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Trypping up antigenic variation in sleeping sickness

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Science Immunology  02 Nov 2018:
Vol. 3, Issue 29, eaav7758
DOI: 10.1126/sciimmunol.aav7758

Abstract

Histone variants ensure proper genome partitioning in trypanosomes to restrict antigenic variation.

The ability to vary the expression of antigens is a mechanism by which microorganisms evade immune recognition. Trypanosoma brucei—the cause of sleeping sickness—modulates the expression of variant surface glycoproteins (VSGs). T. brucei contains hundreds of VSG genes, but the number expressed at any time is tightly restricted. If an effective adaptive response develops against any particular VSG antigen during a human infection, a subpopulation of T. brucei with switched VSG usage can emerge in order to evade recognition. T. brucei VSG genes are concentrated within subtelomeric regions of the genome, which are hard to analyze by conventional short-read sequencing because of their repetitive and heterogeneous structure. To circumvent this, Müller and colleagues used long-read sequencing (Pac-Bio) and DNA-DNA contact frequency maps (Hi-C) of a common isolate of T. brucei to perform de novo, haplotype-specific assembly of VSG regions. The authors show that subtelomeric VSG regions are partitioned into highly compacted chromatin compartments, which maintain strong overall repression of VSG loci while permitting selective and uniform expression of a single VSG gene (VSG-2). The authors deleted two histone variants, H3.V and H4.V of this compartment structure, which may be involved in maintaining chromatin compartment boundaries. By single-cell RNA sequencing, they found that H3.V/H4.V double mutant cells switched expression away from VSG2 and toward other VSG genes, notably VSG11. A very small number of double mutant cells also transiently contained transcripts from multiple VSG genes, suggesting a loss in mutually exclusive VSG expression. Further long-read sequencing and Hi-C analyses showed that the switch in VSG expression in H3.V/H4.V mutant cells resulted from increased DNA-DNA contact frequencies and homologous recombination events between new VSG genes (VSG11) and loci associated with the original VSG2. These findings suggest that histone variants and 3D genome architecture play a critical role in regulating VSG in T. brucei. This raises the interesting possibility that targeted modulation of VSG loci genome compartment structure could be a therapeutic strategy for inducing more effective immune responses against T. brucei or other microorganisms that exploit a similar mechanism for immune evasion.

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