Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites

Russell, Timothy J.; Silva, Erandi K. De; Crowley, Valerie M.; Shaw‐Saliba, Kathryn; Dube, Namita; Josling, Gabrielle A.; Pasaje, Charisse Flerida A.; Panagiotou, Gianni; Niles, Jacquin C.; Jacobs-­Lorena, Marcelo; Okafor, C. Denise; Gamo, Francisco‐Javier; Llinás, Manuel

doi:10.1371/journal.ppat.1010887

Cited by 19 publications

(27 citation statements)

References 90 publications

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“…Our AP2-LT ChIP-seq results identified an overlap with some AP2-EXP genome-wide binding sites, and previous work reported an overlap of AP2-I and AP2-EXP in vivo binding site preference 105 . Therefore, to expand the comparison to include all three factors, we identified the overlapping ChIP-seq peaks between AP2-LT (CACACA-binder), AP2-I (GTGCAC-binder), and AP2-EXP (TGCATGCA-binder) (Supplemental Figure 7D).…”

Section: Sequence Context Chromatin State and Timing Of Expression Di...supporting

confidence: 82%

“…In this context, we found several solutions including TFs that rely on sequence context to differentiate genome-wide binding site selection and others that are coordinated through changes in chromatin state features. Our findings are also relevant from a therapeutic perspective since ApiAP2 TFs are unique to plant and eukaryotic parasite genomes and have therefore been proposed as future antiparasitic drug targets 105,[111][112][113][114][115] .…”

Section: Discussionmentioning

confidence: 86%

“…Recent work has identified putative antimalarial compounds that interact with AP2 domains in silico and in vitro which arrest Plasmodium spp. development at multiple stages of the parasite life cycle 105 . The concept of a "pan-ApiAP2 inhibitor" design would allow for the inhibition of multiple ApiAP2 TFs, such as the group of CACACA-binding TFs that regulate divergent developmental pathways, with one drug.…”

Section: Discussionmentioning

confidence: 99%

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DNA sequence context and the chromatin landscape differentiate sequence-specific transcription factor binding in the human malaria parasite,Plasmodium falciparum

Bonnell

Zhang

Brown

et al. 2023

Preprint

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Development of the human malaria parasite,Plasmodium falciparum, is regulated by a limited number of sequence-specific transcription factors (TFs). However, the mechanisms by which these TFs recognize genome-wide binding sites is still largely unknown. To address TF specificity, we investigated the binding of two TF subsets that either bind CACACA or GTGCAC DNA sequence motifs and further characterized PfAP2-G and PfAP2-EXP which bind unique DNA motifs (GTAC and TGCATGCA). We interrogated the impact of DNA sequence and chromatin context onP. falciparumTF binding by integrating high-throughputin vitroandin vivobinding assays, DNA shape predictions, epigenetic post-translational modifications, and chromatin accessibility. We determined that DNA sequence context minimally impacts binding site selection for CACACA-binding TFs, while chromatin accessibility, epigenetic patterns, co-factor recruitment, and dimerization contribute to differential binding. In contrast, GTGCAC-binding TFs prefer different DNA sequence context in addition to chromatin dynamics. Finally, we find that TFs that preferentially bind divergent DNA motifs may bind overlapping genomic regionsin vivodue to low-affinity binding to other sequence motifs. Our results demonstrate that TF binding site selection relies on a combination of DNA sequence and chromatin features, thereby contributing to the complexity ofP. falciparumgene regulatory mechanisms.

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Section: Sequence Context Chromatin State and Timing Of Expression Di...supporting

confidence: 82%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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DNA sequence context and the chromatin landscape differentiate sequence-specific transcription factor binding in the human malaria parasite,Plasmodium falciparum

Bonnell

Zhang

Brown

et al. 2023

Preprint

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“…Here we have begun unravelling one of the networks responsible for this process by placing the AP2XII-2-directed HDAC3/MORC complex above two genes that function in sexual stages, AP2X-10 and AAH1. In addition to utilizing a candidate-based approach as we have relied on for this study, the recent report highlighting inhibitors of AP2-family member activity may prove yet another tool for interrogating the role of AP2 factors in Toxoplasma developmental transitions (35).…”

Section: Resultsmentioning

confidence: 99%

AP2XII-2 coordinates transcriptional repression forToxoplasma gondiisexual commitment

