Current Genetics

, Volume 65, Issue 2, pp 435–443 | Cite as

Chromatin architecture and virulence-related gene expression in eukaryotic microbial pathogens

  • Alejandro Juárez-Reyes
  • Irene CastañoEmail author


A fundamental question in biology is to understand how appropriate transcriptional regulation and dense packaging of the genetic material within the eukaryotic nucleus are achieved. The exquisite gene expression control and other metabolic processes of DNA require a highly complex, multilayered, three-dimensional architecture of the chromatin and its specific compartmentalization within the nucleus. Some of these architectural and sub-nuclear positioning mechanisms have been extensively co-opted by eukaryotic pathogens to keep fine expression control and expansion of virulence-related gene families in Plasmodium falciparum, Trypanosoma brucei and Candida glabrata. For example non-linear interactions between distant cis-acting regions and the formation of chromatin loops are required for appropriate regulation of the expression of virulence-related multi-gene families encoding cell surface proteins. These gene families are located near the chromosome ends and tethered to the nuclear periphery. Consequently, only one or very few genes of the family are expressed at a time. These genes are involved in antigenic variation in parasites and the generation of subpopulations of cells with diverse antigenic proteins at the surface in some pathogenic fungi, making them highly efficient pathogens.


DNA loop TADs Epigenetics Chromatin interactome Fungal pathogens 



The authors wish to thank Alejandro De Las Peñas for critical review of the manuscript. We are indebted to Eunice López-Fuentes and Guadalupe Gutiérrez-Escobedo for helpful comments and reviewing of the manuscript. This work was supported by Consejo Nacional de Ciencia y Tecnología (CONACyT) Grant no. CB-2014-239629 to I.C.N.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The manuscript has been prepared following all the ethical standards of the journal.


