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Whole genome expression profiling across the life cycle of PfBDP1 overexpressing P. falciparum malaria parasites

ABSTRACT: Erythrocyte invasion is an essential step in the life cycle of the malaria parasite Plasmodium falciparum that involves specific interactions between host cell receptors and parasite ligands. How the parasite regulates the expression of invasion-related genes is to date largely unknown. Here we show that a novel, parasite-specific bromodomain protein (PfBDP1) binds to chromatin at the transcriptional start site of invasion-related genes and directly controls their expression. Conditional PfBDP1 knockdown causes a dramatic defect in parasite invasion and growth and results in transcriptional down-regulation of multiple invasion-related genes at a time point critical for invasion. This is the first report of a histone binding protein that activates genes in P. falciparum and our data place PfBDP1 in a central position for controlling the coordinated expression of invasion genes. Bromodomains are emerging therapeutic targets and drugs that specifically inhibit PfBDP1 could be an invaluable tool in the effort to eradicate malaria.

ORGANISM(S): Plasmodium falciparum 3D7 Plasmodium falciparum

PROVIDER: GSE64690 | GEO | 2015/01/07

SECONDARY ACCESSION(S): PRJNA271649

REPOSITORIES: GEO

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Project description:Control of malaria is threatened by emerging parasite resistance to artemisinin drug (ART) therapies. The molecular details of how Plasmodium malaria parasites response to ART and how this relates to resistance is not clear. To determine how parasites respond to ART by altering gene expression, we performed a transcriptomic study of dihydroartemisinin (DHA) response in P. falciparum K1 strain and in P. berghei ANKA strain. Microarray data from DHA-treated P. falciparum trophozoite stage parasites were compared with data from other ART treatments. Genes with consistent changes in expression were identified, which includes notably down-regulation of cytosolic ribosomal protein genes. RNA-seq data revealed a similar pattern of transcriptomic change, although the pattern was much clearer in that more than one-third of P. falciparum trophozoite genes are differentially expressed with greater statistical support for down-regulation of ribosomal protein genes. The poor overlap of differentially-expressed genes between microarray and RNA-seq and less-well defined patterns for the former suggests that the accuracy of microarray is limited by technological bias. The trophozoite response to DHA is overall âring-likeâ and less âtrophozoite-likeâ, which is consistent with previous findings that Plasmodium can enter a quiescent ring-like state to resist ART. RNA-seq data from DHA-treated P. falciparum rings reveal a more muted response, although there is considerable overlap of differentially expressed genes with DHA-treated trophozoites. In contrast, P. falciparum schizonts are unresponsive to DHA, suggesting that the protective response acts mainly to arrest parasite development through the G2/M checkpoint. The transcriptional response of P. berghei to DHA treatment in vivo in infected mice is strikingly similar to the P. falciparum in vitro ring and trophozoite responses, in which ribosomal protein genes are notably down-regulated. These results suggest Plasmodium species respond to DHA in the same way. This knowledge could be applied to outwit the parasite to deliver more effective artemisinin therapies, and maybe hinder the development of drug resistance. Two condition drug-treatment experiment, Dihydroartemisinin vs. Vehicle control treatment with matched reference untreated controls. Biological replicates: 5 independently grown and harvested experimental culture replicates. One replicate of treatment/reference time-point per array.

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Whole genome expression profiling across the life cycle of PfBDP1 overexpressing P. falciparum malaria parasites

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