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CURATOR
A pinboard by
Hanh Nguyen

PhD Candidate, The University of Melbourne

PINBOARD SUMMARY

To study the mechanism of bromodomain proteins in P.falciparum and evaluate them as drug targets

Malaria remains one of the major infectious diseases of the world despite much effort since the first initiation of a malaria eradication program 60 years ago. The human malaria parasite Plasmodium falciparum life cycle is complicated and involves a human host and a female Anopheles mosquito vector. For each time point in its life cycle, the parasite expresses a specific group of genes. Despite this knowledge, we do not know the function for majority of the genes in P. falciparum genome and why they are specific to the parasite’s different life stage. Therefore, the way the parasite operate maintains somewhat a mystery and this is one of reasons why battling with malaria remains a challenge. Like humans and other organisms, P. falciparum parasite has histones, which are proteins that DNA wraps around to become ordered in the nucleus. Theses histones can be modified which can influence interaction between histones, DNA and other nuclear proteins. As a result, genes can be switch on or off depending on the combination of histone modifications like codes to a lock. And while the study of histone codes in P. falciparum is essential, my study is to look at a group of proteins that can read the codes which is called bromodomain proteins. In human, it is known that various types of cancer associates with dysfunction of certain bromodomain proteins; and inhibitors of bromodomain have shown promise in the treatment of cancer and other diseases. In P. falciparum, there are eight bromodomain proteins which is unique for the apicomplexan parasite and can be targeted by inhibitors.

8 ITEMS PINNED

Expression of P. falciparum var genes involves exchange of the histone variant H2A.Z at the promoter.

Abstract: Plasmodium falciparum employs antigenic variation to evade the human immune response by switching the expression of different variant surface antigens encoded by the var gene family. Epigenetic mechanisms including histone modifications and sub-nuclear compartmentalization contribute to transcriptional regulation in the malaria parasite, in particular to control antigenic variation. Another mechanism of epigenetic control is the exchange of canonical histones with alternative variants to generate functionally specialized chromatin domains. Here we demonstrate that the alternative histone PfH2A.Z is associated with the epigenetic regulation of var genes. In many eukaryotic organisms the histone variant H2A.Z mediates an open chromatin structure at promoters and facilitates diverse levels of regulation, including transcriptional activation. Throughout the asexual, intraerythrocytic lifecycle of P. falciparum we found that the P. falciparum ortholog of H2A.Z (PfH2A.Z) colocalizes with histone modifications that are characteristic of transcriptionally-permissive euchromatin, but not with markers of heterochromatin. Consistent with this finding, antibodies to PfH2A.Z co-precipitate the permissive modification H3K4me3. By chromatin-immunoprecipitation we show that PfH2A.Z is enriched in nucleosomes around the transcription start site (TSS) in both transcriptionally active and silent stage-specific genes. In var genes, however, PfH2A.Z is enriched at the TSS only during active transcription in ring stage parasites. Thus, in contrast to other genes, temporal var gene regulation involves histone variant exchange at promoter nucleosomes. Sir2 histone deacetylases are important for var gene silencing and their yeast ortholog antagonises H2A.Z function in subtelomeric yeast genes. In immature P. falciparum parasites lacking Sir2A or Sir2B high var transcription levels correlate with enrichment of PfH2A.Z at the TSS. As Sir2A knock out parasites mature the var genes are silenced, but PfH2A.Z remains enriched at the TSS of var genes; in contrast, PfH2A.Z is lost from the TSS of de-repressed var genes in mature Sir2B knock out parasites. This result indicates that PfH2A.Z occupancy at the active var promoter is antagonized by PfSir2A during the intraerythrocytic life cycle. We conclude that PfH2A.Z contributes to the nucleosome architecture at promoters and is regulated dynamically in active var genes.

Pub.: 08 Mar '11, Pinned: 29 Jun '17

Epigenetic regulation of the Plasmodium falciparum genome.

Abstract: Recent research has highlighted some unique aspects of chromatin biology in the malaria parasite Plasmodium falciparum. During its erythrocytic lifecycle P. falciparum maintains its genome primarily as unstructured euchromatin. Indeed there is no clear role for chromatin-mediated silencing of the majority of the developmentally expressed genes in P. falciparum. However discontinuous stretches of heterochromatin are critical for variegated expression of contingency genes that mediate key pathogenic processes in malaria. These range from invasion of erythrocytes and antigenic variation to solute transport and growth adaptation in response to environmental changes. Despite lack of structure within euchromatin the nucleus maintains functional compartments that regulate expression of many genes at the nuclear periphery, particularly genes with clonally variant expression. The typical components of the chromatin regulatory machinery are present in P. falciparum; however, some of these appear to have evolved novel species-specific functions, e.g. the dynamic regulation of histone variants at virulence gene promoters. The parasite also appears to have repeatedly acquired chromatin regulatory proteins through lateral transfer from endosymbionts and from the host. P. falciparum chromatin regulators have been successfully targeted with multiple drugs in laboratory studies; hopefully their functional divergence from human counterparts will allow the development of parasite-specific inhibitors.

Pub.: 12 Dec '13, Pinned: 29 Jun '17

Activation and clustering of a Plasmodium falciparum var gene are affected by subtelomeric sequences.

Abstract: The P. falciparum var multigene family encodes the cytoadhesive, variant antigen PfEMP1. P. falciparum antigenic variation and cytoadhesion specificity are controlled by epigenetic switching between the single, or few, simultaneously expressed var genes. Most var genes are maintained in perinuclear clusters of heterochromatic telomeres. The active var gene(s) occupy a single, perinuclear var expression site. It is unresolved whether the var expression site forms in situ at a telomeric cluster or whether it is an extant compartment to which single chromosomes travel, thus controlling var switching. Here we show that transcription of a var gene did not require decreased co-localisation with clusters of telomeres, supporting var expression site formation in situ. However following recombination within adjacent subtelomeric sequences the same var gene was persistently activated and did co-localise less with telomeric clusters. Thus participation in stable, heterochromatic, telomere clusters and var switching are independent but are both affected by subtelomeric sequences. The var expression site co-localised with the euchromatic mark H3K27ac to a greater extent than it did with heterochromatic H3K9me3. H3K27ac was enriched within the active var gene promoter even when the var gene was transiently repressed in mature parasites and thus H3K27ac may contribute to var gene epigenetic memory. This article is protected by copyright. All rights reserved.

Pub.: 20 Nov '16, Pinned: 29 Jun '17