title: VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes.
abstract: Allelic exclusion underpins antigenic variation and immune evasion in African trypanosomes. These bloodstream parasites use RNA polymerase-I (pol-I) to transcribe just one telomeric variant surface glycoprotein (VSG) gene at a time, producing superabundant and switchable VSG coats. We identified trypanosome VSG exclusion-1 (VEX1) using a genetic screen for defects in telomere-exclusive expression. VEX1 was sequestered by the active VSG and silencing of other VSGs failed when VEX1 was either ectopically expressed or depleted, indicating positive and negative regulation, respectively. Positive regulation affected VSGs and nontelomeric pol-I-transcribed genes, whereas negative regulation primarily affected VSGs. Negative regulation by VEX1 also affected telomeric pol-I-transcribed reporter constructs, but only when they contained blocks of sequence sharing homology with a pol-I-transcribed locus. We conclude that restricted positive regulation due to VEX1 sequestration, combined with VEX1-dependent, possibly homology-dependent silencing, drives a "winner-takes-all" mechanism of allelic exclusion.
authors.affiliation: Division of Biological Chemistry & Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors.forename: Lucy
authors.initials: L
authors.lastname: Glover
authors.affiliation: Division of Biological Chemistry & Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hutchinson
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.
authors.forename: Sam
authors.identifier: 0000-0001-8621-4920
authors.initials: S
authors.lastname: Alsford
authors.affiliation: Division of Biological Chemistry & Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; d.horn@dundee.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Horn
mesh_terms: D000940:Antigenic Variation / Q000235:genetics*; D016615:Telomere / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000235:genetics*; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000235:genetics*
chemical_list: D014643:Variant Surface Glycoproteins, Trypanosoma
keywords: Trypanosoma brucei; epigenetic; monoallelic; silencing; telomere