtelomeres. Wellcome Open Res. 3, 52 (2018).

    PubMed  PubMed Central  Google Scholar 

  26. Freitas-Junior, L. H. et al. Frequent ectopic recombination of virulence factor genes in telomeric chromosome clusters of P. falciparum. Nature 407, 1018–1022 (2000).

    CAS  PubMed  Google Scholar 

  27. Su, X. Z. et al. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82, 89–100 (1995).

    CAS  PubMed  Google Scholar 

  28. Kraemer, S. M. et al. Patterns of gene recombination shape var gene repertoires in Plasmodium falciparum: comparisons of geographically diverse isolates. BMC Genom. 8, 45 (2007).

    Google Scholar 

  29. Kyes, S. et al. Plasmodium falciparum var gene expression is developmentally controlled at the level of RNA polymerase II-mediated transcription initiation. Mol. Microbiol. 63, 1237–1247 (2007).

    CAS  PubMed  Google Scholar 

  30. Schieck, E., Pfahler, J. M., Sanchez, C. P. & Lanzer, M. Nuclear run-on analysis of var gene expression in Plasmodium falciparum. Mol. Biochem. Parasitol. 153, 207–212 (2007).

    CAS  PubMed  Google Scholar 

  31. Calderwood, M. S., Gannoun-Zaki, L., Wellems, T. E. & Deitsch, K. W. Plasmodium falciparum var genes are regulated by two regions with separate promoters, one upstream of the coding region and a second within the intron. J. Biol. Chem. 278, 34125–34132 (2003).

    CAS  PubMed  Google Scholar 

  32. Epp, C., Li, F., Howitt, C. A., Chookajorn, T. & Deitsch, K. W. Chromatin associated sense and antisense noncoding RNAs are transcribed from the var gene family of virulence genes of the malaria parasite Plasmodium falciparum. RNA 15, 116–127 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Siegel, T. N. et al. Strand-specific RNA-Seq reveals widespread and developmentally regulated transcription of natural antisense transcripts in Plasmodium falciparum. BMC Genom. 15, 150 (2014).

    Google Scholar 

  34. Duraisingh, M. T. et al. Heterochromatin silencing and locus repositioning linked to regulation of virulence genes in Plasmodium falciparum. Cell 121, 13–24 (2005).

    CAS  PubMed  Google Scholar 

  35. Navarro, M. & Gull, K. A pol I transcriptional body associated with VSG mono-allelic expression in Trypanosoma brucei. Nature 414, 759–763 (2001).

    CAS  PubMed  Google Scholar 

  36. Markenscoff-Papadimitriou, E. et al. Enhancer interaction networks as a means for singular olfactory receptor expression. Cell 159, 543–557 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Chess, A. Monoallelic gene expression in mammals. Annu. Rev. Genet. 50, 317–327 (2016).

    CAS  PubMed  Google Scholar 

  38. Hozumi, N. & Tonegawa, S. Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions. Proc. Natl Acad. Sci. USA 73, 3628–3632 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Raulet, D. H., Garman, R. D., Saito, H. & Tonegawa, S. Developmental regulation of T-cell receptor gene expression. Nature 314, 103–107 (1985).

    CAS  PubMed  Google Scholar 

  40. Landeira, D. & Navarro, M. Nuclear repositioning of the VSG promoter during developmental silencing in Trypanosoma brucei. J. Cell Biol. 176, 133–139 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. DuBois, K. N. et al. NUP-1 Is a large coiled-coil nucleoskeletal protein in trypanosomes with lamin-like functions. PLoS Biol. 10, e1001287 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Chaves, I. et al. Subnuclear localization of the active variant surface glycoprotein gene expression site in Trypanosoma brucei. Proc. Natl Acad. Sci. USA 95, 12328–12333 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Budzak, J. et al. Dynamic colocalization of 2 simultaneously active VSG expression sites within a single expression-site body in Trypanosoma brucei. Proc. Natl Acad. Sci. USA 116, 16561–16570 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Maishman, L. et al. Co-dependence between trypanosome nuclear lamina components in nuclear stability and control of gene expression. Nucleic Acids Res. 44, 10554–10570 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Müller, L. S. M. et al. Genome organization and DNA accessibility control antigenic variation in trypanosomes. Nature 563, 121–125 (2018).