Srivastava

Holmes

White

et al. 2022

Preprint

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Toxoplasma gondii is a widespread protozoan parasite that has significant impact on human and veterinary health. The parasite undergoes a complex life cycle involving multiple hosts and developmental stages. How Toxoplasma transitions between life cycle stages is poorly understood, yet central to controlling transmission. Of particular neglect are the factors that contribute to its sexual development, which takes place exclusively in feline intestines. While epigenetic repressors have been shown to play an important role in silencing spurious gene expression of sexually committed parasites, the specific factors that recruit this generalized machinery to the appropriate genes remains largely unexplored. Here, we establish that a member of the AP2 transcription factor family, AP2XII-2, is targeted to genomic loci associated with sexually committed parasites along with the epigenetic regulators of transcriptional silencing, HDAC3 and MORC. Despite widespread association with gene promoters, AP2XII-2 is required for silencing of relatively few genes. Using CUT&Tag methodology, we identify two major genes associated with sexual development downstream of AP2XII-2 control, AP2X-10 and the amino acid hydroxylase AAH1. Our findings show that AP2XII-2 is a key contributor to the gene regulatory pathways modulating Toxoplasma sexual development.

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“…AP2-SP is an ApiAP2 transcription factor with many target genes that are expressed specifically in the sporozoite stage of the Plasmodium life cycle (43,45,46). It has also been shown that disruption of this gene results in the loss of sporozoite formation entirely in the related P. berghei parasite and has important activities in blood stages in P. falciparum (43,(45)(46)(47). Another affected gene is pk4, which encodes an essential eIF2α kinase related enzyme and contains changes in its non-cytoplasmic domain as determined by InterPro domain predictions across 17X and 17XNL strains (48)(49)(50)(51).…”

Section: Variation Between the Py17xnl And Py17x Reference Genomes Pr...mentioning

confidence: 99%

Long-Read Genome Assembly and Gene Model Annotations for the Rodent Malaria ParasitePlasmodium yoelii17XNL

Godin

Sebastian

Albert

et al. 2023

Preprint

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Malaria causes over 200 million infections and over 600 thousand fatalities each year, with most cases attributed to a human-infectious Plasmodium species, Plasmodium falciparum. Many rodent-infectious Plasmodium species, like Plasmodium berghei, Plasmodium chabaudi, and Plasmodium yoelii, have been used as genetically tractable model species that can expedite studies of this pathogen. In particular, P. yoelii is an especially good model for investigating the mosquito and liver stages of parasite development because key attributes closely resemble those of P. falciparum. Because of its importance to malaria research, in 2002 the 17XNL strain of P. yoelii was the first rodent malaria parasite to be sequenced. While sequencing and assembling this genome was a breakthrough effort, the final assembly consisted of >5000 contiguous sequences that impacted the creation of annotated gene models. While other important rodent malaria parasite genomes have been sequenced and annotated since then, including the related P. yoelii 17X strain, the 17XNL strain has not. As a result, genomic data for 17X has become the de facto reference genome for the 17XNL strain while leaving open questions surrounding possible differences between the 17XNL and 17X genomes. In this work, we present a high-quality genome assembly for P. yoelii 17XNL using HiFi PacBio long-read DNA sequencing. In addition, we use Nanopore long-read direct RNA-seq and Illumina short-read sequencing of mixed blood stages to create complete gene models that include not only coding sequences but also alternate transcript isoforms, and 5′and 3′ UTR designations. A comparison of the 17X and this new 17XNL assembly revealed biologically meaningful differences between the strains due to the presence of coding sequence variants. Taken together, our work provides a new genomic and gene expression framework for studies with this commonly used rodent malaria model species.

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Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites

Cited by 19 publications

References 90 publications

DNA sequence context and the chromatin landscape differentiate sequence-specific transcription factor binding in the human malaria parasite,Plasmodium falciparum

DNA sequence context and the chromatin landscape differentiate sequence-specific transcription factor binding in the human malaria parasite,Plasmodium falciparum

AP2XII-2 coordinates transcriptional repression forToxoplasma gondiisexual commitment

Long-Read Genome Assembly and Gene Model Annotations for the Rodent Malaria ParasitePlasmodium yoelii17XNL

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