Abstract
BackgroundRole of epigenetic mechanisms towards regulation of the complex life cycle/pathogenesis of Plasmodium falciparum, the causative agent of malaria, has been poorly understood. To elucidate stage-specific epigenetic regulation, we performed genome-wide mapping of multiple histone modifications of P. falciparum. Further to understand the differences in transcription regulation in P. falciparum and its host, human, we compared their histone modification profiles.ResultsOur comprehensive comparative analysis suggests distinct mode of transcriptional regulation in malaria parasite by virtue of poised genes and differential histone modifications. Furthermore, analysis of histone modification profiles predicted 562 genes producing anti-sense RNAs and 335 genes having bidirectional promoter activity, which raises the intriguing possibility of RNA-mediated regulation of transcription in P. falciparum. Interestingly, we found that H3K36me2 acts as a global repressive mark and gene regulation is fine tuned by the ratio of activation marks to H3K36me2 in P. falciparum. This novel mechanism of gene regulation is supported by the fact that knockout of SET genes (responsible for H3K36 methylation) leads to up-regulation of genes with highest occupancy of H3K36me2 in wild-type P. falciparum. Moreover, virulence (var) genes are mostly poised and marked by a unique set of activation (H4ac) and repression (H3K9me3) marks, which are mutually exclusive to other Plasmodium housekeeping genes.ConclusionsOur study reveals unique plasticity in the epigenetic regulation in P. falciparum which can influence parasite virulence and pathogenicity. The observed differences in the histone code and transcriptional regulation in P. falciparum and its host will open new avenues for epigenetic drug development against malaria parasite.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0029-1) contains supplementary material, which is available to authorized users.
Highlights
Role of epigenetic mechanisms towards regulation of the complex life cycle/pathogenesis of Plasmodium falciparum, the causative agent of malaria, has been poorly understood
We provide evidence that H3K36me2 acts as a global repressive mark in P. falciparum and gene expression is governed by the ratio of activation marks to H3K36me2
Further to confirm if H3K9ac and H3K4me3 co-occupy these loci or it is an effect of cellular heterogeneity, we performed sequential Chromatin immunoprecipitation (ChIP) for H3K9ac followed by H3K4me3 (Additional file 1: Figure S1B)
Summary
Role of epigenetic mechanisms towards regulation of the complex life cycle/pathogenesis of Plasmodium falciparum, the causative agent of malaria, has been poorly understood. Nuclear division during the schizont stage results in the formation of 16–32 merozoites, which can infect the new RBCs. To sustain chronic infection in human hosts, parasite undergoes rapid transitions between morphological states, a mechanism of immune evasion that contributes to pathogenicity. To sustain chronic infection in human hosts, parasite undergoes rapid transitions between morphological states, a mechanism of immune evasion that contributes to pathogenicity These rapid transitions between morphological states are orchestrated by multiple types of transcriptional and epigenetic regulations [1, 2]. Multiple studies have suggested critical roles of HDACs and HMTs in controlling gene expression in P. falciparum [8,9,10]. Epigenetic mechanisms have been implicated in regulation of genes playing role in parasite virulence, differentiation and cell-cycle control [13]
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