The <i>Plasmodium falciparum</i> histone methyltransferase SET10 participates in a chromatin modulation network crucial for intraerythrocytic development

The lifecycle progression of the malaria parasite <i>Plasmodium falciparum</i> requires precise tuning of gene expression including histone methylation. The histone methyltransferase <i>Pf</i>SET10 was previously described as an H3K4 methyltransferase involved in <i>var</i> gene regulation, making it a prominent antimalarial target. In this study, we investigated the role of <i>Pf</i>SET10 in the blood stages of <i>P. falciparum</i> in more detail, using tagged <i>Pf</i>SET10-knockout (KO) and -knockdown (KD) lines. We demonstrate a nuclear localization of <i>Pf</i>SET10 with peak protein levels in schizonts. <i>Pf</i>SET10 deficiency reduces intraerythrocytic growth but has no effect on gametocyte commitment and maturation. Screening of the <i>Pf</i>SET10-KO line for histone methylation variations reveals that lack of <i>Pf</i>SET10 renders the parasites unable to mark H3K18me1, while no reduction in the H3K4 methylation status could be observed. Comparative transcriptomic profiling of <i>Pf</i>SET10-KO schizonts shows an upregulation of transcripts particularly encoding proteins linked to red blood cell remodeling and antigenic variation, suggesting a repressive function of the histone methylation mark. TurboID coupled with mass spectrometry further highlights an extensive nuclear <i>Pf</i>SET10 interaction network with roles in transcriptional regulation and mRNA processing, DNA replication and repair, and chromatin remodeling. The main interactors of <i>Pf</i>SET10 include ApiAP2 transcription factors, epigenetic regulators like <i>Pf</i>HDAC1, chromatin modulators like <i>Pf</i>MORC and <i>Pf</i>ISWI, mediators of RNA polymerase II, and DNA replication licensing factors. The combined data pinpoint <i>Pf</i>SET10 as a histone methyltransferase essential for H3K18 methylation that regulates nucleic acid metabolic processes in the <i>P. falciparum</i> blood stages as part of a comprehensive chromatin modulation network.IMPORTANCEThe fine-tuned regulation of DNA replication and transcription is particularly crucial for the rapidly multiplying blood stages of malaria parasites and proteins involved in these processes represent important drug targets. This study demonstrates that contrary to previous reports the histone methyltransferase <i>Pf</i>SET10 of the malaria parasite <i>Plasmodium falciparum</i> promotes the methylation of histone 3 at lysine K18, a histone mark to date not well understood. Deficiency of <i>Pf</i>SET10 due to genetic knockout affects genes involved in intraerythrocytic development. Furthermore, in the nuclei of blood-stage parasites, <i>Pf</i>SET10 interacts with various protein complexes crucial for DNA replication, remodeling, and repair, as well as for transcriptional regulation and mRNA processing. In summary, this study highlights <i>Pf</i>SET10 as a methyltransferase affecting H3K18 methylation with critical functions in chromatin maintenance during the development of <i>P. falciparum</i> in red blood cells.