Project name: Plasmodium falciparum

Description: BackgroundHistone deacetylase (HDACs) inhibitors are being intensively pursued as potential new antimalarial drugs, and are also emerging as valuable tools for investigating transcriptional control in malaria parasites. In this study, the genome-wide transcriptional effects of three structurally related hydroxamate HDAC inhibitors were profiled in Plasmodium falciparum, the most lethal of the malaria parasite species that infects humans.ResultsFollowing 2h exposure to trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) or a 2-aminosuberic acid derivative (2-ASA-9), ~18-28% of genes in P. falciparum trophozoite-stage parasites were regulated greater than two fold. This global induction was transitory, with fewer genes (3-5%) regulated after removing the compounds and culturing for a further 2h. Just nine genes, including alpha-II-tubulin, were up-regulated by all three compounds. Despite structural similarity, the three inhibitors caused quite diverse transcriptional effects, possibly reflecting subtle differences in mode of action or cellular distribution.ConclusionsThree structurally related HDAC inhibitors have been found to cause profound, genome-wide, transcriptional changes in P. falciparum parasites, but most effects were transitory. This highlights the dynamic and exquisitely controlled nature of transcription in these malaria parasites. We also identified a small subset of nine genes over-expressed by all three HDAC inhibitors that may represent the first recognized set of transcriptional markers that signify HDAC inhibition in malaria parasites. This data set is an important contribution to our understanding of gene regulation in malaria parasites and supports growing evidence for the potential of HDAC inhibitors as new antimalarial agents.Overall design: Trophozoite-stage P. falciparum cells were treated with different compounds at IC90 concentrations (SAHA, 200nM, TSA 50nM, and 2-ASA-9 80nM) or DMSO vehicle control (<0.005%) for 2h, then harvested (termed 2h+). In parallel, after 2h exposure to compound, a second matched replicate was washed to remove the drug and cultured for a further 2h (termed 2h+/2h-). RNA extracted from these samples was processed for microarray analysis.

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: Medical

Release date: 2012-05-01

Last updated: 2010-11-29