Spatial integration of transcription and splicing in a dedicated compartment sustains monogenic antigen expression in African trypanosomes

Joana Faria, Vanessa Luzak, Laura S. M. Müller, Benedikt G. Brink, Sebastian Hutchinson, Lucy Glover, David Horn, T. Nicolei Siegel (2021) Nature Microbiology. https://doi.org/10.1038/s41564-020-00833-4

Abstract cited directly from the paper:

"Highly selective gene expression is a key requirement for antigenic variation in several pathogens, allowing evasion of host immune responses and maintenance of persistent infections1. African trypanosomes—parasites that cause lethal diseases in humans and  livestock—employ an antigenic variation mechanism that involves monogenic antigen expression from a pool of >2,600 antigen-coding genes2. In other eukaryotes, the expression of individual genes can be enhanced by mechanisms involving the juxtaposition of otherwise distal chromosomal loci in the three-dimensional nuclear space3,4,5. However, trypanosomes lack classical enhancer sequences or regulated transcription initiation6,7. In this context, it has remained unclear how genome architecture contributes to  monogenic transcription elongation and transcript processing. Here, we show that the single expressed antigen-coding gene displays a  specific inter-chromosomal interaction with a major messenger RNA splicing locus. Chromosome conformation capture (Hi-C) revealed a dynamic reconfiguration of this inter-chromosomal interaction upon activation of another antigen. Super-resolution microscopy showed the interaction to be heritable and splicing dependent. We found a specific association of the two genomic loci with the antigen exclusio  complex, whereby VSG exclusion 1 (VEX1) occupied the splicing locus and VEX2 occupied the antigen-coding locus. Following VEX2 depletion, loss of monogenic antigen expression was accompanied by increased interactions between previously silent antigen genes an  the splicing locus. Our results reveal a mechanism to ensure monogenic expression, where antigen transcription and messenger RNA splicing occur in a specific nuclear compartment. These findings suggest a new means of post-transcriptional gene regulation."

See LMU Munich press release.