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Nature. 2018 Nov;563(7729):121-125. doi: 10.1038/s41586-018-0619-8. Epub 2018 Oct 17.

Genome organization and DNA accessibility control antigenic variation in trypanosomes.

Author information

1
Department of Veterinary Sciences, Experimental Parasitology, Ludwig-Maximilians-Universität München, Munich, Germany.
2
Biomedical Center Munich, Department of Physiological Chemistry, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
3
Research Center for Infectious Diseases, University of Würzburg, Würzburg, Germany.
4
ZB MED - Information Centre for Life Sciences, Cologne, Germany.
5
TH Köln, Faculty of Information Science and Communication Studies, Cologne, Germany.
6
Core Unit Systems Medicine, Institute of Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
7
Centre for Infectious Diseases, Parasitology, Heidelberg University Hospital, Heidelberg, Germany.
8
Department of Physiology, Biophysics & Systems Biology, Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
9
Department of Cell & Developmental Biology, Biocenter, University of Würzburg, Würzburg, Germany.
10
Helmholtz Institute for RNA-based Infection Research, Würzburg, Germany.
11
RNA Biology Group, Institute of Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
12
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
13
Centre of Immunobiology, Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
14
Icahn Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
15
Department of Veterinary Sciences, Experimental Parasitology, Ludwig-Maximilians-Universität München, Munich, Germany. n.siegel@lmu.de.
16
Biomedical Center Munich, Department of Physiological Chemistry, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany. n.siegel@lmu.de.
17
Research Center for Infectious Diseases, University of Würzburg, Würzburg, Germany. n.siegel@lmu.de.

Abstract

Many evolutionarily distant pathogenic organisms have evolved similar survival strategies to evade the immune responses of their hosts. These include antigenic variation, through which an infecting organism prevents clearance by periodically altering the identity of proteins that are visible to the immune system of the host1. Antigenic variation requires large reservoirs of immunologically diverse antigen genes, which are often generated through homologous recombination, as well as mechanisms to ensure the expression of one or very few antigens at any given time. Both homologous recombination and gene expression are affected by three-dimensional genome architecture and local DNA accessibility2,3. Factors that link three-dimensional genome architecture, local chromatin conformation and antigenic variation have, to our knowledge, not yet been identified in any organism. One of the major obstacles to studying the role of genome architecture in antigenic variation has been the highly repetitive nature and heterozygosity of antigen-gene arrays, which has precluded complete genome assembly in many pathogens. Here we report the de novo haplotype-specific assembly and scaffolding of the long antigen-gene arrays of the model protozoan parasite Trypanosoma brucei, using long-read sequencing technology and conserved features of chromosome folding4. Genome-wide chromosome conformation capture (Hi-C) reveals a distinct partitioning of the genome, with antigen-encoding subtelomeric regions that are folded into distinct, highly compact compartments. In addition, we performed a range of analyses-Hi-C, fluorescence in situ hybridization, assays for transposase-accessible chromatin using sequencing and single-cell RNA sequencing-that showed that deletion of the histone variants H3.V and H4.V increases antigen-gene clustering, DNA accessibility across sites of antigen expression and switching of the expressed antigen isoform, via homologous recombination. Our analyses identify histone variants as a molecular link between global genome architecture, local chromatin conformation and antigenic variation.

PMID:
30333624
PMCID:
PMC6784898
DOI:
10.1038/s41586-018-0619-8
[Indexed for MEDLINE]
Free PMC Article

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