Abstract
BackgroundThe dynamics of histone modifications in Plasmodium falciparum indicates the existence of unique mechanisms that link epigenetic factors with transcription. Here, we studied the impact of acetylated histone code on transcriptional regulation during the intraerythrocytic developmental cycle (IDC) of P. falciparum.ResultsUsing a dominant-negative transgenic approach, we showed that acetylations of histone H4 play a direct role in transcription. Specifically, these histone modifications mediate an inverse transcriptional relationship between the factors of cell proliferation and host–parasite interaction. Out of the four H4 acetylations, H4K8ac is likely the rate-limiting, regulatory step, which modulates the overall dynamics of H4 posttranslational modifications. H4K8ac exhibits maximum responsiveness to HDAC inhibitors and has a highly dynamic distribution pattern along the genome of P. falciparum during the IDC. Moreover, H4K8ac functions mainly in the euchromatin where its occupancy shifts from intergenic regions located upstream of 5′ end of open reading frame into the protein coding regions. This shift is directly or indirectly associated with transcriptional activities at the corresponding genes. H4K8ac is also active in the heterochromatin where it stimulates expression of the main antigenic gene family (var) by its presence in the promoter region.ConclusionsOverall, we demonstrate that H4K8ac is a potential major regulator of chromatin-linked transcriptional changes during P. falciparum life cycle which is associated not only with euchromatin but also with heterochromatin environment. This is potentially a highly significant finding that suggests a regulatory connection between growth and parasite–host interaction both of which play a major role in malaria parasite virulence.
Highlights
The dynamics of histone modifications in Plasmodium falciparum indicates the existence of unique mechanisms that link epigenetic factors with transcription
Studying 13 canonical post transcriptional modification (PTM) of H4 and H3, we have previously shown that acetylation of H4 at lysine residue 8 (H4K8ac) is among the most dynamic modifications occupying predominantly the 5′ intergenic regions (5′IGRs) and 5′ termini of the open reading frames (ORFs) of more than half of the P. falciparum genes [21]
There was an increase in the plasmid copy number and expression of the transgenic H4 proteins in P. falciparum grown in 10 μg/ml of blasticidin compared to 2.5 μg/ml in all parasite lines (Additional file 2: Figure S1a and Fig. 1a, respectively)
Summary
The dynamics of histone modifications in Plasmodium falciparum indicates the existence of unique mechanisms that link epigenetic factors with transcription. Occupancy of histone variants contributes to the dynamic chromatin remodeling throughout the P. falciparum IDC with some variants which associate with actively transcribed genes, while others play roles in chromatin structure [20, 26,27,28]. The dynamics is reflected in occupancy of RNA polymerase II exhibiting distinct patterns for early and late expressed genes [38]. These findings suggest that the time component of the occupancy profiles across the IDC is one of the variables of the overall “histone code” playing a key fundamental role in gene expression during the Plasmodium life cycle
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