Targeting epigenetics for antimalarial development

表观遗传调控是真核生物调控基因表达的重要手段。在疟疾寄生虫疟原虫中，染色质重塑因子涉及致病性的各个方面，包括激活入侵相关基因，抑制细胞粘附受体以保护免疫逃避，以及发育承诺可传播的性形式。然而，我们的理解特定的染色质修饰因子在动态调控基因表达的不同生命周期阶段的顶复门寄生虫的作用是不完整的。此外，针对基本表观遗传靶点开发的化学抑制剂为探索寄生虫生物学提供了重要工具，并可作为新药发现的起点。该项目将结合基于联合收割机的CRISPR基因组编辑和化学生物学方法，探索表观遗传密码的“读者、作家和橡皮擦”的作用。该项目将采用两种平行方法，使用CRISPR基因组编辑生成几种表观遗传调节因子的条件性敲除系，并将使用具有抗疟活性的表观遗传探针化合物（“epi-probes”）在体外进化抗性，以建立其靶标。然后，这些遗传和化学资源将用于评估表观遗传调节对寄生虫生命周期转变的影响以及参与免疫逃避的多基因家族的表达。

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.