Quantitative chromatin proteomics reveals a dynamic histone post-translational modification landscape that defines asexual and sexual Plasmodium falciparum parasites

Coetzee, Nanika; Sidoli, Simone; Biljon, Riëtte van; Painter, Heather J.; Llinás, Manuel; Garcia, Benjamin A.; Birkholtz, Lyn‐Marié

doi:10.1038/s41598-017-00687-7

Cited by 74 publications

(172 citation statements)

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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).…”

Section: Histone-associated Epigenetic Regulators Remain Overrepresensupporting

confidence: 63%

“…The primary evaluation of the activity of epi-drugs against the multiple life cycle stages indicated that early stage gametocytes were particularly susceptible to epi-drug inhibition, supported by reports of a unique epigenetic repertoire associated with these stages, where the switch between asexual and sexual stages was accompanied by dynamic histone PTM landscape alterations (7). The differentiation between the compounds active against the different life cycle stages correlates with unique and stage-specific histone PTM dynamics during the parasite's life cycle, with clear peaks abundances for some epigenetic marks associated with particular life cycle stages (7,48,49) and highlights the importance of these activities to parasite development.…”

Section: Histone-associated Epigenetic Regulators Remain Overrepresenmentioning

confidence: 91%

“…Plasmodium falciparum relies heavily on epigenetic mechanisms to drive both asexual proliferation and sexual differentiation (reviewed in (7)(8)(9)(10)(11)). The parasite's genome encodes a unique complement of histone modifying enzymes including histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs, including lysine HKMT), protein arginine methyltransferases (PRMTs), and histone demethylases (HDMs) (11) in addition to other non-histone epigenetic modifiers.…”

Section: Introductionmentioning

confidence: 99%

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Multistage activity within a diverse set of epi-drugs against Plasmodium falciparum parasites

Coetzee

Grüning

Watt

et al. 2019

Preprint

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The epigenome of the malaria parasite, Plasmodium falciparum, is associated with control of various essential processes in the parasite including control of proliferation of asexual development as well as sexual differentiation. The unusual nature of the epigenome has prompted investigations of the potential to target epigenetic modulators with novel chemotypes. Here, we explored the diversity associated with a library of 95 compounds, active against various epigenetic modifiers within cancerous cells, for activity against multiple stages of P. falciparum development. We show that P. falciparum is differentially susceptible to epigenetic perturbation during asexual and sexual development, with early stage gametocytes particularly sensitive to epi-drugs targeting both histone and non-histone epigenetic modifiers. Moreover, 4 compounds targeting histone acetylation and methylation, show potent multistage activity against asexual parasites, early and late stage gametocytes, with transmission-blocking potential. Overall, these results warrant further examination of the potential antimalarial properties of these hit compounds.

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Section: Histone-associated Epigenetic Regulators Remain Overrepresensupporting

confidence: 63%

Section: Histone-associated Epigenetic Regulators Remain Overrepresenmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Multistage activity within a diverse set of epi-drugs against Plasmodium falciparum parasites

Coetzee

Grüning

Watt

et al. 2019

Preprint

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“…(C) The genes expressed during maturation (cluster 10) showed a significant association ( P <0.0001, two-tailed Fisher’s exact test) with genes stabilized post-transcriptionally during commitment (18) and H3K36me3-associated genes in asexual development (16,73) before a sharp increase at stage IV-V of development (dashed line). Blocks indicate the timing of stabilization of the transcripts (18) or abundance of the H3K36me3 mark (65) and the overlap between the 3 datasets are indicated in the Venn diagram. Genes of interest within the three functional datasets are highlighted in heatmap.…”

Section: Resultsmentioning

confidence: 99%

Hierarchical transcriptional control regulatesPlasmodium falciparumsexual differentiation

