H3K36 methylation reprograms gene expression to drive early gametocyte development in Plasmodium falciparum
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ABSTRACT:
PROVIDER: PRJNA686098 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13268240.fastq.gz | Fastqsanger.gz | |||
| SRR13268241.fastq.gz | Fastqsanger.gz | |||
| SRR13268242.fastq.gz | Fastqsanger.gz | |||
| SRR13268243.fastq.gz | Fastqsanger.gz | |||
| SRR13268244.fastq.gz | Fastqsanger.gz |
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Project description:The Plasmodium sexual gametocyte stages are the only transmissible form of the malaria parasite and are thus responsible for the continued transmission of the disease. Gametocytes undergo extensive functional and morphological changes from commitment to maturity, directed by an equally extensive control program. Several interconnected mechanisms governing sexual commitment have been described. However, the processes that drive the subsequent differentiation and development of the gametocyte remain largely unexplored. Using chromatin immunoprecipitation followed by high-throughput sequencing we map the genome-wide occupancy of H3K36me2 and H3K36me3 during early gametocyte development and describe an association between these histone modifications and the global changes in the transcriptional program driving gametocyte development post-commitment.
2021-04-20 | GSE163432 | GEO
Project description:BackgroundThe Plasmodium sexual gametocyte stages are the only transmissible form of the malaria parasite and are thus responsible for the continued transmission of the disease. Gametocytes undergo extensive functional and morphological changes from commitment to maturity, directed by an equally extensive control program. However, the processes that drive the differentiation and development of the gametocyte post-commitment, remain largely unexplored. A previous study reported enrichment of H3K36 di- and tri-methylated (H3K36me2&3) histones in early-stage gametocytes. Using chromatin immunoprecipitation followed by high-throughput sequencing, we identify a stage-specific association between these repressive histone modifications and transcriptional reprogramming that define a stage II gametocyte transition point.ResultsHere, we show that H3K36me2 and H3K36me3 from stage II gametocytes are associated with repression of genes involved in asexual proliferation and sexual commitment, indicating that H3K36me2&3-mediated repression of such genes is essential to the transition from early gametocyte differentiation to intermediate development. Importantly, we show that the gene encoding the transcription factor AP2-G as commitment master regulator is enriched with H3K36me2&3 and actively repressed in stage II gametocytes, providing the first evidence of ap2-g gene repression in post-commitment gametocytes. Lastly, we associate the enhanced potency of the pan-selective Jumonji inhibitor JIB-04 in gametocytes with the inhibition of histone demethylation including H3K36me2&3 and a disruption of normal transcriptional programs.ConclusionsTaken together, our results provide the first description of an association between global gene expression reprogramming and histone post-translational modifications during P. falciparum early sexual development. The stage II gametocyte-specific abundance of H3K36me2&3 manifests predominantly as an independent regulatory mechanism targeted towards genes that are repressed post-commitment. H3K36me2&3-associated repression of genes is therefore involved in key transcriptional shifts that accompany the transition from early gametocyte differentiation to intermediate development.
| S-EPMC8017609 | biostudies-literature
Project description:Plasmodium falciparum gametocyte stages represent a small fraction of the entire parasite biomass that is present during human malaria infection, yet they alone lead to the transmission of this devastating disease. One of the critical gaps in malaria transmission biology and surveillance is our lack of knowledge about gametocyte biology, especially sexual dimorphic development that may influence transmission from the human to the mosquito. Ratios of male and female gametocytes in the peripheral blood can vary significantly; influenced in part by asexual blood stage and gametocyte density as well as vertebrate and invertebrate host factors. Moreover, the role of sex ratios on gametocyte transmission potential to mosquitoes is unknown and dissecting this process has been hampered by the lack of sex-specific protein markers for the circulating, mature stage V gametocytes. The current evidence suggests a high degree of conservation in gametocyte gene complement across Plasmodium, and therefore presumably for sex-specific genes as well. Therefore, to better our understanding of gametocyte development and subsequent infectiousness to mosquitoes, we undertook a two pronged approach. First, we acquired the mixed, male and female stage V gametocyte proteomes of the NF54 isolate and mature stage V female proteome from Dd2, a strain that is defective in producing mature males. Second, we then undertook a Systematic Subtractive Bioinformatic analysis (filtering) approach to identify sex-specific P. falciparum NF54 protein markers based on a comparison with the Dd2 strain and syntenic male and female proteins from the reanalyzed and updated P. berghei (related rodent malaria parasite) gametocyte proteomes. This has produced a short list of putative 174 male- and 258 female-specific P. falciparum stage V proteins. Furthermore, we generated antibodies against three putative female-specific gametocyte stage V proteins in P. falciparum and confirmed sex-specificity for two proteins and also the loss sex-partitioning for a putative female-specific protein in rodent malaria parasites.
