The g9a histone methyltransferase inhibitor BIX-01294 modulates gene expression during plasmodium falciparum gametocyte development and transmission

Che Julius Ngwa, Meike Jutta Kiesow, Lindsey Marie Orchard, Afia Farrukh, Manuel Llinás, Gabriele Pradel

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number5087
JournalInternational journal of molecular sciences
Volume20
Issue number20
DOIs
StatePublished - Oct 2 2019

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gametocytes
Methylation
gene expression
Plasmodium falciparum
Gene expression
Histones
inhibitors
Gene Expression
Culicidae
methylation
Genes
Acetylation
Deregulation
Gametogenesis
Transcription
Anopheles
genes
Falciparum Malaria
Zygote
Antimalarials

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

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title = "The g9a histone methyltransferase inhibitor BIX-01294 modulates gene expression during plasmodium falciparum gametocyte development and transmission",
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.",
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The g9a histone methyltransferase inhibitor BIX-01294 modulates gene expression during plasmodium falciparum gametocyte development and transmission. / Ngwa, Che Julius; Kiesow, Meike Jutta; Orchard, Lindsey Marie; Farrukh, Afia; Llinás, Manuel; Pradel, Gabriele.

In: International journal of molecular sciences, Vol. 20, No. 20, 5087, 02.10.2019.

Research output: Contribution to journalArticle

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

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