Targeting epigenetics for antimalarial development

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Epigenetic regulation is an important means of controlling gene expression in eukaryotes. In the malaria parasite, Plasmodium, chromatin remodelling factors are implicated in diverse aspects of pathogenicity, including the activation of invasion-related genes, the suppression of cytoadherence receptors to preserve immune evasion, and the developmental commitment to transmissible sexual forms. However, our understanding of the roles of specific chromatin modifying factors in the dynamic regulation of gene expression across the different life-cycle stages of this apicomplexan parasite is incomplete. Furthermore, chemical inhibitors developed against essential epigenetic targets provide important tools for probing parasite biology, and could act as starting points for new drug discovery. This project will combine CRISPR-based genome editing and chemical biology approaches to probe the roles of the "readers, writers and erasers" of the epigenetic code. Taking two parallel approaches, this project will generate conditional knock-out lines of several epigenetic regulators using CRISPR genome editing, and will use epigenetic probe compounds ('epi-probes') with antimalarial activity to evolve resistance in vitro in order to establish their targets. These genetic and chemical resources will then be used to evaluate the impact of epigenetic regulation on lifecycle transitions of the parasite and the expression of multigene families involved in immune evasion.