Transcriptional and histone post translation modification differences during the Plasmodium schizont-to-ring transition.. Plasmodium

Gene expression in malaria parasites is subject to various layers of regulation, including histone post-translational modifications (PTMs). Gene regulatory mechanisms have been extensively studied during the main developmental stages of Plasmodium parasites inside erythrocytes, from the ring stage following invasion to the schizont stage leading up to egress. However, gene regulation in merozoites that mediate the transition from one host cell to the next is an understudied area of parasite biology. Here, we sought to characterize gene expression and the corresponding histone PTM landscape during this stage of the parasite lifecycle through RNA-seq and ChIP-seq on P. falciparum blood stage schizonts, merozoites, and rings, as well as P. berghei liver stage merozoites. Rapid changes in gene expression occurred during merozoite maturation. We identified a subset of genes with a unique histone PTM profile characterized by depletion of H3K4me3 flanked by enrichment of H3K27ac and H3K9ac in the promoter regions of merozoites, which shared a DNA motif. These genes were upregulated in merozoites and rings and had roles in protein export and host cell remodeling. We observed a similar DNA motif in H3K4me3 depleted regions in the promoters of merozoite and ring stage genes in P. berghei merosomes, indicating similar regulatory mechanisms may underlie merozoite formation in the liver and blood stages. We also observed that H3K4me2 was deposited in gene bodies of gene families encoding variant surface antigens in merozoites, which may facilitate switching of gene expression between different members of these families. Finally, H3K18me and H2K27me were uncoupled from gene expression and were enriched around the centromeres, suggesting roles in the maintenance of chromosomal organization during schizogony. Together, our results demonstrate that extensive changes in gene expression and histone landscape occur during the schizont-to-ring transition to facilitate productive erythrocyte infection. The dynamic remodeling of the transcriptional program in merozoites makes this stage attractive as a target for novel anti-malarial approaches that may have activity against both the liver and blood stages.