Abstract
The apparent paucity of molecular factors of transcriptional control in the genomes of Plasmodium parasites raises many questions about the mechanisms of life cycle regulation in these malaria parasites. Epigenetic regulation has been suggested to play a major role in the stage specific gene expression during the Plasmodium life cycle. To address some of these questions, we analyzed global transcriptional responses of Plasmodium falciparum to a potent inhibitor of histone deacetylase activities (HDAC). The inhibitor apicidin induced profound transcriptional changes in multiple stages of the P. falciparum intraerythrocytic developmental cycle (IDC) that were characterized by rapid activation and repression of a large percentage of the genome. A major component of this response was induction of genes that are otherwise suppressed during that particular stage of the IDC or specific for the exo-erythrocytic stages. In the schizont stage, apicidin induced hyperacetylation of histone lysine residues H3K9, H4K8 and the tetra-acetyl H4 (H4Ac4) and demethylation of H3K4me3. Interestingly, we observed overlapping patterns of chromosomal distributions between H4K8Ac and H3K4me3 and between H3K9Ac and H4Ac4. There was a significant but partial association between the apicidin-induced gene expression and histone modifications, which included a number of stage specific transcription factors. Taken together, inhibition of HDAC activities leads to dramatic de-regulation of the IDC transcriptional cascade, which is a result of both disruption of histone modifications and up-regulation of stage specific transcription factors. These findings suggest an important role of histone modification and chromatin remodeling in transcriptional regulation of the Plasmodium life cycle. This also emphasizes the potential of P. falciparum HDACs as drug targets for malaria chemotherapy.
Highlights
Gene expression in the asexual intraerythrocytic developmental cycle (IDC) of Plasmodium falciparum and vivax occurs in a continuous cascade with the induction of most genes occurring just once in the cycle, presumably at the time when their products are required [1,2,3]
We show that inhibition of histone deacetylase activities results in activation and repression of transcriptionally regulated genes in multiple stages of the P. falciparum asexual life cycle
We show that inhibition disrupts the steady-state level of histone acetylation and methylation across the P. falciparum genome
Summary
Gene expression in the asexual intraerythrocytic developmental cycle (IDC) of Plasmodium falciparum and vivax occurs in a continuous cascade with the induction of most genes occurring just once in the cycle, presumably at the time when their products are required [1,2,3]. Emerging evidence from other eukaryotes indicates that chromatin structure regulates gene expression through histone modifications such as acetylation, deacetylation and methylation [4]. Histone acetyltransferases (HATs) catalyze acetylation of lysine residues located within histones, thereby reducing chromatin compaction and making the DNA more accessible to regulatory proteins resulting in transcriptional activation. The removal of acetyl groups from the lysine residues is catalyzed by histone deacetylases (HDACs) resulting in chromatin condensation and transcriptional repression. Specific recruitment of HAT and HDAC containing complexes to selected promoter elements generate localized domains of modified histones that influence transcriptional activity [5,6]. HATs and HDACs function globally throughout the genome resulting in a highly dynamic equilibrium of histone acetylation and deacetylation reactions, which maintains a steadystate level of histone acetylation across the entire genome [7,8]
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