The G9a Histone Methyltransferase Inhibitor BIX-01294 Modulates Gene Expression during Plasmodium falciparum Gametocyte Development and Transmission

Int J Mol Sci. 2019 Oct 14;20(20):5087. doi: 10.3390/ijms20205087.


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.

Keywords: gametocytes; gene expression; histone methylation; malaria; transmission.

MeSH terms

  • Animals
  • Anopheles / drug effects
  • Anopheles / parasitology
  • Antimalarials / metabolism
  • Antimalarials / therapeutic use
  • Azepines / pharmacology
  • Gene Expression Regulation, Developmental / drug effects
  • Germ Cells / growth & development*
  • Germ Cells / metabolism
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Malaria, Falciparum / drug therapy
  • Malaria, Falciparum / genetics*
  • Malaria, Falciparum / parasitology
  • Plasmodium falciparum / genetics*
  • Plasmodium falciparum / growth & development
  • Quinazolines / pharmacology


  • Antimalarials
  • Azepines
  • BIX 01294
  • Quinazolines
  • Histone-Lysine N-Methyltransferase