Global transcriptional repression: An initial and essential step for
            <i>Plasmodium</i>
            sexual development

Yuda, Masao; Iwanaga, Shiro; Kaneko, Ikuyo; Kato, Tomomi

doi:10.1073/pnas.1504389112

Cited by 111 publications

(172 citation statements)

References 19 publications

Supporting

Mentioning

164

Contrasting

Order By: Relevance

“…(A) Genetic disruption of the PyApiAP2 gene and its effects on parasite development in mice and mosquitoes. Genes in yellow are those that have been disrupted in P. berghei (9) and in this study; those in orange are genes that were successfully disrupted in this study but could not be disrupted in P. berghei (9); those in light green are genes that could not be disrupted in either P. berghei (9) or P. yoelii (this study); and those without color are genes that have been characterized in previous studies (12)(13)(14)(15)(16)(17)(18) and were not included in this study. AS1, asexual stages; Gam, gametocytes; Exf, exflagellation; Ook, ookinete; Ooc, oocyst; Oo.…”

Section: Figmentioning

confidence: 51%

“…Two ApiAP2 genes (Pfap2-g/Pbap2-g and Pbap2-g2) have been shown to play a critical role in gametocytogenesis in P. falciparum and/or P. berghei (9,(12)(13)(14). To investigate whether the genes are also critical to P. yoelii gametocytogenesis, we used the CRISPR-Cas9 method to disrupt the Pyap2-g and Pyap2-g2 genes.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have individually investigated 11 Plasmodium ApiAP2 genes functioning in sexual, mosquito, and liver stages in other species (12)(13)(14)(15)(16)(17)(18)(19). In particular, a recent study attempted to knock out all of the ApiAP2 genes and succeeded in disrupting 10 genes in P. berghei (9).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Systematic CRISPR-Cas9-Mediated Modifications of Plasmodium yoelii ApiAP2 Genes Reveal Functional Insights into Parasite Development

Zhang

Cui

et al. 2017

mBio

115

View full text Add to dashboard Cite

Malaria parasites have a complex life cycle with multiple developmental stages in mosquito and vertebrate hosts, and different developmental stages express unique sets of genes. Unexpectedly, many transcription factors (TFs) commonly found in eukaryotic organisms are absent in malaria parasites; instead, a family of genes encoding proteins similar to the plant Apetala2 (ApiAP2) transcription factors is expanded in the parasites. Several malaria ApiAP2 genes have been shown to play a critical role in parasite development; however, the functions of the majority of the ApiAP2 genes remain to be elucidated. In particular, no study on the Plasmodium yoelii ApiAP2 (PyApiAP2) gene family has been reported so far. This study systematically investigated the functional roles of PyApiAP2 genes in parasite development. Twenty-four of the 26 PyApiAP2 genes were selected for disruption, and 12 were successfully knocked out using the clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9 (CRISPR-Cas9) method. The effects of gene knockout (KO) on parasite development in mouse and mosquito stages were evaluated. Ten of 12 successfully disrupted genes, including two genes that have not been functionally characterized in any Plasmodium species previously, were shown to be critical for P. yoelii development of sexual and mosquito stages. Additionally, seven of the genes were labeled for protein expression analysis, revealing important information supporting their functions. This study represents the first systematic functional characterization of the P. yoelii ApiAP2 gene family and discovers important insights on the roles of the ApiAP2 genes in parasite development.IMPORTANCE Malaria is a parasitic disease that infects hundreds of millions of people, leading to an estimated 0.35 million deaths in 2015. A better understanding of the mechanism of gene expression regulation during parasite development may provide important clues for disease control and prevention. In this study, systematic gene disruption experiments were performed to study the functional roles of members of the Plasmodium yoelii ApiAP2 (PyApiAP2) gene family in parasite development. Genes that are critical for the development of male and female gametocytes, oocysts, and sporozoites were characterized. The protein expression profiles for seven of the PyApiAP2 gene products were also analyzed, revealing important information on their functions. This study provides expression and functional information for many PyApiAP2 genes, which can be explored for disease management.

show abstract

Section: Figmentioning

confidence: 51%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Systematic CRISPR-Cas9-Mediated Modifications of Plasmodium yoelii ApiAP2 Genes Reveal Functional Insights into Parasite Development

Zhang

Cui

et al. 2017

mBio

115

View full text Add to dashboard Cite

show abstract

“…Unlike P. falciparum, P. vivax gametocytogenesis occurs early and concomitantly with the asexual cycle, so by the time a person is symptomatic or is diagnosed with P. vivax malaria, that person already harbors infectious gametocytes capable of infecting mosquitoes (39). It appears that a key step in Plasmodium gametocytogenesis is accomplished by transcriptional repression via an AP2 family transcription factor that blocks asexual replication and promotes conversion to the sexual stage (40). In fact, the P. falciparum ortholog of the principal AP2 gene identified in our study has been associated with transcriptional regulation of gametocytogenesis (41).…”

