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Plasmodium falciparum SET10 is a histone H3 lysine K18 methyltransferase regulating nucleic acid metabolic processes during intraerythrocytic development

ABSTRACT: Lifecycle progression of the malaria parasite Plasmodium falciparum requires a finely tuned regulation of gene expression including histone methylation. The histone methyltransferase PfSET10 was previously identified as a histone H3 lysine K4 methyltransferase involved in var gene regulation, making it a prominent antimalarial target. We here investigated the role of PfSET10 in the P. falciparum blood stages in more detail, using tagged PfSET10-knockout (KO) and -knockdown (KD) lines. We demonstrated a nuclear localization of PfSET10 in the P. falciparum blood stages with peak protein levels in schizonts. PfSET10 deficiency resulted in reduced intraerythrocytic growth, but had no effect on gametocyte formation. When the PfSET10-KO line was screened for histone methylation variations, lack of PfSET10 rendered the parasites unable to mark H3K18me1, while no significant changes in the H3K4 methylation status were observed. Comparative transcriptomic profiling of PfSET10-KO schizonts demonstrated the up-regulation of transcripts particularly encoding proteins of erythrocyte invasion and multi gene family proteins, suggesting a suppressive function of the histone methylation mark. TurboID coupled with mass spectrometry further revealed an extensive nuclear PfSET10 interaction network with roles in transcriptional regulation, DNA replication and repair, chromatin remodeling and mRNA processing. Main interactors of PfSET10 included ApiAP2 transcription factors, epigenetic regulators, mediators of RNA polymerase II and DNA replication licensing factors. The combined data pinpoint PfSET10 as a histone H3 lysine K18 methyltransferase regulating DNA and RNA metabolic processes important for intraerythrocytic development of P. falciparum.

ORGANISM(S): Cellular Organisms

SUBMITTER: Gabriele Pradel

PROVIDER: PXD052931 | JPOST Repository | Tue Sep 24 00:00:00 BST 2024

REPOSITORIES: jPOST

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			Action	DRS
	20200420_up_5445entries_plasmodium_falicparum_refence_proteome_UP000001450_isolate3D7.fasta	Fasta
	I220602_22.raw	Raw
	I220602_23.raw	Raw
	I220602_24.raw	Raw
	I220602_25.raw	Raw

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Project description:This model is described in the article: Kinetics of histone gene expression during early development of Xenopus laevis. Koster JG, Destrée OH and Westerhoff HV. J Theor Biol. 1988 Nov 21;135(2):139-67. PMID: 3267765 Abstract: Using literature data for transcriptional and translational rate constants, gene copy numbers, DNA concentrations, and stability constants, we have calculated the expected concentrations of histones and histone mRNA during embryogenesis of Xenopus laevis. The results led us to conclude that: (i) for X. laevis the gene copy number of the histone genes is too low to ensure the synthesis of sufficient histones during very early development, inheritance from the oocyte of either histone protein or histone mRNA (but not necessarily both) is necessary; (ii) from the known storage of histones in the oocyte and the rates of histone synthesis determined by Adamson and Woodland (1977), there would be sufficient histones to structure the newly synthesized DNA up to gastrulation but not thereafter (these empirical rates of histone synthesis may be underestimates); (iii) on the other hand, the amount of H3 mRNA recently observed during early embryogenesis (Koster, 1987, Koster et al., 1988) could direct a higher and sufficient synthesis of H3 protein, also after gastrulation. We present a quantitative model that accounts both for the observed H3 mRNA concentration as a function of time during embryogenesis and for the synthesis of sufficient histones to structure the DNA throughout early embryogenesis. The model suggests that X. laevis exhibits a major (i.e. some 14-fold) reduction in transcription of histone genes approximately 11 hours after fertilization. This reduction could be due to a decrease in the number of transcribed histone genes, a decreased rate constant of transcription with continued transcription of all the histone genes, and/or a reduction in the time during the cell cycle in which histone mRNA synthesis takes place. Alternatively, the histone mRNA stability might decrease approximately 16-fold 11 hours after fertilization. This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Plasmodium falciparum SET10 is a histone H3 lysine K18 methyltransferase regulating nucleic acid metabolic processes during intraerythrocytic development

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