Abstract
Malaria is caused by the proliferation of Plasmodium parasites in the vertebrate host blood stream through repeated cycles of asexual multiplication inside erythrocytes. During these cycles, parasites dynamically change their transcriptome at each developmental step to express genes exactly when required; however, the mechanisms regulating these transcriptomic changes remain unclear. In this study, we reveal that the AP2-family transcription factor PbAP2-TR is essential for the asexual blood stage development of the rodent malaria parasite Plasmodium berghei, as a transcriptional repressor. Conditional knockout of pbap2-tr causes developmental arrest at the trophozoite stage, i.e., the cell growth phase of asexual blood stage development. The expression of PbAP2-TR target genes is upregulated in pbap2-tr-knockout parasites, and introduction of mutations into the binding motifs increases the promoter activity of the target genes. Time-course transcriptome analysis shows that PbAP2-TR is largely responsible for the transcriptional downregulation from early to late trophozoite development. Furthermore, our data demonstrate that PbAP2-TR recruits a putative chromatin remodeler, PbMORC, as a co-factor. These results indicate that transcriptional repression by PbAP2-TR-PbMORC complex contributes on precise control of transcription peak patterns during the asexual blood stage development.
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Data availability
All ChIP-sequencing, RNA-sequencing and DIP-sequencing data generated in this study have been deposited in the Gene Expression Omnibus database under accession numbers GSE290541, GSE290542, GSE290544, and GSE290545. All MS/MS data for RIME have been deposited in the ProteomeXchange Consortium under dataset PXD067426. Source data are provided with this paper.
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Acknowledgements
This work was supported by the Japan Agency for Medical Research and Development (253fa627002h to S.I.), the Japan Society for the Promotion of Science (24K10187 to TN; 23H02709 to YM; 23K06515 to IK), and the Grant for Joint Research Project of the Research Institute for Microbial Diseases, The University of Osaka (JRPRIMD25B9 to IK). We would like to express our gratitude to Dr. Hiroko Kato and Dr. Ryohei Narumi, Central Instrumentation Laboratory, Research Institute for Microbial Diseases, The University of Osaka for performing analysis using timsTOF Pro and providing insight and expertise that greatly assisted the research.
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T.N. and Y.M. designed the study. T.N. performed all experiments, except for next generation sequencing and liquid chromatography-tandem mass spectrometry analysis. These analyses were performed by DNAFORM and Central Instrumentation Laboratory, Research Institute for Microbial Diseases, The University of Osaka, respectively. T.N. performed all formal data analyses and statistical analyses. I.K. contributed to the generation of transgenic parasites. S.I. contributed technical assistance/suggestions. All obtained funding for the study. Y.M. supervised the project. T.N. and Y.M. wrote the paper.
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Nishi, T., Kaneko, I., Iwanaga, S. et al. Precise gene regulation through transcriptional repression is essential for Plasmodium berghei asexual blood stage development. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68222-1
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DOI: https://doi.org/10.1038/s41467-025-68222-1