  1. Ay F et al (2014) 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. CrossRefGoogle Scholar
  2. Barry JD, Ginger ML, Burton P, McCulloch R (2003) Why are parasite contingency genes often associated with telomeres? Int J Parasitol 33:29–45CrossRefGoogle Scholar
  3. Barry JD et al (2005) What the genome sequence is revealing about trypanosome antigenic variation. Biochem Soc Trans 33:986–989. CrossRefGoogle Scholar
  4. Batugedara G, Le Roch KG (2018) Unraveling the 3D genome of human malaria parasites. Semin Cell Dev Biol. Google Scholar
  5. Bernstein BE et al (2002) Methylation of histone H3 Lys 4 in coding regions of active genes. Proc Natl Acad Sci USA 99:8695–8700. CrossRefGoogle Scholar
  6. Bonev B, Cavalli G (2016) Organization and function of the 3D genome. Nat Rev Genet 17:772. CrossRefGoogle Scholar
  7. Castano I, Pan SJ, Zupancic M, Hennequin C, Dujon B, Cormack BP (2005) Telomere length control and transcriptional regulation of subtelomeric adhesins in Candida glabrata. Mol Microbiol 55:1246–1258. CrossRefGoogle Scholar
  8. Chittock EC, Latwiel S, Miller TC, Muller CW (2017) Molecular architecture of polycomb repressive complexes. Biochem Soc Trans 45:193–205. CrossRefGoogle Scholar
  9. Crane E et al (2015) Condensin-driven remodelling of X chromosome topology during dosage compensation. Nature 523:240–244. CrossRefGoogle Scholar
  10. Creyghton MP et al (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA 107:21931–21936. CrossRefGoogle Scholar
  11. de Bruin D, Kantrow SM, Liberatore RA, Zakian VA (2000) Telomere folding is required for the stable maintenance of telomere position effects in yeast. Mol Cell Biol 20:7991–8000. CrossRefGoogle Scholar
  12. de Bruin D, Zaman Z, Liberatore RA, Ptashne M (2001) Telomere looping permits gene activation by a downstream UAS in yeast. Nature 409:109–113. CrossRefGoogle Scholar
  13. De Las Penas A, Pan SJ, Castano I, Alder J, Cregg R, Cormack BP (2003) Virulence-related surface glycoproteins in the yeast pathogen Candida glabrata are encoded in subtelomeric clusters and subject to RAP1- and SIR-dependent transcriptional silencing. Genes Dev 17:2245–2258. CrossRefGoogle Scholar
  14. Deitsch KW, Calderwood MS, Wellems TE (2001) Malaria. Cooperative silencing elements in var genes. Nature 412:875–876. CrossRefGoogle Scholar
  15. Dekker J, Rippe K, Dekker M, Kleckner N (2002) Capturing chromosome conformation. Science 295:1306–1311. CrossRefGoogle Scholar
  16. Dixon JR et al (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485:376–380. CrossRefGoogle Scholar
  17. Domergue R et al (2005) Nicotinic acid limitation regulates silencing of Candida adhesins during UTI. Science 308:866–870. CrossRefGoogle Scholar
  18. Ellahi A, Thurtle DM, Rine J (2015) The chromatin and transcriptional landscape of native Saccharomyces cerevisiae telomeres and subtelomeric domains. Genetics 200:505–521. CrossRefGoogle Scholar
  19. Engreitz JM et al (2013) The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341:767. (Artn 1237973) CrossRefGoogle Scholar
  20. Erlendson AA, Friedman S, Freitag M (2017) A matter of scale and dimensions: chromatin of chromosome landmarks in the fungi. Microbiol Spectr. Google Scholar
  21. Figueiredo LM, Freitas-Junior LH, Bottius E, Olivo-Marin JC, Scherf A (2002) A central role for Plasmodium falciparum subtelomeric regions in spatial positioning and telomere length regulation. EMBO J 21:815–824. CrossRefGoogle Scholar
  22. Freitas-Junior LH et al (2000) Frequent ectopic recombination of virulence factor genes in telomeric chromosome clusters of P. falciparum. Nature 407:1018–1022. CrossRefGoogle Scholar
  23. Gallegos-Garcia V et al (2012) A novel downstream regulatory element cooperates with the silencing machinery to repress EPA1 expression in Candida glabrata. Genetics 190:1285–1297. CrossRefGoogle Scholar
  24. Ganji M, Shaltiel IA, Bisht S, Kim E, Kalichava A, Haering CH, Dekker C (2018) Real-time imaging of DNA loop extrusion by condensin. Science 360:102–105. CrossRefGoogle Scholar
  25. Gottschling DE, Aparicio OM, Billington BL, Zakian VA (1990) Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 63:751–762CrossRefGoogle Scholar
  26. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T (1999) Mammalian telomeres end in a large duplex loop. Cell 97:503–514CrossRefGoogle Scholar
  27. Grunstein M, Gasser SM (2013) Epigenetics in Saccharomyces cerevisiae. Cold Spring Harb Perspect Biol. Google Scholar
  28. Guelen L et al (2008) Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453:948–951. CrossRefGoogle Scholar
  29. Guillemette B, Bataille AR, Gevry N, Adam M, Blanchette M, Robert F, Gaudreau L (2005) Variant histone H2A.Z is globally localized to the promoters of inactive yeast genes and regulates nucleosome positioning. PLoS Biol 3:e384 CrossRefGoogle Scholar
  30. Guillemette B et al (2011) H3 lysine 4 is acetylated at active gene promoters and is regulated by H3 lysine 4 methylation. PLoS Genet 7:e1001354 CrossRefGoogle Scholar
