Cell cycle-regulated ApiAP2s and parasite development: the Toxoplasma paradigm

Zarringhalam, Kourosh; Ye, Sida; Lou, Jingjing; Rezvani, Yasaman; Gubbels, Marc-Jan

doi:10.1016/j.mib.2023.102383

Cited by 8 publications

(3 citation statements)

References 46 publications

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“…Since transcriptional waves are AP2 driven, we examined the expression and chromatin access of the 32 cyclically expressed AP2s ( Figure S3 ). They resolve in four expression clusters and largely match our recent analysis of the microarray time-course gene-expression data matching known functions of experimentally probed AP2 factors [16, 18]. In general, expression profiles are well mirrored in the chromatin access profiles, but there are some exceptions, e.g., AP2XI-3 and AP2VIIb−3.…”

Section: Resultssupporting

confidence: 69%

“…Archetypical apicomplexan AP2 factors (ApiAP2s) are defined by 1-2 AP2 DNA binding domains and harbor no other functional domains [9–12]. AP2s are capable of homo- or hetero-dimerization and can act cooperatively or competitively as repressors and/or activators on the same gene [13–16]. T. gondii harbors 67 AP2 encoding genes [17–19].…”

Section: Introductionmentioning

confidence: 99%

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Single cell expression and chromatin access of theToxoplasma gondiilytic cycle identifies AP2XII-8 as an essential pivotal controller of a ribosome regulon

Lou,

Rezvani,

Arriojas

et al. 2023

Preprint

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Sequential lytic cycles driven by cascading transcriptional waves underlie pathogenesis in the apicomplexan parasiteToxoplasma gondii. This parasite’s unique division by internal budding, short cell cycle, and jumbled up classically defined cell cycle stages have restrained in-depth transcriptional program analysis. Here, unbiased transcriptome and chromatin accessibility maps throughout the lytic cell cycle were established at the single cell level. Correlated pseudo-timeline assemblies of expression and chromatin profiles mapped transcriptional versus chromatin level transition points promoting the cell division cycle. Sequential clustering analysis identified putatively functionally related gene groups facilitating parasite division. Promoter DNA motif mapping revealed patterns of combinatorial regulation. Pseudo-time trajectory analysis revealed transcriptional bursts at different cell cycle points. The dominant burst in G1 was driven by transcription factor AP2XII-8, which engages TGCATGCG/A and TATAAGCCG motifs, and promoted the expression of a regulon encoding 40 ribosomal proteins. Overall, the study provides integrated, multi-level insights into apicomplexan transcriptional regulation.

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Section: Resultssupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Single cell expression and chromatin access of theToxoplasma gondiilytic cycle identifies AP2XII-8 as an essential pivotal controller of a ribosome regulon

Lou,

Rezvani,

Arriojas

et al. 2023

Preprint

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“…These are found only in the protist ApiAP2 proteins and in the AP2/ERF family of plant transcription factors (Balaji, 2005;Feng et al, 2020). ApiAP2 proteins are encoded by all apicomplexan parasites and have been shown to play essential roles in transcriptional activation or repression throughout parasite development (Jeninga et al, 2019;Zarringhalam et al, 2023). Due to their essentiality and lack of mammalian orthologues, ApiAP2 proteins are considered as putative drug targets (Russell et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Structural characterization of the ACDC domain from ApiAP2 proteins of the malaria parasite

Le Berre,

Tubiana,

Reuterswärd Waldner

et al. 2024

Preprint

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The Apicomplexan AP2 (ApiAP2) proteins are the best characterized family of DNA-binding proteins in the malaria parasite. Apart from the AP2 DNA-binding domain, there is little sequence similarity between ApiAP2 proteins and no other functional domains have been extensively characterized. One protein domain, which is present in a subset of the ApiAP2 proteins, is the conserved AP2-coincident domain mostly at the C-terminus (ACDC domain). Here we solved for the first time the crystal structure of the ACDC domain from two distinctPlasmodium falciparumApiAP2 proteins and one orthologue fromP. vivax, revealing a non-canonical four-helix bundle. Despite little sequence conservation between the ACDC domains from the two proteins, the structures are remarkably similar and do not resemble that of any other known protein domains. Due to their unique protein architecture and lack of homologues in the human genome, we performedin silicodocking calculations against a library of known antimalarial compounds and we identified a small molecule that can potentially bind to any Apicomplexan ACDC domain within a pocket highly conserved amongst ApiAP2 proteins. Inhibitors based on this compound would disrupt the function of the ACDC domain and thus of the ApiAP2 proteins containing it, providing a new therapeutic window for targeting the malaria parasite and other Apicomplexans.

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