Abstract
BackgroundSchistosomiasis is a parasitic disease infecting hundreds of millions of people worldwide. Treatment depends on a single drug, praziquantel, which kills the Schistosoma spp. parasite only at the adult stage. HDAC inhibitors (HDACi) such as Trichostatin A (TSA) induce parasite mortality in vitro (schistosomula and adult worms), however the downstream effects of histone hyperacetylation on the parasite are not known.Methodology/Principal findingsTSA treatment of adult worms in vitro increased histone acetylation at H3K9ac and H3K14ac, which are transcription activation marks, not affecting the unrelated transcription repression mark H3K27me3. We investigated the effect of TSA HDACi on schistosomula gene expression at three different time points, finding a marked genome-wide change in the transcriptome profile. Gene transcription activity was correlated with changes on the chromatin acetylation mark at gene promoter regions. Moreover, combining expression data with ChIP-Seq public data for schistosomula, we found that differentially expressed genes having the H3K4me3 mark at their promoter region in general showed transcription activation upon HDACi treatment, compared with those without the mark, which showed transcription down-regulation. Affected genes are enriched for DNA replication processes, most of them being up-regulated. Twenty out of 22 genes encoding proteins involved in reducing reactive oxygen species accumulation were down-regulated. Dozens of genes encoding proteins with histone reader motifs were changed, including SmEED from the PRC2 complex. We targeted SmEZH2 methyltransferase PRC2 component with a new EZH2 inhibitor (GSK343) and showed a synergistic effect with TSA, significantly increasing schistosomula mortality.Conclusions/SignificanceGenome-wide gene expression analyses have identified important pathways and cellular functions that were affected and may explain the schistosomicidal effect of TSA HDACi. The change in expression of dozens of histone reader genes involved in regulation of the epigenetic program in S. mansoni can be used as a starting point to look for possible novel schistosomicidal targets.
Highlights
It has been widely recognized in recent years that epigenetic effectors of chromatin remodeling are promising targets for therapeutic intervention, because they play a key role in epigenetic regulation of gene expression in all eukaryotes [1,2]
The extent of histone acetylation in S. mansoni adult worms under the effect of the histone deacetylases (HDACs) inhibitors (HDACi) Trichostatin A (TSA) was investigated after 24 h of parasite exposure to the drug
To explore the effect of HDACi on gene expression, three independent biological replicates of schistosomula were exposed in vitro to TSA or drug vehicle and large-scale gene expression changes were accessed by microarrays
Summary
It has been widely recognized in recent years that epigenetic effectors of chromatin remodeling are promising targets for therapeutic intervention, because they play a key role in epigenetic regulation of gene expression in all eukaryotes [1,2]. New therapeutic interventions are highly desirable [3] because it is a parasitic disease that affects over 250 million individuals worldwide [4,5], praziquantel is the only approved drug available for treatment [6] and resistant isolates of the Schistosoma mansoni parasite have been identified [7,8]. A range of modifications on the amino-terminal tail of histones, such as acetylation, methylation, ubiquitination, phosphorylation and sumoylation, are involved in chromatin remodeling and transcription regulation. These histone modifications are dynamically laid down and removed by histone modifying enzymes (HMEs) [10]. HDAC inhibitors (HDACi) such as Trichostatin A (TSA) induce parasite mortality in vitro (schistosomula and adult worms), the downstream effects of histone hyperacetylation on the parasite are not known
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