Abstract
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.

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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. https://doi.org/10.1101/gr.169417.113
Barry JD, Ginger ML, Burton P, McCulloch R (2003) Why are parasite contingency genes often associated with telomeres? Int J Parasitol 33:29–45
Barry JD et al (2005) What the genome sequence is revealing about trypanosome antigenic variation. Biochem Soc Trans 33:986–989. https://doi.org/10.1042/BST20050986
Batugedara G, Le Roch KG (2018) Unraveling the 3D genome of human malaria parasites. Semin Cell Dev Biol. https://doi.org/10.1016/j.semcdb.2018.07.015
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. https://doi.org/10.1073/pnas.082249499
Bonev B, Cavalli G (2016) Organization and function of the 3D genome. Nat Rev Genet 17:772. https://doi.org/10.1038/nrg.2016.147
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. https://doi.org/10.1111/j.1365-2958.2004.04465.x
Chittock EC, Latwiel S, Miller TC, Muller CW (2017) Molecular architecture of polycomb repressive complexes. Biochem Soc Trans 45:193–205. https://doi.org/10.1042/BST20160173
Crane E et al (2015) Condensin-driven remodelling of X chromosome topology during dosage compensation. Nature 523:240–244. https://doi.org/10.1038/nature14450
Creyghton MP et al (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA 107:21931–21936. https://doi.org/10.1073/pnas.1016071107
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. https://doi.org/10.1128/Mcb.20.21.7991-8000.2000
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. https://doi.org/10.1038/35051119
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. https://doi.org/10.1101/gad.1121003
Deitsch KW, Calderwood MS, Wellems TE (2001) Malaria. Cooperative silencing elements in var genes. Nature 412:875–876. https://doi.org/10.1038/35091146
Dekker J, Rippe K, Dekker M, Kleckner N (2002) Capturing chromosome conformation. Science 295:1306–1311. https://doi.org/10.1126/science.1067799
Dixon JR et al (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485:376–380. https://doi.org/10.1038/nature11082
Domergue R et al (2005) Nicotinic acid limitation regulates silencing of Candida adhesins during UTI. Science 308:866–870. https://doi.org/10.1126/science.1108640
Ellahi A, Thurtle DM, Rine J (2015) The chromatin and transcriptional landscape of native Saccharomyces cerevisiae telomeres and subtelomeric domains. Genetics 200:505–521. https://doi.org/10.1534/genetics.115.175711
Engreitz JM et al (2013) The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341:767. https://doi.org/10.1126/Science.1237973 (Artn 1237973)
Erlendson AA, Friedman S, Freitag M (2017) A matter of scale and dimensions: chromatin of chromosome landmarks in the fungi. Microbiol Spectr. https://doi.org/10.1128/microbiolspec.FUNK-0054-2017
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. https://doi.org/10.1093/emboj/21.4.815
Freitas-Junior LH et al (2000) Frequent ectopic recombination of virulence factor genes in telomeric chromosome clusters of P. falciparum. Nature 407:1018–1022. https://doi.org/10.1038/35039531
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. https://doi.org/10.1534/genetics.111.138099
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. https://doi.org/10.1126/science.aar7831
Gottschling DE, Aparicio OM, Billington BL, Zakian VA (1990) Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 63:751–762
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 97:503–514
Grunstein M, Gasser SM (2013) Epigenetics in Saccharomyces cerevisiae. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a017491
Guelen L et al (2008) Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453:948–951. https://doi.org/10.1038/nature06947
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 https://doi.org/10.1371/journal.pbio.0030384
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 https://doi.org/10.1371/journal.pgen.1001354
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. https://doi.org/10.15252/embr.201541809
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 12:2076–2089
Henikoff S (1997) Nuclear organization and gene expression: homologous pairing and long-range interactions. Curr Opin Cell Biol 9:388–395
Hertz-Fowler C et al (2008) Telomeric expression sites are highly conserved in Trypanosoma brucei. PLoS One 3:e3527 https://doi.org/10.1371/journal.pone.0003527
Jiang L et al (2013) PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum. Nature 499:223–227. https://doi.org/10.1038/nature12361
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. https://doi.org/10.1534/genetics.111.135251
Kakui Y, Uhlmann F (2018) SMC complexes orchestrate the mitotic chromatin interaction landscape. Curr Genet 64:335–339. https://doi.org/10.1007/s00294-017-0755-y
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. https://doi.org/10.1186/1471-2164-13-424
Keely SP et al (2005) Gene arrays at Pneumocystis carinii telomeres. Genetics 170:1589–1600. https://doi.org/10.1534/genetics.105.040733
Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705. https://doi.org/10.1016/j.cell.2007.02.005
Krebs JE (2007) Moving marks: dynamic histone modifications in yeast. Mol BioSyst 3:590–597. https://doi.org/10.1039/b703923a
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 8:653–656
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. https://doi.org/10.1101/gad.1199404
Li B (2015) DNA double-strand breaks and telomeres play important roles in Trypanosoma brucei antigenic variation. Eukaryot Cell 14:196–205. https://doi.org/10.1128/EC.00207-14
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. https://doi.org/10.1073/pnas.0507975102
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. https://doi.org/10.1371/journal.pbio.0030328
