Plasmodium falciparum gametocytes display global chromatin remodelling during sexual differentiation

Jeninga, Myriam D.; Tang, Jingyi; Selvarajah, Shamista A.; Maier, Alexander G.; Duffy, Michael; Petter, Michaela

doi:10.1186/s12915-023-01568-4

Cited by 12 publications

(6 citation statements)

References 139 publications

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“…However, we can at least speculate that PfSET10 may deposit H3K4me3 modifications at certain loci specifically in the maternal genome to mark these genes for activation during the gamete-to-zygote/ookinete transition and/or subsequent oocyst and sporozoite development. Interestingly, a recent study indeed reported significantly elevated H3K4me3 enrichment levels in female gametocytes at genes that are upregulated in ookinetes and oocysts 61 .…”

Section: Discussionmentioning

confidence: 95%

ThePlasmodium falciparumhistone methyltransferase PfSET10 is dispensable for the regulation of antigenic variation and gene expression in blood stage parasites

Wyss,

Kanyal,

Niederwieser

et al. 2024

Preprint

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The malaria parasitePlasmodium falciparumemploys antigenic variation of the virulence factorP. falciparumerythrocyte membrane protein 1 (PfEMP1) to escape adaptive immune responses during blood infection. Antigenic variation of PfEMP1 occurs through epigenetic switches in the mutually exclusive expression of individual members of the multi-copyvargene family.vargenes are located in perinuclear clusters of transcriptionally inactive heterochromatin. Singularvargene activation is linked to locus repositioning into a dedicated zone at the nuclear periphery and deposition of histone 3 lysine 4 di-/trimethylation (H3K4me2/3) and H3K9 acetylation marks in the promoter region. While previous work identified the putative H3K4-specific methyltransferase PfSET10 as an essential enzyme and positive regulator ofvargene expression, a recent study reported conflicting data. Here, we used iterative genome editing to engineer a conditional PfSET10 knockout line tailored to study the function of PfSET10 invargene regulation. We demonstrate that PfSET10 is not required for mutually exclusivevargene expression and switching. We also show that PfSET10 is dispensable not only for asexual parasite proliferation but also for sexual conversion and gametocyte differentiation. Furthermore, comparative RNA-seq experiments revealed that PfSET10 plays no obvious role in regulating gene expression during asexual parasite development and gametocytogenesis. Interestingly, however, PfSET10 shows different subnuclear localization patterns in asexual and sexual stage parasites and female-specific expression in mature gametocytes. In summary, our work confirms in detail that PfSET10 is not involved in regulatingvargene expression and not required for blood stage parasite viability, indicating PfSET10 may be important for life cycle progression in the mosquito vector or during liver stage development.

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Section: Discussionmentioning

confidence: 95%

ThePlasmodium falciparumhistone methyltransferase PfSET10 is dispensable for the regulation of antigenic variation and gene expression in blood stage parasites

Wyss,

Kanyal,

Niederwieser

et al. 2024

Preprint

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“…Moreover, both PfMYST and H4K8ac are enriched in the promoter of the activated var genes ( 15 , 31 ), suggesting that PfNuA4 and PfSWR1 are specifically involved in the regulation of antigenic variation in P. falciparum . Interestingly, a recent study showed that PfH2A.Z/PfH2B.Z were specifically enriched in the heterochromatin of female gametocytes ( 65 ). Whether PfNuA4 and PfSWR1 are involved in this regulation remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

MYST regulates DNA repair and forms a NuA4-like complex in the malaria parasite Plasmodium falciparum

