DAAD project: Characterization of HDAC-regulated zinc finger proteins crucial for Plasmodium falciparum transmission

 

Duration: 3 years

Application period: since 2019

Scholar: Afia Farrukh

Summary:

During the last decade, epigenetic mechanisms of gene expression have gained increasing attention due to their crucial roles in altering gene expression and in consequence cell fate. A tight control of gene regulation is particularly important for cells with high replication rates including protozoan parasites like Plasmodium falciparum, the causative agent of the deadly malaria tropica. While epigenetic control mechanisms have been studied extensively in the asexual blood stages of P. falciparum and were here shown to be particularly important for immune evasion, little is known about these mechanisms in gametocytes. These transmissible stages develop in the human red blood cells during a period of 10 days and once being taken up by a blood-feeding Anopheles mosquito undergo gametogenesis to initiate sexual reproduction. Gametocytes thus have crucial roles for human-to-mosquito transmission of the malaria parasite. To gain more insights into the mechanisms of post-translational regulation in gametocytes, my proposed host laboratory recently employed a chemical loss-of-function technique using the histone deacetylase inhibitor Trichostatin A (TSA). TSA-treatment impaired gametocyte maturation and lead to histone hyper-acetylation, thereby resulting in the transcriptional deregulation of over 294 genes in the different gametocyte stages. Interestingly, they identified a small group of seven genes encoding for zinc finger proteins (ZFPs), which were highly upregulated in their transcript levels in TSA-treated gametocytes, indicating that they may be controlled in their expression levels by histone acetylation/deacetylation. ZFPs are a diverse family of zinc ion-binding proteins that serve as interactors for DNAs, RNAs, and proteins and which among others function as transcription factors. Although the P. falciparum genome encodes more than 200 proteins with zinc finger domains, to date not much is known about their roles during the life cycle of the malaria parasite. The main aim of this project is to functionally characterize the HDAC-regulated ZFPs in detail in order to identify potential targets for antimalarials and transmission-blocking agents.