Epigenetically-regulated RNA-binding proteins signify malaria hypnozoite dormancy [single-cell RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA747274 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15177567_1.fastq.gz | Fastqsanger.gz | |||
| SRR15177567_2.fastq.gz | Fastqsanger.gz | |||
| SRR15177568_1.fastq.gz | Fastqsanger.gz | |||
| SRR15177568_2.fastq.gz | Fastqsanger.gz | |||
| SRR15177569_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetically-regulated RNA-binding proteins signify malaria hypnozoite dormancy
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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.
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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.
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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.
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Project description:Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus under dormancy, which can be induced in vitro through mTOR inhibition. Dormancy features silencing of the genome and abundant heterochromatin formation, which conflicts with the permissive and uncommitted genomic profile of pluripotent cells. Cellular strategies to maintain pluripotency in the fate of this conflict are not known. Here we probed chromatin regulation during embryonic stem cells’ (ESC) entry into dormancy to identify mechanisms that ensure nsure faithful propagation of cellular identity through dormancy. We show a global increase in DNA methylation and loss of chromatin accessibility in dormant ESCs and find that TET DNA demethylases are essential to counteract this trend at key pluripotency regulatory elements. Perturbation of TET activity compromises transcriptional programs and embryo survival through dormancy; whereas its enhancement improves survival rates. We propose that key regulatory elements are bookmarked coordinately by TETs and transcription factors in dormancy for maintenance of cellular identity. Our results reveal the first essential chromatin regulator in establishing mammalian dormancy and paves the way to building its temporal regulatory code in embryonic and adult tissues.
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Project description:Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus under dormancy, which can be induced in vitro through mTOR inhibition. Dormancy features silencing of the genome and abundant heterochromatin formation, which conflicts with the permissive and uncommitted genomic profile of pluripotent cells. Cellular strategies to maintain pluripotency in the fate of this conflict are not known. Here we probed chromatin regulation during embryonic stem cells’ (ESC) entry into dormancy to identify mechanisms that ensure nsure faithful propagation of cellular identity through dormancy. We show a global increase in DNA methylation and loss of chromatin accessibility in dormant ESCs and find that TET DNA demethylases are essential to counteract this trend at key pluripotency regulatory elements. Perturbation of TET activity compromises transcriptional programs and embryo survival through dormancy; whereas its enhancement improves survival rates. We propose that key regulatory elements are bookmarked coordinately by TETs and transcription factors in dormancy for maintenance of cellular identity. Our results reveal the first essential chromatin regulator in establishing mammalian dormancy and paves the way to building its temporal regulatory code in embryonic and adult tissues.
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