VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes

Allelic exclusion underpins antigenic variation and immune evasion in African trypanosomes. These bloodstream parasites employ 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 non-telomeric pol-I transcribed genes while 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-take-all' mechanism of allelic exclusion.