  31. Harr JC, Gonzalez-Sandoval A, Gasser SM (2016) Histones and histone modifications in perinuclear chromatin anchoring: from yeast to man. EMBO Rep 17:139–155. CrossRefGoogle Scholar
  32. Hediger F, Neumann FR, Van Houwe G, Dubrana K, Gasser SM (2002) Live imaging of telomeres: yKu and Sir proteins define redundant telomere-anchoring pathways in yeast. Curr Biol 12:2076–2089CrossRefGoogle Scholar
  33. Henikoff S (1997) Nuclear organization and gene expression: homologous pairing and long-range interactions. Curr Opin Cell Biol 9:388–395CrossRefGoogle Scholar
  34. Hertz-Fowler C et al (2008) Telomeric expression sites are highly conserved in Trypanosoma brucei. PLoS One 3:e3527 CrossRefGoogle Scholar
  35. Jiang L et al (2013) PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum. Nature 499:223–227. CrossRefGoogle Scholar
  36. Juarez-Reyes A, Ramirez-Zavaleta CY, Medina-Sanchez L, De Las Penas A, Castano I (2012) A protosilencer of subtelomeric gene expression in Candida glabrata with unique properties. Genetics 190:101–111. CrossRefGoogle Scholar
  37. Kakui Y, Uhlmann F (2018) SMC complexes orchestrate the mitotic chromatin interaction landscape. Curr Genet 64:335–339. CrossRefGoogle Scholar
  38. Karmodiya K, Krebs AR, Oulad-Abdelghani M, Kimura H, Tora L (2012) H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells. BMC Genom 13:424. CrossRefGoogle Scholar
  39. Keely SP et al (2005) Gene arrays at Pneumocystis carinii telomeres. Genetics 170:1589–1600. CrossRefGoogle Scholar
  40. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705. CrossRefGoogle Scholar
  41. Krebs JE (2007) Moving marks: dynamic histone modifications in yeast. Mol BioSyst 3:590–597. CrossRefGoogle Scholar
  42. Laroche T, Martin SG, Gotta M, Gorham HC, Pryde FE, Louis EJ, Gasser SM (1998) Mutation of yeast Ku genes disrupts the subnuclear organization of telomeres. Curr Biol 8:653–656CrossRefGoogle Scholar
  43. Larrivee M, LeBel C, Wellinger RJ (2004) The generation of proper constitutive G-tails on yeast telomeres is dependent on the MRX complex. Genes Dev 18:1391–1396. CrossRefGoogle Scholar
  44. Li B (2015) DNA double-strand breaks and telomeres play important roles in Trypanosoma brucei antigenic variation. Eukaryot Cell 14:196–205. CrossRefGoogle Scholar
  45. Li B et al (2005) Preferential occupancy of histone variant H2AZ at inactive promoters influences local histone modifications and chromatin remodeling. Proc Natl Acad Sci USA 102:18385–18390. CrossRefGoogle Scholar
  46. Liu CL, Kaplan T, Kim M, Buratowski S, Schreiber SL, Friedman N, Rando OJ (2005) Single-nucleosome mapping of histone modifications in S. cerevisiae. PLoS Biol 3:e328. CrossRefGoogle Scholar
  47. Lopez-Fuentes E, Gutierrez-Escobedo G, Timmermans B, Van Dijck P, De Las Penas A, Castano I (2018a) Candida glabrata’s genome plasticity confers a unique pattern of expressed cell wall proteins. J Fungi. Google Scholar
  48. Lopez-Fuentes E, Hernandez-Hernandez G, Castanedo L, Gutierrez-Escobedo G, Oktaba K, De Las Penas A, Castano I (2018b) Chromatin loop formation induced by a subtelomeric protosilencer represses EPA genes in Candida glabrata. Genetics 210:113–128. CrossRefGoogle Scholar
  49. Lopez-Rubio JJ, Mancio-Silva L, Scherf A (2009) Genome-wide analysis of heterochromatin associates clonally variant gene regulation with perinuclear repressive centers in malaria parasites. Cell Host Microbe 5:179–190. CrossRefGoogle Scholar
  50. Lue NF, Yu EY (2017) Telomere recombination pathways: tales of several unhappy marriages. Curr Genet 63:401–409. CrossRefGoogle Scholar
  51. Maclary E, Hinten M, Harris C, Kalantry S (2013) Long nonoding RNAs in the X-inactivation center. Chromosome Res Int J Mol Supramol Evol Asp Chromosome Biol 21:601–614. CrossRefGoogle Scholar
  52. Magraner-Pardo L, Pelechano V, Coloma MD, Tordera V (2014) Dynamic remodeling of histone modifications in response to osmotic stress in Saccharomyces cerevisiae. BMC Genom 15:247. CrossRefGoogle Scholar
  53. Mason JMO, McEachern MJ (2018) Chromosome ends as adaptive beginnings: the potential role of dysfunctional telomeres in subtelomeric evolvability. Curr Genet 64:997–1000. CrossRefGoogle Scholar
  54. Messier TL et al (2016) Histone H3 lysine 4 acetylation and methylation dynamics define breast cancer subtypes. Oncotarget 7:5094–5109. CrossRefGoogle Scholar
  55. Millar CB, Xu F, Zhang K, Grunstein M (2006) Acetylation of H2AZ Lys 14 is associated with genome-wide gene activity in yeast. Genes Dev 20:711–722. CrossRefGoogle Scholar
  56. Morris SA et al (2007) Identification of histone H3 lysine 36 acetylation as a highly conserved histone modification. J Biol Chem 282:7632–7640. CrossRefGoogle Scholar
  57. Navarro M, Gull K (2001) A pol I transcriptional body associated with VSG mono-allelic expression in Trypanosoma brucei. Nature 414:759–763. CrossRefGoogle Scholar
  58. Ng HH, Feng Q, Wang H, Erdjument-Bromage H, Tempst P, Zhang Y, Struhl K (2002) Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association. Genes Dev 16:1518–1527. CrossRefGoogle Scholar
