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VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes

Significance Despite intense interest over a period of decades, mechanisms of allelic exclusion have remained unsolved mysteries in the field of eukaryotic gene expression control. Parasitic African trypanosomes express variant surface glycoproteins (VSGs) in a monoallelic fashion and have long been a paradigm for studies in this area. We used an RNA interference screen for loss of exclusion and identified and characterized VSG exclusion 1 (VEX1). VEX1 sequestration restricts expression and prevents the simultaneous establishment of more than one active VSG gene. VEX1 also appears to reinforce sequestration-based exclusion through homology-dependent repression. Our results indicate a “winner-takes-all” mechanism that allows parasitic trypanosomes to express just one VSG gene at a time. 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.