A major genome region underlying artemisinin resistance in malaria
Ontology highlight
ABSTRACT:
ORGANISM(S): Plasmodium falciparum
SUBMITTER: Michael Ferdig
PROVIDER: E-GEOD-33002 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Optimize SNP genotyping probes and demonstrate a new P. falciparum microarray platform that includes CGH and resequencing probes on the same chip 3D7 common reference; lab samples: HB3, Dd2, SC05, 7C126; field patient samples: M1176, M1069, M1094, M1321, M1064, M1111
2011-04-01 | E-GEOD-28287 | biostudies-arrayexpress
Project description:Evolving resistance to artemisinin-based compounds in SE Asia threatens to derail attempts to control and eliminate malaria. Resistance has been confirmed in western Cambodia, has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CR) from the blood following treatment. We used a two-phase approach to identify the genes underlying this ongoing selective event. Comparison of geographical differentiation and haplotype structure at 6,969 polymorphic SNPs in 91 parasites from western Cambodia, western Thailand and Laos identified 33 strongly selected genome regions. We screened SNPs and microsatellites within these genome regions in 718 parasites from western Thailand, and identified a 35kb region of chr 13 showing strong association (P=10-6 to 10-11) with slow CR. This region contains several compelling candidate loci, such as HSP70, for assessment by transfection. These results illustrate the efficacy of targeted association for identifying the genetic basis of adaptive traits.
2012-05-01 | GSE33002 | GEO
Project description:Artemisinin resistance in Plasmodium falciparum malaria has emerged in western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. Using DNA microarrays we identify key features of a transcriptional profile that are associated with the delayed parasite clearance phenotype. These include reduced expression of several basic metabolic and cellular pathways in the early stages, and increased expression of essentially all functionalities associated with protein metabolism in the later stages of P. falciparum intraerythrocytic development. This is consistent with the reduced ring stage susceptibility that characterizes artemisinin resistant P. falciparum. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of several regulatory proteins such as transcription factors of chromatin remodeling associated factors. In addition, the artemisinin resistant phenotype is strongly associated with a specific pattern of copy number variations, some of which are linked with differential expression of several regulatory proteins such as histone 4 and zinc permease. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides a set of candidate genes for further investigation. 6 P. falciparum parasites (field isolates) which are either Artemsinin resistant or sensitive from 3 study sites (Pailin in Cambodia, Xepon in Laos, Mae Sot in Thailand) were sampled and harvested for genomic DNA. gDNA from a total of 6 samples were extracted by phenol chloroform. Synthesis of labelled target DNA was carried out as previously described: Mackinnon, M.J. et al. Comparative transcriptional and genomic analysis of Plasmodium falciparum field isolates. PLoS Pathog 5, e1000644 (2009), and used in comparative genomic microarray hybridizations (CGH).
2010-12-07 | E-GEOD-25879 | biostudies-arrayexpress
Project description:Artemisinin resistance in Plasmodium falciparum malaria has emerged in western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. Using DNA microarrays we identify key features of a transcriptional profile that are associated with the delayed parasite clearance phenotype. These include reduced expression of several basic metabolic and cellular pathways in the early stages, and increased expression of essentially all functionalities associated with protein metabolism in the later stages of P. falciparum intraerythrocytic development. This is consistent with the reduced ring stage susceptibility that characterizes artemisinin resistant P. falciparum. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of several regulatory proteins such as transcription factors of chromatin remodeling associated factors. In addition, the artemisinin resistant phenotype is strongly associated with a specific pattern of copy number variations, some of which are linked with differential expression of several regulatory proteins such as histone 4 and zinc permease. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides a set of candidate genes for further investigation. 11 P. falciparum parasites (field isolates) which are either Artemsinin resistant or sensitive from 3 study sites (Pailin in Cambodia, Xepon in Laos, Mae Sot in Thailand) were sampled, grown ex-vivo over 48 hours and harvested at regular intervals. RNA from a total of 91 samples were extracted. Synthesis of target DNA was carried out as previously described: Mackinnon, M.J. et al. Comparative transcriptional and genomic analysis of Plasmodium falciparum field isolates. PLoS Pathog 5, e1000644 (2009), and used in microarray hybridizations.
2010-12-07 | E-GEOD-25878 | biostudies-arrayexpress
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Project description:Two chromosome-targeting and gene regulatory systems are present in Drosophila melanogaster. The male X-chromosome is targeted by the male-specific lethal complex believed to mediate the two-fold up-regulation of the X-linked genes. The highly heterochromatic 4th chromosome is specifically targeted by the Painting of Fourth (POF) protein which together with heterochromatin protein 1 (HP1) modulate the expression level of genes on the 4th chromosome. Here we report high-resolution mapping of POF and HP1 on the 4th chromosome using chromatin immunoprecipitation followed by tiling microarrays (ChIP-chip) in S2 cells and salivary glands. The enrichments are compared to transcript profiles of the two cell types used. POF specifically binds to genes with a strong preference for exons. The POF binding profile correlates to the binding profile of HP1 which in addition displays a typical M-bM-^@M-^\peakM-bM-^@M-^] in the promoter regions of bound genes. POF and HP1 binds to active genes and the binding correlates with levels of transcription and changes in binding levels are paralleled by a comparable change in transcription. Our results provide a high resolution description of the chromosome 4 specific gene regulatory system provided by the combinatorial effects of POF and HP1. Keywords: Transcript profiling Transcript profiling in S2 cells and salivary glands. Two biological replicates, one replicate per array.