  59. Ng HH, Ciccone DN, Morshead KB, Oettinger MA, Struhl K (2003) Lysine-79 of histone H3 is hypomethylated at silenced loci in yeast and mammalian cells: a potential mechanism for position-effect variegation. Proc Natl Acad Sci USA 100:1820–1825. CrossRefGoogle Scholar
  60. Nikolaou C (2018) Invisible cities: segregated domains in the yeast genome with distinct structural and functional attributes. Curr Genet 64:247–258. CrossRefGoogle Scholar
  61. Noma K, Cam HP, Maraia RJ, Grewal SI (2006) A role for TFIIIC transcription factor complex in genome organization. Cell 125:859–872. CrossRefGoogle Scholar
  62. Nora EP et al (2012) Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485:381–385. CrossRefGoogle Scholar
  63. O’Sullivan JM, Tan-Wong SM, Morillon A, Lee B, Coles J, Mellor J, Proudfoot NJ (2004) Gene loops juxtapose promoters and terminators in yeast. Nat Genet 36:1014–1018. CrossRefGoogle Scholar
  64. Obado SO, Glover L, Deitsch KW (2016) The nuclear envelope and gene organization in parasitic protozoa: specializations associated with disease. Mol Biochem Parasitol 209:104–113. CrossRefGoogle Scholar
  65. Oppikofer M, Kueng S, Gasser SM (2013) SIR-nucleosome interactions: structure-function relationships yeast silent chromatin. Gene 527:10–25. CrossRefGoogle Scholar
  66. Perez-Martin J, Uria JA, Johnson AD (1999) Phenotypic switching in Candida albicans is controlled by a SIR2 gene. EMBO J 18:2580–2592. CrossRefGoogle Scholar
  67. Perrod S, Gasser SM (2003) Long-range silencing and position effects at telomeres and centromeres: parallels and differences. Cell Mol Life Sci 60:2303–2318. CrossRefGoogle Scholar
  68. Raisner RM et al (2005) Histone variant H2A.Z marks the 5′ ends of both active and inactive genes in euchromatin. Cell 123:233–248. CrossRefGoogle Scholar
  69. Rao B, Shibata Y, Strahl BD, Lieb JD (2005) Dimethylation of histone H3 at lysine 36 demarcates regulatory and nonregulatory chromatin genome-wide. Mol Cell Biol 25:9447–9459. CrossRefGoogle Scholar
  70. Rao SS et al (2014) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159:1665–1680. CrossRefGoogle Scholar
  71. Saldana-Meyer R, Gonzalez-Buendia E, Guerrero G, Narendra V, Bonasio R, Recillas-Targa F, Reinberg D (2014) CTCF regulates the human p53 gene through direct interaction with its natural antisense transcript, Wrap53. Gene Dev 28:723–734. CrossRefGoogle Scholar
  72. Schmid-Siegert E, Richard S, Luraschi A, Muhlethaler K, Pagni M, Hauser PM (2017) Mechanisms of surface antigenic variation in the human pathogenic fungus Pneumocystis jirovecii. mBio. Google Scholar
  73. Sexton T, Bantignies F, Cavalli G (2009) Genomic interactions: chromatin loops and gene meeting points in transcriptional regulation. Semin Cell Dev Biol 20:849–855. CrossRefGoogle Scholar
  74. Sexton T et al (2012) Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148:458–472. CrossRefGoogle Scholar
  75. Shogren-Knaak M, Ishii H, Sun JM, Pazin MJ, Davie JR, Peterson CL (2006) Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311:844–847. CrossRefGoogle Scholar
  76. Simon MD et al (2013) High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. Nature 504:465–465+. CrossRefGoogle Scholar
  77. Taylor HM, Kyes SA, Newbold CI (2000) Var gene diversity in Plasmodium falciparum is generated by frequent recombination events. Mol Biochem Parasitol 110:391–397CrossRefGoogle Scholar
  78. Tham WH, Zakian VA (2002) Transcriptional silencing at Saccharomyces telomeres: implications for other organisms. Oncogene 21:512–521. CrossRefGoogle Scholar
  79. Towbin BD et al (2012) Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery. Cell 150:934–947. CrossRefGoogle Scholar
  80. Trojer P, Reinberg D (2007) Facultative heterochromatin: is there a distinctive molecular signature? Mol Cell 28:1–13. CrossRefGoogle Scholar
  81. Trojer P et al (2007) L3MBTL1, a histone-methylation-dependent chromatin lock. Cell 129:915–928. CrossRefGoogle Scholar
  82. Vale-Silva L, Beaudoing E, Tran VDT, Sanglard D (2017) Comparative genomics of two sequential Candida glabrata clinical isolates. G3 7:2413–2426 CrossRefGoogle Scholar
  83. Wakimoto BT (1998) Beyond the nucleosome: epigenetic aspects of position–effect variegation in Drosophila. Cell 93:321–324CrossRefGoogle Scholar
  84. Winter DJ et al (2018) Repeat elements organise 3D genome structure and mediate transcription in the filamentous fungus Epichloe festucae. PLoS Genet 14:e1007467. CrossRefGoogle Scholar
  85. Zaman Z, Heid C, Ptashne M (2002) Telomere looping permits repression “at a distance” in yeast. Curr Biol 12:930–933CrossRefGoogle Scholar
  86. Zhang H, Roberts DN, Cairns BR (2005) Genome-wide dynamics of Htz1, a histone H2A variant that poises repressed/basal promoters for activation through histone loss. Cell 123:219–231. CrossRefGoogle Scholar
  87. Zhang T, Cooper S, Brockdorff N (2015) The interplay of histone modifications—writers that read. EMBO Rep 16:1467–1481. CrossRefGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.División de Biología MolecularIPICYT, Instituto Potosino de Investigación Científica y TecnológicaSan Luis PotosíMexico

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