    PubMed  PubMed Central  Google Scholar 

  46. Glover, L., Hutchinson, S., Alsford, S. & Horn, D. VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes. Proc. Natl Acad. Sci. USA 113, 7225–7230 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Faria, J. et al. Spatial integration of transcription and splicing in a dedicated compartment sustains monogenic antigen expression in African trypanosomes. Nat. Microbiol. 6, 289–300 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Faria, J. et al. Monoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex. Nat. Commun. 10, 3023 (2019).

    PubMed  PubMed Central  Google Scholar 

  49. López-Escobar, L. et al. Stage-specific transcription activator ESB1 regulates monoallelic antigen expression in Trypanosoma brucei. Nat. Microbiol. 7, 1280–1290 (2022).

    PubMed  PubMed Central  Google Scholar 

  50. Lopez-Farfan, D., Bart, J. M., Rojas-Barros, D. I. & Navarro, M. SUMOylation by the E3 Ligase TbSIZ1/PIAS1 positively regulates VSG expression in Trypanosoma brucei. PLoS Pathog. 10, e1004545 (2014).

    PubMed  PubMed Central  Google Scholar 

  51. Budzak, J., Jones, R., Tschudi, C., Kolev, N. G. & Rudenko, G. An assembly of nuclear bodies associates with the active VSG expression site in African trypanosomes. Nat. Commun. 13, 101 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Perry, K. L., Watkins, K. P. & Agabian, N. Trypanosome mRNAs have unusual “cap 4” structures acquired by addition of a spliced leader. Proc. Natl Acad. Sci. USA 84, 8190–8194 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Nelson, R. G. et al. Sequences homologous to the variant antigen mRNA spliced leader are located in tandem repeats and variable orphons in Trypanosoma brucei. Cell 34, 901–909 (1983).

    CAS  PubMed  Google Scholar 

  54. Ralph, S. A., Scheidig-Benatar, C. & Scherf, A. Antigenic variation in Plasmodium falciparum is associated with movement of var loci between subnuclear locations. Proc. Natl Acad. Sci. USA 102, 5414–5419 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Lopez-Rubio, J. J., Mancio-Silva, L. & Scherf, A. Genome-wide analysis of heterochromatin associates clonally variant gene regulation with perinuclear repressive centers in malaria parasites. Cell Host Microbe 5, 179–190 (2009).

    CAS  PubMed  Google Scholar 

  56. Freitas-Junior, L. H. et al. Telomeric heterochromatin propagation and histone acetylation control mutually exclusive expression of antigenic variation genes in malaria parasites. Cell 121, 25–36 (2005).

    CAS  PubMed  Google Scholar 

  57. Chookajorn, T. et al. Epigenetic memory at malaria virulence genes. Proc. Natl Acad. Sci. USA 104, 899–902 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang, Q. et al. A critical role of perinuclear filamentous actin in spatial repositioning and mutually exclusive expression of virulence genes in malaria parasites. Cell Host Microbe 10, 451–463 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Wei, G., Zhao, Y., Zhang, Q. & Pan, W. Dual regulatory effects of non-coding GC-rich elements on the expression of virulence genes in malaria parasites. Infect. Genet. Evol. 36, 490–499 (2015).

    CAS  PubMed  Google Scholar 

  60. Guizetti, J., Barcons-Simon, A. & Scherf, A. Trans-acting GC-rich non-coding RNA at var expression site modulates gene counting in malaria parasite. Nucleic Acids Res. 44, 9710–9718 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Barcons-Simon, A., Cordon-Obras, C., Guizetti, J., Bryant, J. M. & Scherf, A. CRISPR interference of a clonally variant GC-rich noncoding RNA family leads to general repression of var genes in Plasmodium falciparum. mBio 11, e03054–19 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Diffendall, G. M. et al. Discovery of RUF6 ncRNA-interacting proteins involved in P. falciparum immune evasion. Life Sci. Alliance 6, e202201577 (2023).