Biljon

Wyk

Painter³

et al. 2019

Preprint

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18Although malaria is characterized by cyclic waves of infection by asexual parasites, 19 only sexual gametocyte forms of the malaria parasite can be transmitted between the 20 infected human and the mosquito host. Here we provide a high-resolution 21 transcriptome of P. falciparum as it commits to and develops through 22 gametocytogenesis and prepares for transmission to the mosquito vector. As 23 anticipated, the gametocyte-associated transcriptome is significantly different from 24 that of the asexual blood cycle, and a dynamic shift in gene expression characterizes 25 early, intermediate and late-stage gametocyte development. Moreover, we show a 26 differential timing in the expression of sex-specific transcripts and we highlight early 27 male and female gametocyte markers for functional evaluation. The striking temporal 28 transcript abundance profiles suggest that strict transcriptional control underlies the 29 10-day gametocyte developmental program in P. falciparum. We identify putative 30 regulators of transcriptional dynamics, including epigenetic mechanisms driving active 31 repression of processes typically associated with proliferation and ApiAP2 32 transcription factors expressed during gametocyte maturation. The gametocyte 33 transcriptome serves as the blueprint for sexual differentiation at the mRNA transcript 34 level and will be a rich resource for future functional studies on this critical stage of 35 Plasmodium development, as the intraerythrocytic transcriptome has been for our 36 understanding of the 48-hour asexual cycle. 3 37 Author Summary 38The ability of the malaria parasite Plasmodium falciparum to smoothly transition 39 between the human and the female mosquito hosts is one of the hallmarks of the 40 pathogenicity of the disease. Only sexually dimorphic, mature gametocyte stages of 41 the parasite life cycle can complete the human-to-mosquito transmission task. 42However, we do not clearly understand how these gametocytes develop and mature. 43Here, we report the highest resolution investigation of the gametocyte's transcriptional 44 profile during development and differentiation. This information sheds light on several 45 possible regulators that mediate parasite maturation into transmission-competent 46 stage V gametocytes. We find that 15% of the parasite's transcripts are 47 developmentally regulated within three distinct phases of sexual development, each 48 corresponding to essential biological events allowing for regulated and staged 49 differentiation. Our study lays the foundation for future projects aiming to 50 therapeutically target these transmissible stages and comprises an invaluable 51 resource for the study of malaria parasite pathogenesis. 52 53 54 55 4 57 Introduction 58 Sustained malaria prevalence is ensured through continued human-to-mosquito 59 transmission of Plasmodium parasites with Plasmodium falciparum being the 60 causative agent of the most severe form of the disease in humans (1). The complex 61 life cycle of P. falciparum encompasses development in ...

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“…The histone core protein and N‐terminal tails are subjected to many modifications including methylation, acetylation, and phosphorylation . At least 500 individual histone PTMs on different amino acid positions were identified recently on P. falciparum histone proteins in a proteomic screen, and so far 106 PTMs were experimentally validated in the follow up studies . The acetylation of histone tails is primarily involved in the gene activation process, whereas methylation is involved in both gene activation and suppression.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Players of Chromatin Structure Regulation in Plasmodium falciparum

Jabeena

Rajavelu

2019

ChemBioChem

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The protozoan parasite Plasmodium has evolved to survive in different hosts and environments. The diverse strategies of adaptation to different niches involve differential gene expression mechanisms mediated by chromatin plasticity that are poorly characterized in Plasmodium. The parasite employs a wide variety of regulatory mechanisms to complete their life cycle and survive inside hosts. Among them, epigenetic‐mediated mechanisms have been implicated for controlling chromatin organization, gene regulation, morphological differentiation, and antigenic variation. The differential gene expression in parasite is largely dependent on the nature of the chromatin structure. The histone core methylation marks and methyl mark readers contribute to chromatin dynamics. Here, we review the recent developments on various epigenetic marks and its enzymes in the Plasmodium falciparum, how these marks play a key role in the regulation of transcriptional activity of variable genes and coordinate the differential gene expression. We also discuss the possible roles of these epigenetic marks in chromatin structure regulation and plasticity at various stages of its development.

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Quantitative chromatin proteomics reveals a dynamic histone post-translational modification landscape that defines asexual and sexual Plasmodium falciparum parasites

Cited by 74 publications

References 88 publications

Multistage activity within a diverse set of epi-drugs against Plasmodium falciparum parasites

Multistage activity within a diverse set of epi-drugs against Plasmodium falciparum parasites

Hierarchical transcriptional control regulatesPlasmodium falciparumsexual differentiation

Epigenetic Players of Chromatin Structure Regulation in Plasmodium falciparum

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