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Snf2L drives Plasmodium just-in-time gene expression and gametocytogenesis

ABSTRACT: The complex life cycle of the malaria parasite Plasmodium falciparum (Pf) involves the differentiation into multiple distinct forms, requiring a tight and dynamic control of gene expression at each stage. However, the full range of variation cannot solely be explained by stage-specific transcription factors, such as ApiAP2-family members, as they are strongly under-represented in Pf. Huge changes in chromatin structure and epigenetic modifications during life cycle progression suggest a central role of these mechanisms in regulating the transcriptional program for parasite development. Pf chromatin is distinct from other eukaryotes with an extraordinarily high AT-content (>80 %) and highly divergent histones lacking typical DNA packaging properties. In addition, the chromatin remodelers, key in shaping chromatin structure, are not conserved and unexplored in Pf. We identified PfSnf2L (PF3D7_1104200) as ISWI-related ATPase actively repositioning Pf nucleosomes in vitro. Knockout studies demonstrate that PfSnf2L is essential, regulating asexual development and sexual differentiation. It globally controls just-in-time transcription by spatiotemporally determining nucleosome positioning at promoters of stage-specific genes. The unique sequence and functional properties of PfSnf2L allows the identification of an inhibitor that specifically kills Plasmodium falciparum, phenocopies the loss of correct gene expression timing, and inhibits the formation of gametocytes.

ORGANISM(S): Plasmodium falciparum

PROVIDER: GSE237217 | GEO | 2024/10/17

REPOSITORIES: GEO

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Project description:The human malaria parasite Plasmodium falciparum has a complex and multi-stage life cycle that requires extensive immune escape, invasion of human liver and blood cells, and transmission through the female Anopholes mosquito. To date, the regulatory elements orchestrating these critical parasite processes remain largely unknown. However, there is mounting evidence across a broad range of species that intergenic long non-coding RNA (lncRNA) and antisense RNA can regulate chromatin state and gene expression. To pursue such functional roles for lncRNAs in P. falciparum, we performed deep, strand-specific RNA sequencing of fifteen non-polyA-selected blood stage samples, and assembled and characterized the properties of 660 intergenic lncRNAs, 474 antisense RNAs, and 1381 circular RNAs (circRNAs). We further validated the non-canonical splice junctions of seven P. falciparum circRNAs, an emerging class of non-coding RNA with regulatory potential and unexplored functional significance in P. falciparum. Our comprehensive analysis of P. falciparum lncRNAs indicates a functional role for these transcripts; P. falciparum intergenic lncRNAs and antisense RNAs are developmentally regulated in a similar periodic fashion to annotated transcripts, and sense-antisense pair expression is significantly anti-correlated. Notable outliers include intergenic lncRNAs that strongly peak in expression during parasite invasion, such as the telomere-associated lncRNA-TARE family, antisense transcripts that drop in expression during parasite invasion, and a highly correlated, multi-exonic, antisense counterpart to P. falciparum Gametocyte Developmental Protein 1 (PfGDV1). Taken together, our results present over two thousand P. falciparum intergenic lncRNA, antisense, and circRNA candidates and highlight promising P. falciparum lncRNAs for future investigation. We harvested fifteen blood stage samples from two biological replicate time-courses. The first time-course comprised of eleven samples that finely map temporal changes during P. falciparum blood stage development. We harvested samples over 56 hours, at roughly 4-hour time intervals, from a tightly synchronized P. falciparum 3D7 parasite population. As the asexual blood stage is an approximately 48-hour cycle, this time-course allowed us to profile gene expression during RBC rupture and parasite invasion. The second time-course comprised of four samples harvested in synchronous P. falciparum 3D7 parasites approximately four hours before and after the ring to trophozoite and trophozoite to schizont morphological stage transitions, which occur during the blood stage at 24 hours post invasion (hpi) and 36 hpi, respectively.

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Snf2L drives Plasmodium just-in-time gene expression and gametocytogenesis

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