Characterization of the essential chromatin remodeling enzyme pfSnf2L in Plasmodium falciparum

• Applicants: Professor Dr. Gernot M. Längst; Professor Dr. Markus Meißner
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 534335380

The malaria causing parasite Plasmodium falciparum (Pf) is an unicellular eukaryote with a complex life cycle between human host and mosquito vector. Each life cycle stage can be characterized by a specific transcriptional profile, suggesting a complex transcriptional regulation mechanism. The parasite is unique, having the AT-richest genome sequenced to date, the most divergent histone proteins in the eukaryotic domain, resulting in a lack of global nucleosome positioning and exhibiting a 10-fold reduction in number of transcription factors, when compared to organisms of similar complexity. Therefore, it is not understood how the tightly regulated gene expression profile during developmental stage transition is established. It is suggested that the regulation of the gene expression cascade depends on epigenetic mechanisms involving nucleosome remodeling.In contrast to other eukaryotes, Pf has a non-redundant set of chromatin remodeling enzymes. This allows the study of the function of individual classes of chromatin remodelers in the cell by inducible knockout systems and associated functional studies. We chose the ISWI-type enzyme pfSnf2L, created inducible knockout parasite lines, and show that pfSnf2L is an essential enzyme for parasite survival. Conditional deletion of pfSnf2L resulted in parasites unable to exit the erythrocyte. In good agreement with this phenotype, gene expression analysis demonstrated that exportome genes are not activated at the correct stage of the intraerythrocytic cycle, in the absence of pfSnf2L. This conditional mutant will allow us to address the effects of pfSnf2L on chromatin structure and gene regulation during the erythrocyte life cycle of Pf. The study is combined with the functional characterization of the recombinant pfSnf2L enzyme, to draw a mechanistic picture of the cellular chromatin changes. We aim to unravel the mechanism of chromatin remodeling and nucleosome positioning on gene expression networks and phenotypical changes of Plasmodium falciparum.

• DFG Programme: Research Grants