Plasmodium falciparumSET10 is a histone H3 lysine K18 methyltransferase that participates in a chromatin modulation network crucial for intraerythrocytic development

Abstract

Lifecycle progression of the malaria parasitePlasmodium falciparumrequires precise tuning of gene expression including histone methylation. The histone methyltransferasePfSET10 was previously described as a H3K4 methyltransferase involved invargene regulation, making it a prominent antimalarial target. In this study, we investigate the role ofPfSET10 in the blood stages ofP. falciparumin more detail, using taggedPfSET10-knockout (KO) and -knockdown (KD) lines. We demonstrate a nuclear localization ofPfSET10 with peak protein levels in schizonts.PfSET10 deficiency results in reduced intraerythrocytic growth, but has no effect on gametocyte formation. When thePfSET10-KO line is screened for histone methylation variations, lack ofPfSET10 renders the parasites unable to mark H3K18me1, while no significant changes in the H3K4 methylation status are observed. Comparative transcriptomic profiling ofPfSET10-KO schizonts demonstrates the upregulation of transcripts particularly encoding proteins linked to erythrocyte invasion and multigene family proteins, suggesting a repressive function of the histone methylation mark. TurboID coupled with mass spectrometry further reveals an extensive nuclearPfSET10 interaction network with roles in transcriptional regulation, DNA replication and repair, chromatin remodeling and mRNA processing. Main interactors ofPfSET10 include ApiAP2 transcription factors, chromatin modulators likePfMORC andPfISWI, mediators of RNA polymerase II, and DNA replication licensing factors. The combined data pinpointPfSET10 as a histone H3 lysine K18 methyltransferase of theP. falciparumblood stages that regulates nucleic acid metabolic processes 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 methyltransferasePfSET10 of the malaria parasitePlasmodium falciparummethylates histone 3 at lysine K18, a histone mark to date not well understood. Deficiency ofPfSET10 due to genetic knockout affects genes involved in intraerythrocytic development. Furthermore, in the nuclei of blood stage parasites,PfSET10 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 highlightsPfSET10 as a H3K18 methyltransferase with critical functions in chromatin maintenance during the development ofP. falciparumin red blood cells.