    CAS  PubMed  Google Scholar 

  63. Ruiz, J. L. et al. Characterization of the accessible genome in the human malaria parasite Plasmodium falciparum. Nucleic Acids Res. 46, 9414–9431 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Canella, D., Praz, V., Reina, J. H., Cousin, P. & Hernandez, N. Defining the RNA polymerase III transcriptome: genome-wide localization of the RNA polymerase III transcription machinery in human cells. Genome Res. 20, 710–721 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Noma, K., Cam, H. P., Maraia, R. J. & Grewal, S. I. A role for TFIIIC transcription factor complex in genome organization. Cell 125, 859–872 (2006).

    CAS  PubMed  Google Scholar 

  66. Raab, J. R. et al. Human tRNA genes function as chromatin insulators. EMBO J. 31, 330–350 (2012).

    CAS  PubMed  Google Scholar 

  67. Kirkland, J. G., Raab, J. R. & Kamakaka, R. T. TFIIIC bound DNA elements in nuclear organization and insulation. Biochim. Biophys. Acta 1829, 418–424 (2013).

    CAS  PubMed  Google Scholar 

  68. Broadbent, K. M. et al. A global transcriptional analysis of Plasmodium falciparum malaria reveals a novel family of telomere-associated lncRNAs. Genome Biol. 12, R56 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Sierra-Miranda, M. et al. Two long non-coding RNAs generated from subtelomeric regions accumulate in a novel perinuclear compartment in Plasmodium falciparum. Mol. Biochem. Parasitol. 185, 36–47 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Voss, T. S. et al. A var gene promoter controls allelic exclusion of virulence genes in Plasmodium falciparum malaria. Nature 439, 1004–1008 (2006).

    CAS  PubMed  Google Scholar 

  71. Brolin, K. J. et al. Simultaneous transcription of duplicated var2csa gene copies in individual Plasmodium falciparum parasites. Genome Biol. 10, R117 (2009).

    PubMed  PubMed Central  Google Scholar 

  72. Chaves, I., Rudenko, G., Dirks-Mulder, A., Cross, M. & Borst, P. Control of variant surface glycoprotein gene-expression sites in Trypanosoma brucei. EMBO J. 18, 4846–4855 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Howitt, C. A. et al. Clonally variant gene families in Plasmodium falciparum share a common activation factor. Mol. Microbiol. 73, 1171–1185 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Lemieux, J. E. et al. Genome-wide profiling of chromosome interactions in Plasmodium falciparum characterizes nuclear architecture and reconfigurations associated with antigenic variation. Mol. Microbiol. 90, 519–537 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ay, F. et al. Three-dimensional modeling of the P. falciparum genome during the erythrocytic cycle reveals a strong connection between genome architecture and gene expression. Genome Res. 24, 974–988 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Bunnik, E. M. Comparative 3D genome organization in apicomplexan parasites. Proc. Natl Acad. Sci USA https://doi.org/10.1073/pnas.1810815116 (2019).

  77. Duan, Z. et al. A three-dimensional model of the yeast genome. Nature 465, 363–367 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Lu, B. et al. The architectural factor HMGB1 is involved in genome organization in the human malaria parasite Plasmodium falciparum. mBio 12, e00148–21 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Mitrentsi, I., Yilmaz, D. & Soutoglou, E. How to maintain the genome in nuclear space. Curr. Opin. Cell Biol. 64, 58–66 (2020).

    CAS  PubMed  Google Scholar 

  80. Hall, J. P., Wang, H. & Barry, J. D. Mosaic VSGs and the scale of Trypanosoma brucei antigenic variation. PLoS Pathog. 9, e1003502 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Boothroyd, C. E. et al. A yeast-endonuclease-generated DNA break induces antigenic switching in Trypanosoma brucei. Nature 459, 278–281 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Glover, L., Alsford, S. & Horn, D. DNA break site at fragile subtelomeres determines probability and mechanism of antigenic variation in african trypanosomes. PLoS Pathog. 9, e1003260 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Glover, L. et al. Antigenic variation in African trypanosomes: the importance of chromosomal and nuclear context in VSG expression control. Cell. Microbiol. 15, 1984–1993 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Hovel-Miner, G., Mugnier, M. R., Goldwater, B., Cross, G. A. & Papavasiliou, F. N. A conserved DNA repeat promotes selection of a diverse repertoire of Trypanosoma brucei surface antigens from the genomic archive. PLoS Genet. 12, e1005994 (2016).

