Abstract
The malaria parasite replicates asexually in the red blood cells of its vertebrate host employing epigenetic mechanisms to regulate gene expression in response to changes in its environment. We used chromatin immunoprecipitation followed by sequencing in conjunction with RNA sequencing to create an epigenomic and transcriptomic map of the developmental transition from asexual blood stages to male and female gametocytes and to ookinetes in the rodent malaria parasite Plasmodium berghei. Across the developmental stages examined, heterochromatin protein 1 associates with variantly expressed gene families localised at subtelomeric regions and variant gene expression based on heterochromatic silencing is observed only in some genes. Conversely, the euchromatin mark histone 3 lysine 9 acetylation (H3K9ac) is abundant in non-heterochromatic regions across all developmental stages. H3K9ac presents a distinct pattern of enrichment around the start codon of ribosomal protein genes in all stages but male gametocytes. Additionally, H3K9ac occupancy positively correlates with transcript abundance in all stages but female gametocytes suggesting that transcription in this stage is independent of H3K9ac levels. This finding together with known mRNA repression in female gametocytes suggests a multilayered mechanism operating in female gametocytes in preparation for fertilization and zygote development, coinciding with parasite transition from host to vector.
Highlights
Silent heterochromatin in P. falciparum is defined as the presence of tri-methylated histone 3 lysine 9 (H3K9me3) which is bound by HP1 (PfHP1)[7,10]
In stark contrast to heterochromatin, the genomic distribution of H3K9ac is dynamic through parasite development: We find that while H3K9ac associates with 5′ untranslated regions (5′ UTRs) of genes, it peaks around the start codon of ribosomal protein genes, a phenomenon previously not reported in any Plasmodium species
We further investigated the mechanisms of maternal-to-zygotic transition (MZT) in P. berghei starting with genes that are differentially upregulated in ookinete sample (OOK) compared to female gametocytes (FG) (Fig. 4C), and compared them to 464 genes previously annotated as controlled by AP2-O26 (Fig. 6A)
Summary
Silent heterochromatin in P. falciparum is defined as the presence of tri-methylated histone 3 lysine 9 (H3K9me3) which is bound by HP1 (PfHP1)[7,10]. Heterochromatin is largely confined to telomeric and subtelomeric regions as well as chromosome-central islands and is almost invariably associated with variantly expressed multigene protein families in P. falciparum, P. vivax, P. chabaudi, P. berghei, P. yoelii and P. knowlesi asexual blood stage parasites[7,10,11,12,13,14], P. falciparum oocysts[15] and P. falciparum and P. vivax sporozoites[15,16,17]. We investigate how epigenetic traits change in malaria parasites during their transition from the murine host to the mosquito vector, using P. berghei asexual blood stages (ABS), female (FG) and male (MG) gametocytes, and ookinetes (OOK). Consistent with previous findings in P. falciparum asexual blood stages[13], H3K9ac enrichment in 5′UTRs correlates with transcript abundance in ABS in P. berghei. Our study adds substantially to our understanding of epigenetic regulation of gene expression during parasite transition from the mammalian host to the mosquito vector
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