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Multiple dimensions of epigenetic gene regulation in the malaria parasite Plasmodium falciparum: gene regulation via histone modifications, nucleosome positioning and nuclear architecture in P. falciparum.

ABSTRACT: Plasmodium falciparum is the most deadly human malarial parasite, responsible for an estimated 207 million cases of disease and 627,000 deaths in 2012. Recent studies reveal that the parasite actively regulates a large fraction of its genes throughout its replicative cycle inside human red blood cells and that epigenetics plays an important role in this precise gene regulation. Here, we discuss recent advances in our understanding of three aspects of epigenetic regulation in P. falciparum: changes in histone modifications, nucleosome occupancy and the three-dimensional genome structure. We compare these three aspects of the P. falciparum epigenome to those of other eukaryotes, and show that large-scale compartmentalization is particularly important in determining histone decomposition and gene regulation in P. falciparum. We conclude by presenting a gene regulation model for P. falciparum that combines the described epigenetic factors, and by discussing the implications of this model for the future of malaria research.

SUBMITTER: Ay F

PROVIDER: S-EPMC4385791 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Multiple dimensions of epigenetic gene regulation in the malaria parasite Plasmodium falciparum: gene regulation via histone modifications, nucleosome positioning and nuclear architecture in P. falciparum.

Ay Ferhat F Bunnik Evelien M EM Varoquaux Nelle N Vert Jean-Philippe JP Noble William Stafford WS Le Roch Karine G KG

BioEssays : news and reviews in molecular, cellular and developmental biology 20141113 2

Plasmodium falciparum is the most deadly human malarial parasite, responsible for an estimated 207 million cases of disease and 627,000 deaths in 2012. Recent studies reveal that the parasite actively regulates a large fraction of its genes throughout its replicative cycle inside human red blood cells and that epigenetics plays an important role in this precise gene regulation. Here, we discuss recent advances in our understanding of three aspects of epigenetic regulation in P. falciparum: chang ...[more]

PMID: 25394267

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Project description:BACKGROUND:Various transcription factors are involved in the process of mutually exclusive expression and clonal variation of the Plasmodium multigene (var) family. Recent studies revealed that a P. falciparum SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (PfSWIB) might trigger stage-specific programmed cell death (PCD), and was not only crucial for the survival and development of parasite, but also had profound effects on the parasite by interacting with other unknown proteins. However, it remains unclear whether PfSIWB is involved in transcriptional regulation of this virulence gene and its functional properties. METHODS:A conditional knockdown system "PfSWIB-FKBP-LID" was introduced to the parasite clone 3D7, and an integrated parasite line "PfSWIB-HA-FKBP-LID" was obtained by drug cycling and clone screening. Growth curve analysis (GCA) was performed to investigate the growth and development of different parasite lines during 96 h in vitro culturing, by assessing parasitemia. Finally, we performed qPCR assays to detect var gene expression profiling in various comparison groups, as well as the mutually exclusive expression pattern of the var genes within a single 48 h life-cycle of P. falciparum in different parasite lines. In addition, RNA-seq was applied to analyze the var gene expression in different lines. RESULTS:GCA revealed that conditional knockdown of PfSWIB could interfere with the growth and development of P. falciparum. The parasitemia of PfSWIB? showed a significant decline at 96 h during in vitro culture compared with the PfSWIB and 3D7 lines (P?<?0.0001). qPCR and RNA-seq analysis confirmed that depletion of PfSWIB not only silences upsA, upsC and partial upsB var genes, as well as removes the silencing of partial upsB var genes at the ring stage in PfSWIB? line, but also leads to aberrant expression of upsA and partial upsB/upsC var genes at the mature stage of P. falciparum, during a single 48-h life-cycle. CONCLUSIONS:We demonstrated that PfSWIB was involved in the process of clonal variation in var gene expression, and crucial for the survival and development of Plasmodium parasite. These findings could provide better understanding of the mechanism and function of PfSWIB contributing to the pathogenesis in malaria parasites.

Project description:In eukaryotic organisms, packaging of DNA into nucleosomes controls gene expression by regulating access of the promoter to transcription factors. The human malaria parasite Plasmodium falciparum encodes relatively few transcription factors, while extensive nucleosome remodeling occurs during its replicative cycle in red blood cells. These observations point towards an important role of the nucleosome landscape in regulating gene expression. However, the relation between nucleosome positioning and transcriptional activity has thus far not been explored in detail in the parasite.Here, we analyzed nucleosome positioning in the asexual and sexual stages of the parasite's erythrocytic cycle using chromatin immunoprecipitation of MNase-digested chromatin, followed by next-generation sequencing. We observed a relatively open chromatin structure at the trophozoite and gametocyte stages, consistent with high levels of transcriptional activity in these stages. Nucleosome occupancy of genes and promoter regions were subsequently compared to steady-state mRNA expression levels. Transcript abundance showed a strong inverse correlation with nucleosome occupancy levels in promoter regions. In addition, AT-repeat sequences were strongly unfavorable for nucleosome binding in P. falciparum, and were overrepresented in promoters of highly expressed genes.The connection between chromatin structure and gene expression in P. falciparum shares similarities with other eukaryotes. However, the remarkable nucleosome dynamics during the erythrocytic stages and the absence of a large variety of transcription factors may indicate that nucleosome binding and remodeling are critical regulators of transcript levels. Moreover, the strong dependency between chromatin structure and DNA sequence suggests that the P. falciparum genome may have been shaped by nucleosome binding preferences. Nucleosome remodeling mechanisms in this deadly parasite could thus provide potent novel anti-malarial targets.

Dataset Information

Multiple dimensions of epigenetic gene regulation in the malaria parasite Plasmodium falciparum: gene regulation via histone modifications, nucleosome positioning and nuclear architecture in P. falciparum.

Publications

Multiple dimensions of epigenetic gene regulation in the malaria parasite Plasmodium falciparum: gene regulation via histone modifications, nucleosome positioning and nuclear architecture in P. falciparum.

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