    PubMed  PubMed Central  Google Scholar 

  85. Dreesen, O. & Cross, G. A. Telomere length in Trypanosoma brucei. Exp. Parasitol. 118, 103–110 (2008).

    CAS  PubMed  Google Scholar 

  86. Dreesen, O., Li, B. & Cross, G. A. Telomere structure and function in trypanosomes: a proposal. Nat. Rev. Microbiol. 5, 70–75 (2007).

    CAS  PubMed  Google Scholar 

  87. da Silva, M. S., Hovel-Miner, G. A., Briggs, E. M., Elias, M. C. & McCulloch, R. Evaluation of mechanisms that may generate DNA lesions triggering antigenic variation in African trypanosomes. PLoS Pathog. 14, e1007321 (2018).

    PubMed  PubMed Central  Google Scholar 

  88. Briggs, E. et al. Trypanosoma brucei ribonuclease H2A is an essential R-loop processing enzyme whose loss causes DNA damage during transcription initiation and antigenic variation. Nucleic Acids Res. 47, 9180–9197 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Sudarshi, D. et al. Human African trypanosomiasis presenting at least 29 years after infection—what can this teach us about the pathogenesis and control of this neglected tropical disease. PLoS Negl. Trop. Dis. 8, e3349 (2014).

    PubMed  PubMed Central  Google Scholar 

  90. Welburn, S., Picozzi, K., Coleman, P. G. & Packer, C. Patterns in age-seroprevalence consistent with acquired immunity against Trypanosoma brucei in Serengeti lions. PLoS Negl. Trop. Dis. 2, e347 (2008).

    PubMed  PubMed Central  Google Scholar 

  91. Turner, C. M. The rate of antigenic variation in fly-transmitted and syringe-passaged infections of Trypanosoma brucei. FEMS Microbiol. Lett. 153, 227–231 (1997).

    CAS  PubMed  Google Scholar 

  92. Berriman, M. et al. The genome of the African trypanosome Trypanosoma brucei. Science 309, 416–422 (2005).

    CAS  PubMed  Google Scholar 

  93. Bachmann, A. et al. Highly co-ordinated var gene expression and switching in clinical Plasmodium falciparum isolates from non-immune malaria patients. Cell. Microbiol. 13, 1397–1409 (2011).

    CAS  PubMed  Google Scholar 

  94. Otto, T. D. et al. Genomes of all known members of a Plasmodium subgenus reveal paths to virulent human malaria. Nat. Microbiol. 3, 687–697 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Gross, M. R., Hsu, R. & Deitsch, K. W. Evolution of transcriptional control of antigenic variation and virulence in human and ape malaria parasites. BMC Ecol. Evol. 21, 139 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Mok, B. W. et al. Default pathway of var2csa switching and translational repression in Plasmodium falciparum. PLoS ONE 3, e1982 (2008).

    PubMed  PubMed Central  Google Scholar 

  97. Ukaegbu, U. E. et al. A unique virulence gene occupies a principal position in immune evasion by the malaria parasite Plasmodium falciparum. PLoS Genet. 11, e1005234 (2015).

    PubMed  PubMed Central  Google Scholar 

  98. Zhang, X. et al. A coordinated transcriptional switching network mediates antigenic variation of human malaria parasites. eLife 11, e83840 (2022).

    PubMed  PubMed Central  Google Scholar 

  99. Bopp, S. E. et al. Mitotic evolution of Plasmodium falciparum shows a stable core genome but recombination in antigen families. PLoS Genet. 9, e1003293 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Claessens, A. et al. Generation of antigenic diversity in Plasmodium falciparum by structured rearrangement of Var genes during mitosis. PLoS Genet. 10, e1004812 (2014).

    PubMed  PubMed Central  Google Scholar 

  101. Calhoun, S. F. et al. Chromosome end repair and genome stability in Plasmodium falciparum. mBio 8, e00547–17 (2017).

