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

TY - JOUR

T1 - Monoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex

AU - Correia Faria, Joana

AU - Glover, Lucy

AU - Hutchinson, Sebastian

AU - Boehm, Cordula

AU - Field, Mark C.

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].

PY - 2019/7/9

Y1 - 2019/7/9

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.

KW - African trypanosome

KW - nucleolus

KW - silencing

KW - telomere

UR - http://www.scopus.com/inward/record.url?scp=85068601339&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-10823-8

DO - 10.1038/s41467-019-10823-8

M3 - Article

C2 - 31289266

VL - 10

SP - 1

EP - 14

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 3023

ER -