Cohesin is involved in transcriptional repression of invasion-related genes

The most virulent human malaria parasite, Plasmodium falciparum, has a complex life cycle between its human host and mosquito vector. Each stage of the cycle is driven by a specific transcriptional program, but with only 27 specific transcription factors and approximately 6,000 genes in the genome, it is unclear how genes are activated or silenced at specific times. The P. falciparum genome is relatively euchromatic compared to the mammalian genome, except for specific genes that are uniquely heterochromatinized via HP1. In general, there seems to be an association between gene activity and spatial organization; however, the molecular mechanisms behind genome organization are unclear. While P. falciparum lacks lamins and CCCTC-binding factor - key genome organizing proteins in metazoans - it does have all core components of the cohesin complex. In other eukaryotes, the cohesin complex is involved in sister chromatid cohesion, transcription, and genome organization. To investigate the role of cohesin in P. falciparum, we combined genome editing, mass-spectrometry, chromatin immunoprecipitation and sequencing (ChIP-seq), and RNA sequencing to functionally characterize the cohesin subunit Structural Maintenance of Chromosomes protein 3 (SMC3). SMC3 inducible knockdown in early stages of the intraerythrocytic developmental cycle (IDC) resulted in significant up-regulation of a subset of genes involved in erythrocyte egress and invasion, which are normally expressed at later stages of the IDC. ChIP-seq of SMC3 revealed that over the IDC, enrichment at the promoter regions of these genes inversely correlates with their expression. These data suggest that SMC3 binding helps to repress specific genes until their appropriate time of expression. Further investigation of the cohesin complex will reveal its dynamic role in the repression, and perhaps organization, of genes in the transcriptional cascade that drives the IDC.