Chromatin structure and var2csa - a tango in regulation of var gene expression in the human malaria parasite, Plasmodium falciparum ?
Overview
abstract
UNLABELLED: Over the last few decades, novel methods have been developed to study how chromosome positioning within the nucleus may play a role in gene regulation. Adaptation of these methods in the human malaria parasite, Plasmodium falciparum , has recently led to the discovery that the three-dimensional structure of chromatin within the nucleus may be critical in controlling expression of virulence genes ( var genes). Recent work has implicated an unusual, highly conserved var gene called var2csa in contributing to coordinated transcriptional switching, however how this gene functions in this capacity is unknown. To further understand how var2csa influences var gene switching, targeted DNA double-strand breaks (DSBs) within the sub-telomeric region of chromosome 12 were used to delete the gene and the surrounding chromosomal region. To characterize the changes in chromatin architecture stemming from this deletion and how these changes could affect var gene expression, we used a combination of RNA-seq, Chip-seq and Hi-C to pinpoint epigenetic and chromatin structural modifications in regions of differential gene expression. We observed a net gain of interactions in sub-telomeric regions and internal var gene regions following var2csa knockout, indicating an increase of tightly controlled heterochromatin structures. Our results suggest that disruption of var2csa results not only in changes in var gene transcriptional regulation but also a significant tightening of heterochromatin clusters thereby disrupting coordinated activation of var genes throughout the genome. Altogether our result confirms a strong link between the var2csa locus, chromatin structure and var gene expression. AUTHOR SUMMARY: Malaria remains one of the deadliest parasite-borne diseases, causing not only over a half million deaths annually, but also infecting hundreds of millions more. Plasmodium falciparum, the protozoan parasite that is responsible for the most virulent form of human malaria, is transmitted to humans by infected female mosquitoes during a blood meal. Due to a growing resistance to all existing antimalarials, there is a need to identify novel targets to design new antimalarial strategies. Our research builds on the growing body of evidence that supports the role of genome organization or chromatin structure within the nucleus in controlling the parasite development as well as virulence factors designed to circumvent the host immune response. This study identifies genes and structural elements within the Plasmodium falciparum genome that are controlled, at least partially, by the expression of a single unique and highly conserved virulence gene.
