Histone methylation during Plasmodium falciparum sexual differentiation

• Applicant: Professorin Dr. Gabriele Pradel
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 454761374

Epigenetics plays a crucial role in dynamically regulating genes and is a main driver of lifecycle progression of malaria parasites. In Plasmodium falciparum, epigenetic control largely depends on histone post-translational modifications, particularly H3 acetylation and methylation, which have been implicated in regulating var gene expression and sexual commitment. Previously, we demonstrated that epigenetic drugs targeting histone methylation and deacetylation significantly impair gene expression during gametocyte development and gametogenesis, hence processes essential for malaria parasite transmission to mosquitoes. More recently, we identified the histone methyltransferase SET10 as a mediator of H3K18me1 methylation within a chromatin modulation complex. While SET10 deficiency does not affect intraerythrocytic growth and gametocyte development, preliminary data suggest that it severely impacts parasite transmission. Another key histone methyltransferase, SET2, is responsible for H3K36me2 and H3K36me3 marks in blood-stage parasites. We found that the loss of SET2 leads to aborted gametocytogenesis and severe defects in cytoskeletal organization and membrane integrity. Comparative transcriptomic analyses further revealed that SET2-deficient parasites exhibit a deregulation of genes associated with sexual commitment, mitochondrial function, and cytoskeletal organization. Collectively, these findings suggest that SET2 plays a crucial role in transcriptional shifts during gametocyte induction. In this renewal proposal, we will extend our research on SET2 and SET10. Our first objective (Aim 1) is to further investigate SET2’s role in gametocyte development. We will conduct in-depth morphological analyses of SET2-knockout parasites using super-resolution microscopy and characterize the SET2 interactome in ring stages and gametocytes. Additionally, we will identify SET2 target genes during gametocyte induction and development through chromatin immunoprecipitation. Our second objective (Aim 2) focuses on SET10 in blood-stage parasites. We will investigate the SET10-based chromatin modulation complex in more detail by identifying SET10 interactors in schizonts and gametocytes, which will then be subjected to loss-of-function phenotyping. Additionally, we will explore the SET10 loss-of-function phenotype in the plasmodial transmission stages via super-resolution microscopy. Comparative transcriptomics and chromatin precipitation assays will help to identify target genes of SET10-mediated methylation. The insights gained from this study will advance our understanding of histone methylation-based chromatin remodelling during malaria parasite sexual differentiation and support the development of epigenetic drug strategies for malaria therapy.

• DFG Programme: Research Grants