2007-10-02 | E-GEOD-8297 | biostudies-arrayexpress
Project description:Paper abstract: Neural stem cells must strike a balance between self-renewal and multipotency, and differentiation. Identification of the transcriptional networks regulating stem cell division is an essential step in understanding how this balance is achieved. We have shown that the homeodomain transcription factor, Prospero, acts to repress self-renewal and promote differentiation. Amongst its targets are three neural stem cell transcription factors, Asense, Deadpan and Snail, of which Asense and Deadpan are repressed by Prospero. Here we identify the targets of these three factors throughout the genome. We find a large overlap in their target genes, and indeed with the targets of Prospero, with 245 genomic loci bound by all factors. Many of the genes have been implicated in vertebrate stem cell self-renewal, suggesting that this core set of genes is crucial in the switch between self-renewal and differentiation. We also show that multiply bound loci are enriched for genes previously linked to nervous system phenotypes, thereby providing a short-cut to identifying genes important for nervous system development. Each Dam-fusion-derived sample is compared to a control Dam-only sample. Four biological replicates were performed for Prospero (with 2 dye-swaps). For Asense, Deadpan and Snail, two biological replicates were performed.
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2012-08-05 | E-GEOD-33187 | biostudies-arrayexpress
Project description:Maintenance of genetic integrity is essential for survival of all organisms. Activating transcription factor 3 (ATF3) is a member of the c-AMP response element binding (CREB)/ATF family of transcription factors, and is highly inducible by various stress conditions including DNA damage. However, downstream targets and molecular basis underlying pleiotropic effects of ATF3 on the cell fate have been largely unknown. To identify ATF3 targets in the human genome, we carried out chromatin immunoprecipitation-microarray (ChiP-on-chip) and knockdown-expression profiling analysis using two models where ATF3 was either transiently induced or constitutively expressed. We show that ATF3 binds to an unexpectedly large number of targets; 5,984 promoters in HCT116 cells treated with an alkylating agene methyl methanesulfonate (MMS) and 1,423 promoters in LNCaP cells constitutively expressing ATF3. Importantly, targets of MMS-induced ATF3 are highly enriched not only for CREB/ATF motifs but also for binding sites of several stress sensors including DDIT3/CHOP, Egr1, and c-Ets which are concomitantly induced by MMS. Stress-induced ATF3 affects broad but select biological processes including cell cycle, cell death, adhesion, biosynthesis, and receptor signaling pathways. In addition, ATF3 binds to as many as 40% of the p53 targets and preferentially enhances MMS-induced activation of proapoptotic genes such as DR4, DR5, and PUMA, consistent with the proapoptotic effect of ATF3. These data shed new light on the co-regulatory function of ATF3 in the stress-induced transcription factor network. The comprehensive list of genomic targets of ATF3 will facilitate further understanding the role of ATF3 in determining life and death of cells under both physiological and tumour-associated stress conditions. Maintenance of genetic integrity is fundamental to survival of all organisms. DNA damage can be caused by various agents in environment and elicits complex responses in the cell. ATF3 is one of the transcription factors activated by various stress conditions including DNA damage, and has been shown to have pleiotropic effects on life and death of cells depending on the context of experimental conditions. It has been largely unknown, however, which genes and pathways are regulated by stress-induced ATF3. Here we attempted to answer this question by chromatin immunoprecipitation-microarray analysis of downstream targets of ATF3. We show that ATF3 binds to an unexpectedly large number of promoters (nearly 6,000) in a human colorectal cancer cell lineHCT116 treated with an alkylating agent methyl methanesulfonate. Interestingly, the ATF3 targets are highly enriched for binding sites of other stress sensors shedding light on a transcriptional co-regulatory network of DNA damage response. We further show that ATF3 regulates expression of genes in select biological processes including cell cycle, cell death, adhesion, metabolism, signal transduction, and the p53 pathway. The comprehensive list of ATF3 targets provides new insight into a highly inter-connected network of stress-induced transcription factors around ATF3. ChIP-chip samples: Comparison of ATF3-IP and whole genome DNA (control) Gene expression samples: HCT116 cells pre-transfected with either control siRNA or ATF3 knockdown siRNA and stimulated by methyl methanesulfonate (MMS) for 0, 6, 12, and 24 hours
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