Abstract
Gene expression in Plasmodia integrates post-transcriptional regulation with epigenetic marking of active genomic regions through histone post-translational modifications (PTMs). To generate insights into the importance of histone PTMs to the entire asexual and sexual developmental cycles of the parasite, we used complementary and comparative quantitative chromatin proteomics to identify and functionally characterise histone PTMs in 8 distinct life cycle stages of P. falciparum parasites. ~500 individual histone PTMs were identified of which 106 could be stringently validated. 46 individual histone PTMs and 30 co-existing PTMs were fully quantified with high confidence. Importantly, 15 of these histone PTMs are novel for Plasmodia (e.g. H3K122ac, H3K27me3, H3K56me3). The comparative nature of the data revealed a highly dynamic histone PTM landscape during life cycle development, with a set of histone PTMs (H3K4ac, H3K9me1 and H3K36me2) displaying a unique and conserved abundance profile exclusively during gametocytogenesis (P < 0.001). Euchromatic histone PTMs are abundant during schizogony and late gametocytes; heterochromatic PTMs mark early gametocytes. Collectively, this data provides the most accurate, complete and comparative chromatin proteomic analyses of the entire life cycle development of malaria parasites. A substantial association between histone PTMs and stage-specific transition provides insights into the intricacies characterising Plasmodial developmental biology.
Highlights
Epigenetic heritage describes the ability of cells to transmit chromatin structural modifications during cell division and thereby maintaining differentiation status in eukaryotes
The yields of the histone-enriched, acid-soluble nuclear protein fractions differed between the various life cycle stages (Fig. 1a) with the lowest yield observed during early asexual development and a significant increase observed in schizonts (0.36 ± 0.08 ng/parasite; P < 0.001, n = 3)
This study confirms that the histone post-translational modifications (PTMs) landscape in P. falciparum is highly dynamic with clear stage-specific developmental trends associated with either asexual or sexual development. With this large-scale chromatin proteomics study, we quantitatively identified a set of PTMs on histones in all life cycle forms of P. falciparum parasites, during both asexual proliferation and sexual differentiation
Summary
Epigenetic heritage describes the ability of cells to transmit chromatin structural modifications during cell division and thereby maintaining differentiation status in eukaryotes. Histone acetylation is associated with gene activation in a transcriptionally permissive state, whereas methylation results in repression or activation, in a position-dependent manner[2] Histones and their modifying proteins are conserved between different organisms, they contain alternative sites for modification within early-branched Eukarya, mediated by divergence of the modifying proteins[3, 4]. Histone PTMs are associated with cell type-specific proteins in other organisms and have a high heritability during cell division[37] This leads to the establishment of a global chromatin environment that contributes to the regulation of transcriptional expression[1, 38]. Information on histone PTMs in the sexual gametocyte forms of the parasite is limited to the identification of only two histone PTMs in inhibitor studies[52]
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