    PubMed  PubMed Central  Google Scholar 

  102. Zhang, X. et al. Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum. PLoS Biol. 17, e3000271 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Hanchate, N. K. et al. Single-cell transcriptomics reveals receptor transformations during olfactory neurogenesis. Science 350, 1251–1255 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Farouni, R., Djambazian, H., Ferri, L. E., Ragoussis, J. & Najafabadi, H. S. Model-based analysis of sample index hopping reveals its widespread artifacts in multiplexed single-cell RNA-sequencing. Nat. Commun. 11, 2704 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Yang, S. et al. Decontamination of ambient RNA in single-cell RNA-seq with DecontX. Genome Biol. 21, 57 (2020).

    PubMed  PubMed Central  Google Scholar 

  106. Wang, X. et al. Characterization of the unusual bidirectional ves promoters driving VESA1 expression and associated with antigenic variation in Babesia bovis. Eukaryot. Cell 11, 260–269 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Figueiredo, L. M. & Cross, G. A. Nucleosomes are depleted at the VSG expression site transcribed by RNA polymerase I in African trypanosomes. Eukaryot. Cell 9, 148–154 (2010).

    CAS  PubMed  Google Scholar 

  108. Stanne, T. M. & Rudenko, G. Active VSG expression sites in Trypanosoma brucei are depleted of nucleosomes. Eukaryot. Cell 9, 136–147 (2010).

    CAS  PubMed  Google Scholar 

  109. McCulloch, R. & Barry, J. D. A role for RAD51 and homologous recombination in Trypanosoma brucei antigenic variation. Genes Dev. 13, 2875–2888 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Viegas, I. J. et al. N6-Methyladenosine in poly(A) tails stabilize VSG transcripts. Nature 604, 362–370 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Toenhake, C. G. et al. Chromatin accessibility-based characterization of the gene regulatory network underlying Plasmodium falciparum blood-stage development. Cell Host Microbe 23, 557–569.e9 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Bartfai, R. et al. H2A.Z demarcates intergenic regions of the Plasmodium falciparum epigenome that are dynamically marked by H3K9ac and H3K4me3. PLoS Pathog. 6, e1001223 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Petter, M. et al. H2A.Z and H2B.Z double-variant nucleosomes define intergenic regions and dynamically occupy var gene promoters in the malaria parasite Plasmodium falciparum. Mol. Microbiol. 87, 1167–1182 (2013).

    CAS  PubMed  Google Scholar 

  114. Petter, M. et al. Expression of P. falciparum var genes involves exchange of the histone variant H2A.Z at the promoter. PLoS Pathog. 7, e1001292 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Fraschka, S. A., Henderson, R. W. & Bártfai, R. H3.3 demarcates GC-rich coding and subtelomeric regions and serves as potential memory mark for virulence gene expression in Plasmodium falciparum. Sci. Rep. 6, 31965 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Bryant, J. M. et al. Exploring the virulence gene interactome with CRISPR/dCas9 in the human malaria parasite. Mol. Syst. Biol. 16, e9569 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Huang, Y., Xiao, Y. P. & Allred, D. R. Unusual chromatin structure associated with monoparalogous transcription of the Babesia bovis ves multigene family. Int. J. Parasitol. 43, 163–172 (2013).

    CAS  PubMed  Google Scholar 

  118. Mack, E. A., Tagliamonte, M. S., Xiao, Y. P., Quesada, S. & Allred, D. R. Babesia bovis Rad51 ortholog influences switching of ves genes but is not essential for segmental gene conversion in antigenic variation. PLoS Pathog. 16, e1008772 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Prucca, C. G. et al. Antigenic variation in Giardia lamblia is regulated by RNA interference. Nature 456, 750–754 (2008).

    CAS  PubMed  Google Scholar 

  120. Saraiya, A. A., Li, W., Wu, J., Chang, C. H. & Wang, C. C. The microRNAs in an ancient protist repress the variant-specific surface protein expression by targeting the entire coding sequence. PLoS Pathog. 10, e1003791 (2014).

    PubMed  PubMed Central  Google Scholar 

  121. Gargantini, P. R., Serradell, M. D. C., Ríos, D. N., Tenaglia, A. H. & Luján, H. D. Antigenic variation in the intestinal parasite Giardia lamblia. Curr. Opin. Microbiol. 32, 52–58 (2016).