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. https://doi.org/10.3390/jof4020067
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. https://doi.org/10.1534/genetics.118.301202
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. https://doi.org/10.1016/j.chom.2008.12.012
Lue NF, Yu EY (2017) Telomere recombination pathways: tales of several unhappy marriages. Curr Genet 63:401–409. https://doi.org/10.1007/s00294-016-0653-8
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. https://doi.org/10.1007/s10577-013-9396-2
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. https://doi.org/10.1186/1471-2164-15-247
Mason JMO, McEachern MJ (2018) Chromosome ends as adaptive beginnings: the potential role of dysfunctional telomeres in subtelomeric evolvability. Curr Genet 64:997–1000. https://doi.org/10.1007/s00294-018-0822-z
Messier TL et al (2016) Histone H3 lysine 4 acetylation and methylation dynamics define breast cancer subtypes. Oncotarget 7:5094–5109. https://doi.org/10.18632/oncotarget.6922
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. https://doi.org/10.1101/gad.1395506
Morris SA et al (2007) Identification of histone H3 lysine 36 acetylation as a highly conserved histone modification. J Biol Chem 282:7632–7640. https://doi.org/10.1074/jbc.M607909200
Navarro M, Gull K (2001) A pol I transcriptional body associated with VSG mono-allelic expression in Trypanosoma brucei. Nature 414:759–763. https://doi.org/10.1038/414759a
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. https://doi.org/10.1101/gad.1001502
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. https://doi.org/10.1073/pnas.0437846100
Nikolaou C (2018) Invisible cities: segregated domains in the yeast genome with distinct structural and functional attributes. Curr Genet 64:247–258. https://doi.org/10.1007/s00294-017-0731-6
Noma K, Cam HP, Maraia RJ, Grewal SI (2006) A role for TFIIIC transcription factor complex in genome organization. Cell 125:859–872. https://doi.org/10.1016/j.cell.2006.04.028
Nora EP et al (2012) Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485:381–385. https://doi.org/10.1038/nature11049
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. https://doi.org/10.1038/ng1411
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. https://doi.org/10.1016/j.molbiopara.2016.07.008
Oppikofer M, Kueng S, Gasser SM (2013) SIR-nucleosome interactions: structure-function relationships yeast silent chromatin. Gene 527:10–25. https://doi.org/10.1016/j.gene.2013.05.088
Perez-Martin J, Uria JA, Johnson AD (1999) Phenotypic switching in Candida albicans is controlled by a SIR2 gene. EMBO J 18:2580–2592. https://doi.org/10.1093/emboj/18.9.2580
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. https://doi.org/10.1007/s00018-003-3246-x
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. https://doi.org/10.1016/j.cell.2005.10.002
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. https://doi.org/10.1128/MCB.25.21.9447-9459.2005
Rao SS et al (2014) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159:1665–1680. https://doi.org/10.1016/j.cell.2014.11.021
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. https://doi.org/10.1101/gad.236869.113
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. https://doi.org/10.1128/mBio.01470-17
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. https://doi.org/10.1016/j.semcdb.2009.06.004
Sexton T et al (2012) Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148:458–472. https://doi.org/10.1016/j.cell.2012.01.010
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. https://doi.org/10.1126/science.1124000
Simon MD et al (2013) High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. Nature 504:465–465+. https://doi.org/10.1038/nature12719
Taylor HM, Kyes SA, Newbold CI (2000) Var gene diversity in Plasmodium falciparum is generated by frequent recombination events. Mol Biochem Parasitol 110:391–397
Tham WH, Zakian VA (2002) Transcriptional silencing at Saccharomyces telomeres: implications for other organisms. Oncogene 21:512–521. https://doi.org/10.1038/sj.onc.1205078
Towbin BD et al (2012) Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery. Cell 150:934–947. https://doi.org/10.1016/j.cell.2012.06.051
Trojer P, Reinberg D (2007) Facultative heterochromatin: is there a distinctive molecular signature? Mol Cell 28:1–13. https://doi.org/10.1016/j.molcel.2007.09.011
Trojer P et al (2007) L3MBTL1, a histone-methylation-dependent chromatin lock. Cell 129:915–928. https://doi.org/10.1016/j.cell.2007.03.048
Vale-Silva L, Beaudoing E, Tran VDT, Sanglard D (2017) Comparative genomics of two sequential Candida glabrata clinical isolates. G3 7:2413–2426 https://doi.org/10.1534/g3.117.042887
Wakimoto BT (1998) Beyond the nucleosome: epigenetic aspects of position–effect variegation in Drosophila. Cell 93:321–324
Winter DJ et al (2018) Repeat elements organise 3D genome structure and mediate transcription in the filamentous fungus Epichloe festucae. PLoS Genet 14:e1007467. https://doi.org/10.1371/journal.pgen.1007467
Zaman Z, Heid C, Ptashne M (2002) Telomere looping permits repression “at a distance” in yeast. Curr Biol 12:930–933
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. https://doi.org/10.1016/j.cell.2005.08.036
Zhang T, Cooper S, Brockdorff N (2015) The interplay of histone modifications—writers that read. EMBO Rep 16:1467–1481. https://doi.org/10.15252/embr.201540945
Acknowledgements
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.
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Juárez-Reyes, A., Castaño, I. Chromatin architecture and virulence-related gene expression in eukaryotic microbial pathogens. Curr Genet 65, 435–443 (2019). https://doi.org/10.1007/s00294-018-0903-z
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DOI: https://doi.org/10.1007/s00294-018-0903-z


