Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptome profiling of genetically modified P. falciparum parasite strains with distinct drug resistance phenotypes

ABSTRACT: We compared the transcriptomic profiles between P. falciparum strains displaying mutant or wild-type pfcrt or varying in pfcrt or pfmdr1 expression levels All values were normalized using a background pool constituted of 11 transcriptome data sets that constituted a baseline for gene expression fold change and gene set enrichment. In addition to that reported in the present study, the pool included two IDC transcriptome data sets generated for Dd2 parasites pressured long-term with pulses of dihydroartemisinin (the 3b1 line) and the non-pressured parent (Lisewski et al., Cell, 2014), as well as the transcriptome data set previously reported for the 3D7, Dd2 and HB3 strains (Bozdech et al., PLos Biol 2003, Llinas et al, NAR 2006) We conducted gene expression microarrays over the course of the parasite 48-hr IDC, by sampling parasites every 6-hour, representing 8 different time points. Extracted RNA was labeled with Cy5 dye, while the reference RNA pool consisted of Cy3-coupled cDNA samples prepared from RNAs representing all developmental stages at 6-hour intervals of the IDC of the 3D7 line.

ORGANISM(S): Plasmodium falciparum

SUBMITTER: David Fidock

PROVIDER: E-GEOD-75807 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Quantitative studies of the P. falciparum transcriptome have shown that the tightly controlled progression of the parasite through the intraerythrocytic developmental cycle (IDC) is accompanied by a continuous gene expression cascade where most expressed genes exhibit a single transcriptional peak. Since proteins represent the decisive business end of gene expression, understanding the correlation between mRNA and protein levels is crucial for inferring biological activity from transcriptional gene expression data. While pertinent studies on other organisms show that as little as 20-40% of protein abundance variation may be attributable to corresponding mRNA levels, the situation in Plasmodium is further complicated by the dynamic nature of the cyclic gene expression cascade where the mRNA levels of most genes change constantly during the IDC. In this study, we simultaneously determined mRNA and protein abundance profiles for P. falciparum parasites during the IDC at 2-hour resolution based on spotted oligonucleotide microarrays and 2D-protein gels in combination with DIGE fluorescent dyes. Intriguingly, most proteins are represented by more than one isoform, presumably due to post-translational modifications. Analysis of 366 protein abundance profiles and the corresponding mRNA levels shows that in 67.2% of cases the protein abundance peaks at least 8 hours after the mRNA level peak. While it may be tempting to interpret this as evidence for widespread post-transcriptional gene regulation additional analyses including computer modeling demonstrate that in >60% of these cases the observed protein profiles including the peak lag times could arise as a consequence of the corresponding mRNA levels when simple translation and degradation dynamics are assumed. We further characterize and illustrate these dynamics and show that even human host proteins within the parasite may be subject to similar dynamics as their parasite counterparts. 24 timepoint samples were harvested from a tightly synchronous 6.5 liter biofermenter culture of P. falciparum (Dd2) at 2-hour intervals during one entire intraerythrocytic developmental cycle and compared against a 3D7 RNA reference pool.

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Transcriptome profiling of genetically modified P. falciparum parasite strains with distinct drug resistance phenotypes

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