    CAS  PubMed  Google Scholar 

  122. van Leeuwen, F. et al. Localization of the modified base J in telomeric VSG gene expression sites of Trypanosoma brucei. Genes Dev. 11, 3232–3241 (1997).

    PubMed  PubMed Central  Google Scholar 

  123. Schulz, D., Zaringhalam, M., Papavasiliou, F. N. & Kim, H. S. Base J and H3.V regulate transcriptional termination in Trypanosoma brucei. PLoS Genet. 12, e1005762 (2016).

    PubMed  PubMed Central  Google Scholar 

  124. Reynolds, D. et al. Histone H3 variant regulates RNA polymerase II transcription termination and dual strand transcription of siRNA loci in Trypanosoma brucei. PLoS Genet. 12, e1005758 (2016).

    PubMed  PubMed Central  Google Scholar 

  125. Hughes, K. et al. A novel ISWI is involved in VSG expression site downregulation in African trypanosomes. EMBO J. 26, 2400–2410 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Figueiredo, L. M., Janzen, C. J. & Cross, G. A. M. A histone methyltransferase modulates antigenic variation in African trypanosomes. PLoS Biol. 6, e161 (2008).

    PubMed  PubMed Central  Google Scholar 

  127. Denninger, V. & Rudenko, G. FACT plays a major role in histone dynamics affecting VSG expression site control in Trypanosoma brucei. Mol. Microbiol. 94, 945–962 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Jiang, L. et al. PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum. Nature 499, 223–227 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Chess, A., Simon, I., Cedar, H. & Axel, R. Allelic inactivation regulates olfactory receptor gene expression. Cell 78, 823–834 (1994).

    CAS  PubMed  Google Scholar 

  130. Wang, F., Nemes, A., Mendelsohn, M. & Axel, R. Odorant receptors govern the formation of a precise topographic map. Cell 93, 47–60 (1998).

    CAS  PubMed  Google Scholar 

  131. Clowney, E. J. et al. Nuclear aggregation of olfactory receptor genes governs their monogenic expression. Cell 151, 724–737 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Armelin-Correa, L. M., Gutiyama, L. M., Brandt, D. Y. & Malnic, B. Nuclear compartmentalization of odorant receptor genes. Proc. Natl Acad. Sci. USA 111, 2782–2787 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Bashkirova, E. & Lomvardas, S. Olfactory receptor genes make the case for inter-chromosomal interactions. Curr. Opin. Genet. Dev. 55, 106–113 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all members of the Siegel lab for valuable discussion and ScI-llustrations Carolin Wedel Grafikdesign for help with the figure design. A.B.-S. is funded through the CRC 1064 (213249687), an ERC Starting Grant (3D_Tryps 715466), and an ERC Consolidator Grant (SwitchDecoding 101044320) awarded to T.N.S. M.C. is a Wellcome Investigator (217138/Z/19/Z). Work on this Review has been supported by funds from the University of Cambridge and LMU München strategic partnership scheme.

Author information

Authors and Affiliations

  1. Division of Experimental Parasitology, Faculty of Veterinary Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

    Anna Barcons-Simon & T. Nicolai Siegel

  2. Biomedical Center, Division of Physiological Chemistry, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

    Anna Barcons-Simon & T. Nicolai Siegel

  3. Department of Biochemistry, University of Cambridge, Cambridge, UK

    Mark Carrington

Authors
  1. Anna Barcons-Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark Carrington
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Nicolai Siegel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.B.-S. and T.N.S conceived the main ideas for the Review. A.B.-S. wrote the original draft. A.B.-S., M.C. and T.N.S. reviewed and edited the paper. T.N.S. prepared the figures.

Corresponding author

Correspondence to T. Nicolai Siegel.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Microbiology thanks Mohamed-Ali Hakimi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barcons-Simon, A., Carrington, M. & Siegel, T.N. Decoding the impact of nuclear organization on antigenic variation in parasites. Nat Microbiol 8, 1408–1418 (2023). https://doi.org/10.1038/s41564-023-01424-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41564-023-01424-9

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing