Transcriptional regulator HDP1 regulates expansion of the inner membrane complex during early sexual differentiation of malaria parasites [ChIP-Seq]
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ABSTRACT:
ORGANISM(S): Plasmodium falciparum
PROVIDER: GSE189151 | GEO | 2021/11/21
REPOSITORIES: GEO
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Project description:In this study, we identify HDP1, a previously uncharacterized DNA-binding protein first expressed during early sexual differentiation. The development of HDP1-deficient gametocytes arrests at the Stage I to Stage II transition and ends in loss of viability. Analysis of gene expression and HDP1-binding shows that this protein functions as a positive transcriptional regulator of genes essential for gametocyte development, including genes that are critical for the expansion of the inner membrane complex (IMC) that gives P. falciparum gametocytes their characteristic shape.
2021-11-21 | GSE189196 | GEO
Project description:We described the biological role of a putative zinc finger protein (Plasmodb id: PF3D7_1008600), which plays an important role during the initiation and subsequent progression of gametocytogenesis in P. falciparum. Hence we termed the protein P. falciparum Zinc Finger Protein for Gametocytogenesis (PfZnFP-G). During the asexual intraerythrocyic developmental cycle (IDC), PfZnFP-G levels peak during the schizont stage during which it is localized in the nucleus. During the IDC, PfZnFP-G appears to be stochastically expressed in ~3% parasite population. Deactivation of PfZnFP-G appears to suppress, but not fully inhibit, production of gametocytes and vice versa overproduction of PfZnFP-G stimulates gametocytogenesis. In addition, PfZnFP-G is capable of associating with DNA binding preferentially to intergenic, promoter regions of the genome, and this binding correlates positively with transcription, particularly of other gametocyte specific genes. PfZnFP-G is also expressed in the mid-to-late gametocytes where it is present in the cytoplasm. Overall, these results suggest a dual function of PfZnFP-G in gametocytogenesis including: (i) commitment as a transcription factor and (ii) gametocyte maturation as a putative RNA binding protein. Transgenic 3D7 wild type parasite lines were generated with PfZnFP-G tagged, over-expressed and knocked-out. Transcriptional profiles across the parasite life cycle were generated. Genome occupancy of PfZnFP-G were also investigated and compared to the corresponding transcriptional profiles.
2015-11-24 | E-GEOD-75295 | biostudies-arrayexpress
Project description:Differentiation from asexual blood stages to sexual gametocytes is required for transmission of malaria parasites from the human host to mosquitos, where sexual fertilization occurs to complete the lifecycle. Although preventing gametocyte development would block parasite transmission, the molecular mechanisms underlying sexual commitment and gametocyte maturation are still relatively unknown. Previous studies identified an ApiAP2 protein, AP2-G2, which plays a critical role in gametocyte maturation in rodent malaria parasite Plasmodium berghei by acting as the repressor of asexual stage genes in gametocytes. In this work we characterize the P. falciparum orthologue (PF3D7_1408200) of PbAP2-G2 and report that it plays a critical role in maturation of gametocytes. Disruption of pfap2-g2 did not obstruct commitment to sexual development but the majority of parasites were unable to develop normally beyond stage III gametocytes. In asexual stages PfAP2-G2 binds to the promoters of wide variety of genes expressed in diverse range of parasite’s life cycle stages including gametocytes, mosquito lifecycle stages early ring stage genes and genes encoding for proteins involved in egress and invasion. Surprisingly, we also identify binding of PfAP2-G2 in the gene body of almost 3000 genes. We could also show that PfAP2-G2 interacts with chromatin remodeling proteins and another ApiAP2 protein (PF3D7_1139300) whose motif is also overrepresented in the ChIP-seq data. Overall this work suggests that PfAP2-G2 is a transcriptional regulator that regulates genes possibly by recruiting additional transcription factors and chromatin remodeling machinery and plays a critical role in the development of malaria parasites as they transition from the asexual stage to gametocytes.
2021-02-16 | GSE157753 | GEO
Project description:We described the biological role of a putative zinc finger protein (Plasmodb id: PF3D7_1008600), which plays an important role during the initiation and subsequent progression of gametocytogenesis in P. falciparum. Hence we termed the protein P. falciparum Zinc Finger Protein for Gametocytogenesis (PfZnFP-G). During the asexual intraerythrocyic developmental cycle (IDC), PfZnFP-G levels peak during the schizont stage during which it is localized in the nucleus. During the IDC, PfZnFP-G appears to be stochastically expressed in ~3% parasite population. Deactivation of PfZnFP-G appears to suppress, but not fully inhibit, production of gametocytes and vice versa overproduction of PfZnFP-G stimulates gametocytogenesis. In addition, PfZnFP-G is capable of associating with DNA binding preferentially to intergenic, promoter regions of the genome, and this binding correlates positively with transcription, particularly of other gametocyte specific genes. PfZnFP-G is also expressed in the mid-to-late gametocytes where it is present in the cytoplasm. Overall, these results suggest a dual function of PfZnFP-G in gametocytogenesis including: (i) commitment as a transcription factor and (ii) gametocyte maturation as a putative RNA binding protein.
2015-11-24 | GSE75295 | GEO
Project description:For malaria transmission, the parasite must undergo sexual differentiation into mature gametocytes. However, the molecular basis for this critical transition in the parasites life cycle is unknown. Six previously uncharacterized genes, Pfg14.744, Pfg14.745, Pfg14.748, Pfg14.763, Pfg14.752 and Pfg6.6 that are members of a 36 gene Plasmodium falciparum-specific subtelomeric superfamily were found to be expressed in parasites that are committed to sexual development as suggested by co-expression of Pfs16 and Pfg27. Northern blots demonstrated that Pfg14.744 and Pfg14.748 were first expressed before the parasites differentiated into morphologically distinct gametocytes, transcription continued to increase until stage II gametocytes were formed and then rapidly decreased. Immunofluorescence assays indicated that both proteins were only produced in the subpopulation of ring stage parasites that are committed to gametocytogenesis and both localized to the parasitophorous vacuole (PV)b of the early ring stage parasites. As the parasites continued to develop Pfg14.748 remained within the parasitophorous vacuole, while Pfg14.744 was detected in the erythrocyte. The 5' flanking region of either gene alone was sufficient to drive early gametocyte specific expression of green fluorescent protein (GFP). In parasites transfected with a plasmid containing the Pfg14.748 5' flanking region immediately upstream of GFP, fluorescence was observed in a small number of schizonts the cycle before stage I gametocytes were observed. This expression pattern is consistent with commitment to sexual differentiation prior to merozoite release and erythrocyte invasion. Further investigation into the role of these genes in the transition from asexual to sexual differentiation could provide new strategies to block malaria transmission. Microarray analysis was used to compare two clones derived from Plasmodium falciparum strain 3D7 parasites that differ in their ability to undergo gametocytogenesis. Clone G+ produces gametocytes and clone G- produces very few if any gametocytes. RNA was harvested from the cultures when the asexual parasitemia was 0.9-1.48% (day 4) (n=4) after setting up the gametocyte cultures and 5.2-5.58% (day 6) (n=4) prior to the appearance of morphologically distinct gametocytes and used to generate cDNA that was labeled with Cy3 or Cy5 and hybridized to the Plasmodium falciparum 70 mer oligonucleotide microarray developed by DeRisi and co-workers.
