Gene expression control by a bridge between two chromosomes

A team at the University of Dundee and University of York has determined how a highly selective protein bridge allows cells to express a single gene from a large gene family.

Working with colleagues at the University of York scientists in WCAIR have been able to demonstrate a mechanism that allows parasites to survive in their human and animal hosts, by expressing unique and switchable surface coats. This antigenic variation enables them to escape host immune defences.

Several cellular functions depend upon expression of a single uniform type of surface protein or receptor, not just parasitic trypanosomes, the subject of the current study, but also parasites that cause malaria, and the sensory neurons that sense odours in mammals.

Another selective gene expression mechanism is the inactivation of an X-chromosome in the cells of female mammals. What’s notable here is that the key protein assessed in the current study, known as VEX2, is related to human proteins involved in gene expression choices. Despite intense study, such gene choice mechanisms are not understood in detail in any cell type.

In the current paper published in Nature Communications, David Horn, Professor of Parasite Molecular biology in WCAIR, said that the findings represent both a substantial advance and a novel mechanism.

“We reported our discovery of the VEX1 protein in 2016, the VEX2 protein in 2019, and the spatial proximity of two key chromosomal regions in 2021” he said.The current study reveals a novel gene expression control mechanism, involving highly selective bridging between two chromosomes. The tethered chromosomes locally assemble an expression factory that maximises the output from a single Variant Surface Glycoprotein (VSG) gene”.

The ‘VSG exclusion’ or VEX-complex maintains all other competing VSG genes in a silent state, and the team used a range of approaches, including single-cell analysis, both super-resolution microscopy and scRNA-seq, to demonstrate a collapse of exclusion in the absence of the inter-chromosomal bridge.

Joana Faria, the first author on the paper, who now runs her own research team at the University of York said “VSG expression is a fine example of ‘extreme biology’, whereby such high levels of VSG expression render trypanosomes a highly amenable system to study fundamental mechanisms by which cells selectively activate genes and enhance their expression”.

David said that outstanding questions remain, however; “What remains unclear is how the chromosome-bridging VEX complex acts as a ‘gatekeeper’, resulting in a ‘winner takes all’ scenario and an extreme, 10,000-fold, expression differential. We hope that the new findings will help us to tackle this intriguing question”.

The work was supported by Wellcome, is the result of a collaboration among several colleagues (pictured) and was greatly facilitated by support from, and access to, the Dundee Imaging Facility and the FingerPrints Proteomics Facility at the School of Life Sciences. A behind the paper blog post can be found here and the paper can be found here.

Published on 14^th December 2023