Abstract
Transmission of the malaria parasite Plasmodium falciparum from the human to the mosquito is initiated by specialized sexual cells, the gametocytes. In the human, gametocytes are formed in response to stress signals and following uptake by a blood-feeding Anopheles mosquito initiate sexual reproduction. Gametocytes need to fine-tune their gene expression in order to develop inside the mosquito to continue life-cycle progression. Previously, we showed that post-translational histone acetylation controls gene expression during gametocyte development and transmission. However, the role of histone methylation remains poorly understood. We here use the histone G9a methyltransferase inhibitor BIX-01294 to investigate the role of histone methylation in regulating gene expression in gametocytes. In vitro assays demonstrated that BIX-01294 inhibits intraerythrocytic replication with a half maximal inhibitory concentration (IC50) of 13.0 nM. Furthermore, BIX-01294 significantly impairs gametocyte maturation and reduces the formation of gametes and zygotes. Comparative transcriptomics between BIX-01294-treated and untreated immature, mature and activated gametocytes demonstrated greater than 1.5-fold deregulation of approximately 359 genes. The majority of these genes are transcriptionally downregulated in the activated gametocytes and could be assigned to transcription, translation, and signaling, indicating a contribution of histone methylations in mediating gametogenesis. Our combined data show that inhibitors of histone methylation may serve as a multi-stage antimalarial.
Highlights
The tropical disease malaria still remains a global health burden with about 219 million infections and almost half a million deaths recorded in 2017 [1]
We previously showed by a chemical loss of function study using the histone deacetylases (HDACs) inhibitor Trichostatin A (TSA) that acetylation-based histone modifications are vital for preparing the parasite for human-to-mosquito transmission [5]
In this follow-up study, we report that the histone G9a histone methyl transferases (HMTs) inhibitor BIX-01294 modulates gene expression in gametocytes, thereby confirming a crucial contribution of histone methylation during malaria transmission
Summary
The tropical disease malaria still remains a global health burden with about 219 million infections and almost half a million deaths recorded in 2017 [1]. The intraerythrocytic development of gametocytes as well the activation in the mosquito midgut are supported by a well-coordinated sequence of gene activation and silencing events [4,5,6] These changes in the gene expression pattern are mandatory to prepare the malaria parasite for transmission from the human to the insect host. We previously showed by a chemical loss of function study using the HDAC inhibitor Trichostatin A (TSA) that acetylation-based histone modifications are vital for preparing the parasite for human-to-mosquito transmission [5] In this follow-up study, we report that the histone G9a HMT inhibitor BIX-01294 modulates gene expression in gametocytes, thereby confirming a crucial contribution of histone methylation during malaria transmission
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