2014-07-25 | PXD000813 | Pride
Project description:Plasmodium falciparum PfAP2-G2 KO gametocyte microarray timecourse
| PRJNA674850 | ENA
Project description:Purpose: To carryout comparative transcriptomics between the ZNF4-K0 and the wild type in the ring and mature gametocyte stage of Plasmodium falciparum Methods: Total RNA was isolated from ring stage and percoll- enriched mature (stage V) gametocytes from the ZNF4-KO and NF54 wildtype using the Trizol reagent (Invitrogen) according to the manufacturer’s protocol. . RNA sequencing was performed at the Genomic Facility of the University Clinic at the RWTH University Aachen, Germany. Briefly, the quality of the isolated total RNA samples from ring stage and mature gametocytes of the ZNF4-KO and the wildtype were evaluated by Tapestation 4200 (Agilent). Libraries were generated with TruSeq Stranded mRNA Library Preparation kit (Illumina) from high quality total RNA samples according to the manufacturer´s protocol. The generated libraries, which pass the QC check on Tapestation 4200 (Agilent) were sequenced on a NextSeq 500 (Illumina) with High output Kit v2.5 (150 cycles) for paired-end sequencing according to standard procedure provided by Illumina. Results:Comparative transcriptomics between wildtype and ZNF4-KO in ring and mature gametocyte stages show only 66 genes de-regulated by greater than 2-fold in the ZNF4-KO ring stage while about 473 (274- upregulated and 199 down-regulated) were deregulated in mature gametocytes. Conclusions: Our combine data therefore reveal that ZNF4 plays an important role in male gametocyte exflagellation through the regulation of male gametocyte genes
2022-04-30 | GSE196298 | GEO
Project description:Differentiation from asexual blood stages to sexual gametocytes is required for transmission of malaria parasites from the human to the mosquito host. Preventing gametocyte commitment and development would block parasite transmission, but the underlying molecular mechanisms behind these processes remain poorly understood. Here, we report that the ApiAP2 transcription factor, PfAP2-G2 (PF3D7_1408200) plays a critical role in the maturation of Plasmodium falciparum gametocytes. PfAP2-G2 binds to the promoters of a wide array of genes that are expressed at many stages of the parasite life cycle. Interestingly, we also find binding of PfAP2-G2 within the gene body of almost 3000 genes, which strongly correlates with the location of H3K36me3 and several other histone modifications as well as Heterochromatin Protein 1 (HP1), suggesting that occupancy of PfAP2-G2 in gene bodies may serve as an alternative regulatory mechanism. Disruption of pfap2-g2 does not impact asexual development, parasite multiplication rate, or commitment to sexual development but the majority of sexual parasites are unable to mature beyond stage III gametocytes. The absence of pfap2-g2 leads to overexpression of 28% of the genes bound by PfAP2-G2 and none of the PfAP2-g2 bound are downregulated, suggesting that it is a repressor. We also find that PfAP2-G2 interacts with chromatin remodeling proteins, a microrchidia (MORC) protein, and another ApiAP2 protein (PF3D7_1139300). Overall our data demonstrate that PfAP2-G2 is an important transcription factor that establishes an essential gametocyte maturation program in association with other chromatin-related proteins.
2021-02-01 | GSE160924 | GEO
Project description:The P.falciparum gametocyte proteomes of wild type gametocytes and two clones of Pfg377 depleted gametocytes were obtained for a label free comparative analysis to identify osmiophilic body proteins. Gametocyte samples were analyzed by LC-MS/MS and processed by MaxQuant for identification and LFQ quantification.
2016-07-21 | PXD004124 | Pride
Project description:Proteins released in the cultured medium of eritrocytes infected by Plasmodium Falciparum at the moment of gametocyte egress
2020-12-24 | MSV000086635 | MassIVE
Project description:This work describes the activity of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX) and of its newly identified carboxylic acid metabolite on human malaria parasite Plasmodium falciparum. NBDHEX has been previously identified as a potent cytotoxic agent against murine and human cancer cells as well as towards the protozoan parasite Giardia duodenalis. We show here that NBDHEX is active in vitro against all blood stages of P. falciparum, with the rare feature of killing the parasite stages transmissible to mosquito, the immature and the mature gametocytes, with a 4-fold higher activity than that on the pathogenic asexual stages. This activity importantly translates into blocking parasite transmission through the Anopheles vector in mosquito experimental infections. A mass spectrometry analysis identified covalent NBDHEX modifications in specific cysteine residues of five gametocyte proteins, possibly associated to its antiparasitic effect. The carboxylic acid metabolite of NBDHEX retains the gametocyte preferential inhibitory activity of the parent compound, making this novel P. falciparum transmission blocking chemotype at least as a new tool to uncover biological processes targetable by gametocyte selective drugs. Both NBDHEX and its carboxylic acid metabolite show very limited in vitro cytotoxicity on VERO cells. This result and previous evidence that NBDHEX shows an excellent in vivo safety profile in mice and is orally active against human cancer xenografts make these molecules potential starting points to develop new P. falciparum transmission blocking agents, enriching the repertoire of drugs needed to eliminate malaria.
2022-03-03 | PXD030336 | Pride
Project description:Investigation of whole genome gene expression level changes in Plasmodium falciparum 3D7 delta-PfPuf2 mutant, compared to the wild-type strain 3D7. The mutation engineered into this strain render tanslational control. The mutants analyzed in this study are further described in Miao J, Li J, Fan Q, Li X, Li X, Cui L.2010. The Puf-family RNA-binding protein PfPuf2 regulates sexual development and sex differentiation in the malaria parasite Plasmodium falciparum. J Cell Sci. 123(7):1039-49 (PMID 20197405). A 12 chip study using total RNA recovered from six separate wild-type cultures of Plasmodium falciparum 3D7 at gametocyte stage III (three cultures) and stage V (three cultures) and six separate cultures of dalta PfPuf2 mutant at gametocyte stage III (three cultures) and stage V (three cultures). Each chip measures the expression level of 5,367 genes from Plasmodium falciparum 3D7 with 45-60 mer probes with two replicates on final array of 71618 probes.
2012-07-05 | E-GEOD-39124 | biostudies-arrayexpress