Section: Discussionmentioning

confidence: 99%

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Parobek

Lin

Saunders

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cambodia, in which both Plasmodium vivax and Plasmodium falciparum are endemic, has been the focus of numerous malaria-control interventions, resulting in a marked decline in overall malaria incidence. Despite this decline, the number of P. vivax cases has actually increased. To understand better the factors underlying this resilience, we compared the genetic responses of the two species to recent selective pressures. We sequenced and studied the genomes of 70 P. vivax and 80 P. falciparum isolates collected between 2009 and 2013. We found that although P. falciparum has undergone population fracturing, the coendemic P. vivax population has grown undisrupted, resulting in a larger effective population size, no discernable population structure, and frequent multiclonal infections. Signatures of selection suggest recent, species-specific evolutionary differences. Particularly, in contrast to P. falciparum, P. vivax transcription factors, chromatin modifiers, and histone deacetylases have undergone strong directional selection, including a particularly strong selective sweep at an AP2 transcription factor. Together, our findings point to different population-level adaptive mechanisms used by P. vivax and P. falciparum parasites. Although population substructuring in P. falciparum has resulted in clonal outgrowths of resistant parasites, P. vivax may use a nuanced transcriptional regulatory approach to population maintenance, enabling it to preserve a larger, more diverse population better suited to facing selective threats. We conclude that transcriptional control may underlie P. vivax's resilience to malaria control measures. Novel strategies to target such processes are likely required to eradicate P. vivax and achieve malaria elimination.D uring the last decade, western Cambodia has been the focus of numerous and multimodal interventions to control the spread of artemisinin-resistant Plasmodium falciparum (1, 2). Such interventions, including increased vector control, increased surveillance, and improved access to quality artemisinin-combination therapy (ACT), would be expected to curtail coendemic Plasmodium vivax as well. However, even as P. falciparum infections in Cambodia decreased by 81% between 2009 and 2013, P. vivax cases have increased, making it the predominant species in the Mekong region (3-6). This scenario, repeated in Brazil and other areas of coendemicity, has led to growing awareness that P. vivax, although infecting the same populations and transmitted by the same mosquito vectors, will likely be the more challenging species to eradicate (6-9). In this study, we use population genomics to gain insight into the evolutionary factors underlying P. vivax's resilience to malaria control measures.Population genetic studies have previously hinted at the resilience of P. vivax populations in comparison with P. falciparum. Studies of microsatellites and highly variable antigens of sympatric P. vivax and P. falciparum populations in Southeast Asia and the Southwest Pacific have consistently shown P. viv...

show abstract

“…Subsequent gametocyte development is accompanied by up-and down-regulation of hundreds of transcripts and proteins (12)(13)(14)(15)(16)25). Another member of AP2 family, AP2-G2, may regulate gametocyte development by repression of specific transcripts for asexual and stages beyond gametocyte development (26). In order to prepare for rapid changes and subsequent development in free-living environment in mosquito, gametocytes adopt several strategies including storage of "maternal" mRNAs by the DOZI and possibly Puf protein complexes that can be mobilized rapidly upon stage transition (27)(28)(29)(30)(31), increased expression of protein kinases and phosphatases responsible for signal transduction (32)(33)(34)(35)(36)(37)(38), and activation of tricarboxylic acid cycle and lipid metabolism for energy and lipid requirements (39 -44).…”

mentioning

confidence: 99%

Sex-Specific Biology of the Human Malaria Parasite Revealed from the Proteomes of Mature Male and Female Gametocytes

Miao

Chen

Wang

et al. 2017

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

The gametocytes of the malaria parasites are obligate for perpetuating the parasite's life cycle through mosquitoes, but the sex-specific biology of gametocytes is poorly understood. We generated a transgenic line in the human malaria parasite Plasmodium falciparum, which allowed us to accurately separate male and female gametocytes by flow cytometry. In-depth analysis of the proteomes by liquid chromatography-tandem mass spectrometry identified 1244 and 1387 proteins in mature male and female gametocytes, respectively. GFP-tagging of nine selected proteins confirmed their sex-partitions to be agreeable with the results from the proteomic analysis. The sexspecific proteomes showed significant differences that are consistent with the divergent functions of the two sexes. Although the male-specific proteome (119 proteins) is enriched in proteins associated with the flagella and genome replication, the female-specific proteome (262 proteins) is more abundant in proteins involved in metabolism, translation and organellar functions. Compared with the Plasmodium berghei sex-specific proteomes, this study revealed both extensive conservation and considerable divergence between these two species, which reflect the disparities between the two species in proteins involved in cytoskeleton, lipid metabolism and protein degradation. Comparison with three sex-specific proteomes allowed us to obtain high-confidence lists of 73 and 89 core male-and female-specific/biased proteins conserved in Plasmodium. The identification of sex-specific/biased proteomes in Plasmodium lays a solid foundation for understanding the molecular mechanisms underlying the unique sex-specific biology in this earlybranching eukaryote. Molecular & Cellular Proteomics

show abstract

Global transcriptional repression: An initial and essential step for Plasmodium sexual development

Cited by 111 publications

References 19 publications

Systematic CRISPR-Cas9-Mediated Modifications of Plasmodium yoelii ApiAP2 Genes Reveal Functional Insights into Parasite Development

Systematic CRISPR-Cas9-Mediated Modifications of Plasmodium yoelii ApiAP2 Genes Reveal Functional Insights into Parasite Development

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Sex-Specific Biology of the Human Malaria Parasite Revealed from the Proteomes of Mature Male and Female Gametocytes

Contact Info

Product

Resources

About