Epigenetically-regulated RNA-binding proteins signify malaria hypnozoite dormancy [ATAC-seq]
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PROVIDER: PRJNA747276 | ENA |
REPOSITORIES: ENA
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Project description:Epigenetically-regulated RNA-binding proteins signify malaria hypnozoite dormancy
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Project description:Epigenetically-regulated RNA-binding proteins signify malaria hypnozoite dormancy [ChIP-seq]
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Project description:Epigenetically-regulated RNA-binding proteins signify malaria hypnozoite dormancy [single-cell RNA-seq]
| PRJNA747274 | ENA
Project description:Dormancy enables pathogens to survive unfavorable conditions and maximize their chance for transmission. Relapsing malaria parasites, such as Plasmodium vivax, ovale and cynomolgi employ this strategy. After inoculation by the bite of an infected mosquito, the so-called hypnozoites stay quiescent inside liver cells before reactivating, proliferating and establishing blood stage infection. Despite recent advances in molecular characterization of hypnozoites the mechanisms leading to hypnozoite formation and reactivation remain a mystery. Here we integrate various omics approaches to explore the involvement of gene regulatory mechanisms in these processes. By profiling the genome-wide distribution of repressive and activating epigenetic marks we identify a small set of genes that gets epigenetically silenced during liver stage development, a process that is conserved amongst relapsing parasites. Furthermore, by combining single-cell transcriptomics, chromatin accessibility profiling and fluorescent in situ RNA hybridization we show that these genes are expressed in hypnozoites and their silencing coincides with parasite development. Intriguingly, genes with clear hypnozoite-specific expression are almost exclusively encoding for proteins with RNA-binding domains. Overall, these findings support a model in which repressive RNA-binding proteins keep hypnozoites in a developmentally competent, but dormant state and heterochromatin-mediated silencing of these genes enables hypnozoite reactivation. Further testing of this hypothesis could provide decisive clues for targeted reactivation and killing of these vicious pathogens.
2024-01-24 | GSE180255 | GEO
Project description:Dormancy enables pathogens to survive unfavorable conditions and maximize their chance for transmission. Relapsing malaria parasites, such as Plasmodium vivax, ovale and cynomolgi employ this strategy. After inoculation by the bite of an infected mosquito, the so-called hypnozoites stay quiescent inside liver cells before reactivating, proliferating and establishing blood stage infection. Despite recent advances in molecular characterization of hypnozoites the mechanisms leading to hypnozoite formation and reactivation remain a mystery. Here we integrate various omics approaches to explore the involvement of gene regulatory mechanisms in these processes. By profiling the genome-wide distribution of repressive and activating epigenetic marks we identify a small set of genes that gets epigenetically silenced during liver stage development, a process that is conserved amongst relapsing parasites. Furthermore, by combining single-cell transcriptomics, chromatin accessibility profiling and fluorescent in situ RNA hybridization we show that these genes are expressed in hypnozoites and their silencing coincides with parasite development. Intriguingly, genes with clear hypnozoite-specific expression are almost exclusively encoding for proteins with RNA-binding domains. Overall, these findings support a model in which repressive RNA-binding proteins keep hypnozoites in a developmentally competent, but dormant state and heterochromatin-mediated silencing of these genes enables hypnozoite reactivation. Further testing of this hypothesis could provide decisive clues for targeted reactivation and killing of these vicious pathogens.
2024-01-24 | GSE180256 | GEO
Project description:Dormancy enables pathogens to survive unfavorable conditions and maximize their chance for transmission. Relapsing malaria parasites, such as Plasmodium vivax, ovale and cynomolgi employ this strategy. After inoculation by the bite of an infected mosquito, the so-called hypnozoites stay quiescent inside liver cells before reactivating, proliferating and establishing blood stage infection. Despite recent advances in molecular characterization of hypnozoites the mechanisms leading to hypnozoite formation and reactivation remain a mystery. Here we integrate various omics approaches to explore the involvement of gene regulatory mechanisms in these processes. By profiling the genome-wide distribution of repressive and activating epigenetic marks we identify a small set of genes that gets epigenetically silenced during liver stage development, a process that is conserved amongst relapsing parasites. Furthermore, by combining single-cell transcriptomics, chromatin accessibility profiling and fluorescent in situ RNA hybridization we show that these genes are expressed in hypnozoites and their silencing coincides with parasite development. Intriguingly, genes with clear hypnozoite-specific expression are almost exclusively encoding for proteins with RNA-binding domains. Overall, these findings support a model in which repressive RNA-binding proteins keep hypnozoites in a developmentally competent, but dormant state and heterochromatin-mediated silencing of these genes enables hypnozoite reactivation. Further testing of this hypothesis could provide decisive clues for targeted reactivation and killing of these vicious pathogens.
2024-01-24 | GSE180257 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-01-24 | GSE180258 | GEO
Project description:Transcriptomic analysis of Plasmodium relapsing species identifies potential regulators of hypnozoite commitment and maintenance
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Project description:Natural Killer (NK) cells likely play an important role in immunity to malaria, but whether repeated malaria modifies the NK cell response remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dim NK cells, including decreased expression of PLZF and the Fc receptor g chain, increased histone methylation, and increased protein expression of LAG-3, KIR and LILRB1. CD56neg NK cells were highly functional, displaying greater antibody dependent cellular cytotoxicity than CD56dim NK cells, and higher frequencies of these cells were associated with protection against symptomatic malaria and high parasite densities. Importantly, following marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to malaria is required to maintain this modified, adaptive-like NK cell subset.
2022-12-25 | GSE210943 | GEO
Project description:Background Histone deacetylase (HDACs) inhibitors are being intensively pursued as potential new antimalarial drugs, and are also emerging as valuable tools for investigating transcriptional control in malaria parasites. In this study, the genome-wide transcriptional effects of three structurally related hydroxamate HDAC inhibitors were profiled in Plasmodium falciparum, the most lethal of the malaria parasite species that infects humans. Results Following 2h exposure to trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) or a 2-aminosuberic acid derivative (2-ASA-9), ~18-28% of genes in P. falciparum trophozoite-stage parasites were regulated greater than two fold. This global induction was transitory, with fewer genes (3-5%) regulated after removing the compounds and culturing for a further 2h. Just nine genes, including alpha-II-tubulin, were up-regulated by all three compounds. Despite structural similarity, the three inhibitors caused quite diverse transcriptional effects, possibly reflecting subtle differences in mode of action or cellular distribution. Conclusions Three structurally related HDAC inhibitors have been found to cause profound, genome-wide, transcriptional changes in P. falciparum parasites, but most effects were transitory. This highlights the dynamic and exquisitely controlled nature of transcription in these malaria parasites. We also identified a small subset of nine genes over-expressed by all three HDAC inhibitors that may represent the first recognized set of transcriptional markers that signify HDAC inhibition in malaria parasites. This data set is an important contribution to our understanding of gene regulation in malaria parasites and supports growing evidence for the potential of HDAC inhibitors as new antimalarial agents.
2012-05-01 | GSE25642 | GEO