Kalamuddin,

Shakri,

Wang

et al. 2024

mSphere

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Histone lysine acetyltransferase MYST-associated NuA4 complex is conserved from yeast to humans and plays key roles in cell cycle regulation, gene transcription, and DNA replication/repair. Here, we identified a Plasmodium falciparum MYST-associated complex, PfNuA4, which contains 11 of the 13 conserved NuA4 subunits. Reciprocal pulldowns using PfEAF2, a shared component between the NuA4 and SWR1 complexes, not only confirmed the PfNuA4 complex but also identified the PfSWR1 complex, a histone remodeling complex, although their identities are low compared to the homologs in yeast or humans. Notably, both H2A.Z/H2B.Z were associated with the PfSWR1 complex, indicating that this complex is involved in the deposition of H2A.Z/H2B.Z, the variant histone pair that is enriched in the activated promoters. Overexpression of PfMYST resulted in earlier expression of genes involved in cell cycle regulation, DNA replication, and merozoite invasion, and upregulation of the genes related to antigenic variation and DNA repair. Consistently, PfMYST overexpression led to high basal phosphorylated PfH2A (γ-PfH2A), the mark of DNA double-strand breaks, and conferred protection against genotoxic agent methyl methanesulfonate (MMS), X-rays, and artemisinin, the first-line antimalarial drug. In contrast, the knockdown of PfMYST caused a delayed parasite recovery upon MMS treatment. MMS induced the gradual disappearance of PfMYST in the cytoplasm and concomitant accumulation of PfMYST in the nucleus, suggesting cytoplasm-nucleus shuttling of PfMYST. Meanwhile, PfMYST colocalized with the γ-PfH2A, indicating PfMYST was recruited to the DNA damage sites. Collectively, PfMYST plays critical roles in cell cycle regulation, gene transcription, and DNA replication/DNA repair in this low-branching parasitic protist. IMPORTANCE Understanding gene regulation and DNA repair in malaria parasites is critical for identifying targets for antimalarials. This study found PfNuA4, a PfMYST-associated, histone modifier complex, and PfSWR1, a chromatin remodeling complex in malaria parasite Plasmodium falciparum . These complexes are divergent due to the low identities compared to their homologs from yeast and humans. Furthermore, overexpression of PfMYST resulted in substantial transcriptomic changes, indicating that PfMYST is involved in regulating the cell cycle, antigenic variation, and DNA replication/repair. Consistently, PfMYST was found to protect against DNA damage caused by the genotoxic agent methyl methanesulfonate, X-rays, and artemisinin, the first-line antimalarial drug. Additionally, DNA damage led to the relocation of cytoplasmic PfMYST to the nucleus and colocalization of PfMYST with γ-PfH2A, the mark of DNA damage. In summary, this study demonstrated that the PfMYST complex has critical functions in regulating cell cycle, antigenic variation, and DNA replication/DNA repair in P. falciparum .

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“…Gametocytes were produced and maintained according to standard protocols. Briefly, sexual commitment was induced by culture in partially spent medium and inhibition of asexual stages with N-acetyl-D-glucosamine [ 76 ]. Chromatin and RNA were harvested on day 6 or 8 of gametocyte differentiation (stage III-IV).…”

Section: Methodsmentioning

confidence: 99%

The exception that proves the rule: Virulence gene expression at the onset of Plasmodium falciparum blood stage infections

et al. 2023

Self Cite

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Controlled human malaria infections (CHMI) are a valuable tool to study parasite gene expression in vivo under defined conditions. In previous studies, virulence gene expression was analyzed in samples from volunteers infected with the Plasmodium falciparum (Pf) NF54 isolate, which is of African origin. Here, we provide an in-depth investigation of parasite virulence gene expression in malaria-naïve European volunteers undergoing CHMI with the genetically distinct Pf 7G8 clone, originating in Brazil. Differential expression of var genes, encoding major virulence factors of Pf, PfEMP1s, was assessed in ex vivo parasite samples as well as in parasites from the in vitro cell bank culture that was used to generate the sporozoites (SPZ) for CHMI (Sanaria PfSPZ Challenge (7G8)). We report broad activation of mainly B-type subtelomeric located var genes at the onset of a 7G8 blood stage infection in naïve volunteers, mirroring the NF54 expression study and suggesting that the expression of virulence-associated genes is generally reset during transmission from the mosquito to the human host. However, in 7G8 parasites, we additionally detected a continuously expressed single C-type variant, Pf7G8_040025600, that was most highly expressed in both pre-mosquito cell bank and volunteer samples, suggesting that 7G8, unlike NF54, maintains expression of some previously expressed var variants during transmission. This suggests that in a new host, the parasite may preferentially express the variants that previously allowed successful infection and transmission. Trial registration: ClinicalTrials.gov - NCT02704533; 2018-004523-36

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Plasmodium falciparum gametocytes display global chromatin remodelling during sexual differentiation

Cited by 12 publications

References 139 publications

ThePlasmodium falciparumhistone methyltransferase PfSET10 is dispensable for the regulation of antigenic variation and gene expression in blood stage parasites

ThePlasmodium falciparumhistone methyltransferase PfSET10 is dispensable for the regulation of antigenic variation and gene expression in blood stage parasites

MYST regulates DNA repair and forms a NuA4-like complex in the malaria parasite Plasmodium falciparum

The exception that proves the rule: Virulence gene expression at the onset of Plasmodium falciparum blood stage infections

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