TY - JOUR
T1 - The g9a histone methyltransferase inhibitor BIX-01294 modulates gene expression during plasmodium falciparum gametocyte development and transmission
AU - Ngwa, Che Julius
AU - Kiesow, Meike Jutta
AU - Orchard, Lindsey Marie
AU - Farrukh, Afia
AU - Llinás, Manuel
AU - Pradel, Gabriele
N1 - Funding Information:
Funding: The work was funded by the Deutsche Forschungsgemeinschaft (to G.P., PR905/7-1). M.J.K. and A.F. received fellowships by the Deutscher Akademischer Austauschdienst; C.J.N. received a Theodore von Kármán fellowship from the RWTH Aachen University.
Funding Information:
The work was funded by the Deutsche Forschungsgemeinschaft (to G.P., PR905/7-1). M.J.K. and A.F. received fellowships by the Deutscher Akademischer Austauschdienst; C.J.N. received a Theodore von K?rm?n fellowship from the RWTH Aachen University.
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/10/2
Y1 - 2019/10/2
N2 - 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.
AB - 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.
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U2 - 10.3390/ijms20205087
DO - 10.3390/ijms20205087
M3 - Article
C2 - 31615031
AN - SCOPUS:85073431441
SN - 1661-6596
VL - 20
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 20
M1 - 5087
ER -