2014-10-16 | E-GEOD-62364 | biostudies-arrayexpress
Project description:During the malaria infection, Plasmodium parasites invade the host’s red blood cells where they can differentiate into two different life forms. The majority will replicate asexually and infect new erythrocytes. A small percentage, however, will transform into gametocytes – a specialized sexual stage able to survive and develop when taken up by Anopheles mosquito. As the gametocytes ensure the parasite’s transmission to a new host, their generation is an attractive target for new antimalarial interventions. The molecular mechanisms controlling gametocytogenesis, however, remain largely unknown due to the technical challenges: the early gametocytes are morphologically indistinguishable from asexual parasites and present in very low numbers during the infection. Recently, AP2-G - a transcription factor from an apicomplexa-specific apiAP2 family – was described as indispensable for gametocyte commitment in both human malaria parasite Plasmodium falciparum and rodent malaria model Plasmodium berghei. Therefore, we have decided to test whether the overexpression of this factor alone could increase gametocyte production and enable the investigation of uncharacterised, earliest stages of gametocyte development. To this end, we have engineered PBGAMi - a Plasmodium berghei line, in which all parasites were ap2-g deficient by default but able to overexpress it when induced with rapamycin. While the control parasites (PBGAMi R-), as expected, differentiated into asexual forms (schizonts) only, almost all rapamycin-treated parasites (PBGAMi R+) transformed into gametocytes. We used the generated line to perform RNA-seq analysis of the R- and R+ populations at different time points of their development and identify the changes arising between them, mapping the sequence of events leading to the formation of gametocytes. At the same time we have generated purified transcriptomes of male and female gametocytes for the reference
2021-03-13 | GSE168817 | GEO
Project description:During the malaria infection, Plasmodium parasites invade the host’s red blood cells where they can differentiate into two different life forms. The majority will replicate asexually and infect new erythrocytes. A small percentage, however, will transform into gametocytes – a specialized sexual stage able to survive and develop when taken up by Anopheles mosquito. As the gametocytes ensure the parasite’s transmission to a new host, their generation is an attractive target for new antimalarial interventions. The molecular mechanisms controlling gametocytogenesis, however, remain largely unknown due to the technical challenges: the early gametocytes are morphologically indistinguishable from asexual parasites and present in very low numbers during the infection. Recently, AP2-G - a transcription factor from an apicomplexa-specific apiAP2 family – was described as indispensable for gametocyte commitment in both human malaria parasite Plasmodium falciparum and rodent malaria model Plasmodium berghei. Therefore, we have decided to test whether the overexpression of this factor alone could increase gametocyte production and enable the investigation of uncharacterised, earliest stages of gametocyte development. To this end, we have engineered PBGAMi - a Plasmodium berghei line, in which all parasites were ap2-g deficient by default but able to overexpress it when induced with rapamycin. While the control parasites (PBGAMi R-), as expected, differentiated into asexual forms (schizonts) only, almost all rapamycin-treated parasites (PBGAMi R+) transformed into gametocytes. We used the generated line to perform RNA-seq analysis of the R- and R+ populations at different time points of their development and identify the changes arising between them, mapping the sequence of events leading to the formation of gametocytes.
2018-06-30 | GSE110201 | GEO
Project description:Transmission of Plasmodium falciparum and other malaria parasites requires their differentiation from asexual blood stages into gametocytes, the non-replicative sexual stage necessary to infect the mosquito vector. This transition involves changes in gene expression and chromatin reorganization that result in the activation and silencing of stage-specific genes. However, the genomes of malaria parasites have been noted for their limited number of transcriptional and chromatin regulators, and the molecular mediators of these changes remain largely unknown. We recently identified homeodomain protein 1 (HDP1) as a DNA-binding protein, first expressed in gametocytes, that enhances the expression of key genes critical for early sexual differentiation. The discovery of HDP1 marks a new class of transcriptional regulator in malaria parasites outside of the better-characterized ApiAP2 family. Here, using molecular biology, biochemistry and microscopy techniques, we show that HDP1 is essential for gametocyte maturation, facilitating the necessary upregulation of inner membrane complex components during early gametocytogenesis that gives P. falciparum gametocytes their characteristic shape.
| S-EPMC8852293 | biostudies-literature
Project description:Malaria is caused by Plasmodium parasites that proliferate through iterative cycles of intra-erythrocytic replication. During each cycle a small number of parasites differentiate into gametocytes, the only forms able to infect the mosquito vector and transmit malaria. Sexual commitment is triggered by activation of AP2-G, the master transcriptional regulator of gametocytogenesis. Heterochromatin protein 1 (HP1)-dependent silencing of ap2-g prevents sexual conversion and secures proliferation. Here, we identify gametocyte development 1 (GDV1) as the first upstream activator of the sexual differentiation pathway in P. falciparum. Induction of GDV1 expression is sufficient to activate AP2-G expression and sexual differentiation. We found that GDV1 targets heterochromatin and triggers HP1 eviction preferentially at ap2-g and other gametocyte-specific genes. We further demonstrate that GDV1-dependent activation of ap2-g is controlled via a gdv1 antisense RNA. In summary, we identify GDV1 as an unprecedented cell fate decision factor that induces sexual differentiation by antagonizing HP1-dependent gene silencing.
2018-05-04 | GSE94901 | GEO
Project description:Transcriptional regulator HDP1 regulates expansion of the inner membrane complex during early sexual differentiation of malaria parasites
| PRJNA781928 | ENA