Authors

J Faria²; L Glover¹; S Hutchinson¹; C Boehm²; M C Field²; D Horn²;  ¹ Institut Pasteur, Paris, France;  ² School of Life Sciences University of Dundee

Discussion

Specialised metazoan cells and pathogenic protozoa can activate a single gene from a family of closely related genes, but the underlying mechanisms have remained mysterious. In parasitic trypanosomes, association of one telomeric variant surface glycoprotein (VSG) gene with an RNA-polymerase-I (pol-I) transcription factory known as the expression-site body (ESB), and with VSG exclusion 1 (VEX1), facilitates monotelomeric VSG expression and antigenic variation. We isolated and identified VEX1-interactors: a Vex Histone Chaperone or ‘VHC’ complex incorporates a putative RNA helicase (VEX2) and the conserved replication-associated histone chaperone, chromatin assembly factor 1 (CAF-1). VEX2 forms a single sub-nuclear focus that colocalises with VEX1, immediately adjacent to the ESB, and CAF-1 displays enrichment in the same nuclear compartment, particularly in S-phase. VEX1 displays the properties of a limiting transcription factor, specifically, all known pol-I transcribed genes are activated when VEX1 is overexpressed or when VEX2 is knocked down, which causes VEX1 redistribution. In addition, transcription inhibition leads to redistribution of VEX1 and VEX2 to multiple sub-nuclear foci. VEX2 mediates post-transcriptional suppression of other Expression Site Associated Genes (ESAGs), boosting the proportional output from the VSG, while CAF-1 blocks transcription at other telomeres. In summary, a VHC complex activates one telomeric VSG, excluding others through a mechanism involving locus-specific sequestration of a transcription factor and histone-chaperone dependent silencing of other alleles. Our results provide a new paradigm for the establishment and inheritance of allele-specific epigenetic states.