Monoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex

Joana Correia Faria, Lucy Glover, Sebastian Hutchinson, Cordula Boehm, Mark C. Field, David Horn (Lead / Corresponding author)

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Abstract

The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. Here, we describe a protein complex sustaining variant surface glycoprotein (VSG) allelic exclusion and antigenic variation in Trypanosoma brucei parasites. The VSG-exclusion-1 (VEX1) protein binds both telomeric VSG-associated chromatin and VEX2, an ortholog of nonsense-mediated-decay helicase, UPF1. VEX1 and VEX2 assemble in an RNA polymerase-I transcription-dependent manner and sustain the active, subtelomeric VSG-associated transcription compartment. VSG transcripts and VSG coats become highly heterogeneous when VEX proteins are depleted. Further, the DNA replication-associated chromatin assembly factor, CAF-1, binds to and specifically maintains VEX1 compartmentalisation following DNA replication. Thus, the VEX-complex controls VSG-exclusion, while CAF-1 sustains VEX-complex inheritance in association with the active-VSG. Notably, the VEX2-orthologue and CAF-1 in mammals are also implicated in exclusion and inheritance functions. In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy.
Original languageEnglish
Article number3023
Pages (from-to)1-14
Number of pages14
JournalNature Communications
Volume10
DOIs
Publication statusPublished - 9 Jul 2019

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Trypanosoma Variant Surface Glycoproteins
Trypanosoma brucei brucei
Membrane Glycoproteins
exclusion
Epigenomics
chromatin
proteins
Transcription
trypanosome
DNA Replication
Chromatin
Chromatin Assembly Factor-1
deoxyribonucleic acid
eukaryotes
parasites
control surfaces
mammals
RNA Polymerase I
Immune Evasion
sustaining

Keywords

  • African trypanosome
  • nucleolus
  • silencing
  • telomere

Cite this

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title = "Monoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex",
abstract = "The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. Here, we describe a protein complex sustaining variant surface glycoprotein (VSG) allelic exclusion and antigenic variation in Trypanosoma brucei parasites. The VSG-exclusion-1 (VEX1) protein binds both telomeric VSG-associated chromatin and VEX2, an ortholog of nonsense-mediated-decay helicase, UPF1. VEX1 and VEX2 assemble in an RNA polymerase-I transcription-dependent manner and sustain the active, subtelomeric VSG-associated transcription compartment. VSG transcripts and VSG coats become highly heterogeneous when VEX proteins are depleted. Further, the DNA replication-associated chromatin assembly factor, CAF-1, binds to and specifically maintains VEX1 compartmentalisation following DNA replication. Thus, the VEX-complex controls VSG-exclusion, while CAF-1 sustains VEX-complex inheritance in association with the active-VSG. Notably, the VEX2-orthologue and CAF-1 in mammals are also implicated in exclusion and inheritance functions. In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy.",
keywords = "African trypanosome, nucleolus, silencing, telomere",
author = "{Correia Faria}, Joana and Lucy Glover and Sebastian Hutchinson and Cordula Boehm and Field, {Mark C.} and David Horn",
note = "The work was funded by Wellcome Trust Investigator Awards to D.H. [100320/Z/12/Z] and M.C.F. [204697/Z/16/Z] with additional support from a Wellcome Trust Centre Award [203134/Z/16/Z]. The University of Dundee Flow Cytometry and Imaging Facilities are supported by a Wellcome Trust award [097418/Z/11/Z], and the MRC Next Generation Optical Microscopy award [MR/K015869/1], respectively; while both the Proteomics and Imaging Facilities are supported by a Wellcome Trust Technology Platform award [097945/B/11/Z].",
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AU - Horn, David

N1 - The work was funded by Wellcome Trust Investigator Awards to D.H. [100320/Z/12/Z] and M.C.F. [204697/Z/16/Z] with additional support from a Wellcome Trust Centre Award [203134/Z/16/Z]. The University of Dundee Flow Cytometry and Imaging Facilities are supported by a Wellcome Trust award [097418/Z/11/Z], and the MRC Next Generation Optical Microscopy award [MR/K015869/1], respectively; while both the Proteomics and Imaging Facilities are supported by a Wellcome Trust Technology Platform award [097945/B/11/Z].

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N2 - The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. Here, we describe a protein complex sustaining variant surface glycoprotein (VSG) allelic exclusion and antigenic variation in Trypanosoma brucei parasites. The VSG-exclusion-1 (VEX1) protein binds both telomeric VSG-associated chromatin and VEX2, an ortholog of nonsense-mediated-decay helicase, UPF1. VEX1 and VEX2 assemble in an RNA polymerase-I transcription-dependent manner and sustain the active, subtelomeric VSG-associated transcription compartment. VSG transcripts and VSG coats become highly heterogeneous when VEX proteins are depleted. Further, the DNA replication-associated chromatin assembly factor, CAF-1, binds to and specifically maintains VEX1 compartmentalisation following DNA replication. Thus, the VEX-complex controls VSG-exclusion, while CAF-1 sustains VEX-complex inheritance in association with the active-VSG. Notably, the VEX2-orthologue and CAF-1 in mammals are also implicated in exclusion and inheritance functions. In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy.

AB - The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. Here, we describe a protein complex sustaining variant surface glycoprotein (VSG) allelic exclusion and antigenic variation in Trypanosoma brucei parasites. The VSG-exclusion-1 (VEX1) protein binds both telomeric VSG-associated chromatin and VEX2, an ortholog of nonsense-mediated-decay helicase, UPF1. VEX1 and VEX2 assemble in an RNA polymerase-I transcription-dependent manner and sustain the active, subtelomeric VSG-associated transcription compartment. VSG transcripts and VSG coats become highly heterogeneous when VEX proteins are depleted. Further, the DNA replication-associated chromatin assembly factor, CAF-1, binds to and specifically maintains VEX1 compartmentalisation following DNA replication. Thus, the VEX-complex controls VSG-exclusion, while CAF-1 sustains VEX-complex inheritance in association with the active-VSG. Notably, the VEX2-orthologue and CAF-1 in mammals are also implicated in exclusion and inheritance functions. In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy.

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