A comprehensive epigenome map of Plasmodium falciparum reveals unique mechanisms of transcriptional regulation and identifies H3K36me2 as a global mark of gene suppression

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.

Epigenome mapping highlights chromatin-mediated gene regulation in the protozoan parasite Trichomonas vaginalis

“…However, H3K4me3 and H3K9Ac are spread evenly across both active and inactive genes and do not correlate with transcriptional activity in synchronized ring stage P. falciparum 54. Additionally, H3K27Ac levels in P. falciparum are very low and do not show any correlation with gene activity48, contrary to our observation in T. vaginalis . Another protozoan parasite model, T. gondii , shows euchromatin marks of H4Ac, H3K9Ac, and H3K4me3, which colocalize and mark the promoters of actively transcribed genes55.…”

“…H3K27Ac may also prevent the repressive trimethylation of the same lysine residue, as acetylation and trimethylation of H3K27 (H3K27me3) are considered mutually exclusive in model organisms46. While H3K27me3 is present in Drosophila and mammals, it is absent in simple model organisms, such as S. cerevisiae and P. falciparum 4748. As the presence of repressive marks, such as H3K27me3, has yet to be determined in T. vaginalis , future studies thereon are warranted.…”

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“…The stage-specific inhibition profiles observed for the wide variety of epi-drug inhibitor classes support the findings that the parasite makes use of altered epigenetic regulatory mechanisms to differentiate itself during asexual proliferation and sexual differentiation (7,48,49). Selective Plasmodium inhibition was only shown for 6 compounds of the series, which suggests that the epigenetic modulators targeted by these compounds (HKMT, HDAC and PRMT) show diversity between the parasite and human homologues, as previously shown by the unique set of Plasmodium-specific epigenetic factors that differs vastly from those in its mammalian host (39).…”

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“…Karmodyia et al (2015) performed genome-wide mapping of multiple histone modifications of P. falciparum and reported H3K36me2 as a global repressive mark, with gene regulation being fine-tuned by the ratio of activation marks to H3K36me2 (Karmodiya et al, 2015). Moreover, var genes are mostly poised and marked by a unique set of activation (H4ac) and repression (H3K9me3) marks, which are mutually exclusive to other P. falciparum housekeeping genes.…”