Chromatin-Mediated Epigenetic Regulation in the Malaria Parasite Plasmodium falciparum

Abstract

Malaria is a major public health problem in many developing countries, with the malignant tertian parasite Plasmodium falciparum causing the most malaria-associated mortality. Extensive research, especially with the advancement of genomics and transfection tools, has highlighted the fundamental importance of chromatinmediated gene regulation in the developmental program of this early-branching eukaryote. The Plasmodium parasite genomes reveal the existence of both canonical and variant histones that make up the nucleosomes, as well as a full collection of conserved enzymes for chromatin remodeling and histone posttranslational modifications (PTMs). Recent studies have identified a wide array of both conserved and novel histone PTMs in P. falciparum, indicating the presence of a complex and divergent "histone code." Genome-wide analysis has begun to decipher the nucleosome landscape and histone modifications associated with the dynamic organization of chromatin structures during the parasite's life cycle. Focused studies on malaria-specific phenomena such as antigenic variation and red cell invasion pathways shed further light on the involvement of epigenetic mechanisms in these processes. Here we review our current understanding of chromatin-mediated gene regulation in malaria parasites, with specific reference to exemplar studies on antigenic variation and host cell invasion.Malaria continues to be a major cause of mortality and morbidity in tropical countries, bringing a death toll of ϳ1 million each year. Four human parasites (Plasmodium falciparum, P. vivax, P. malariae, and P. ovale) and a monkey parasite (P. knowlesi) have been found to infect humans naturally. P. falciparum causes the malignant form of malaria and is responsible for most malaria-associated human deaths. Intensified research in the past decade has greatly improved our understanding of the parasites and the disease they cause, especially with the sequencing of multiple parasite genomes. A striking finding from global microarray analyses of parasite gene expression is the tightly regulated transcription program during the parasite's life cycle, with genes expressed in a "just-in-time" manner (12, 93). Bioinformatic analysis has recognized a general conservation of the basal transcription machinery (15), but the scarcity of recognizable specific transcription factors in the parasite genome has led to speculation about the existence of a divergent transcription mechanism used by the malaria parasites (2, 25). However, this speculation may be inaccurate, as recent studies revealed the presence of the AP2 family of transcription factors (4, 35), which have undergone lineagespecific expansion in apicomplexan parasites (75). Nevertheless, the full complement of chromatin-modifying proteins encoded in apicomplexan parasite genomes underlines the significance of epigenetic mechanisms in transcription regulation (2,66,75,140). While epigenetic mechanisms are being intensively studied in model eukaryotes, only recently have they been explored in the m...

Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

“…We argue that these findings point to biological processes used by the parasite to survive drug pressure or circumvent the action of antimalarial compounds. Other genes of interest include those encoding three ABC transporters-a class of transporters known to modulate drug responses in other organisms (28)-and genes proposed to modulate chromatin (29,30), DNA repair (31, 32), or RNA binding (33), pathways that have been shown to potentially be altered in response to drug pressure.…”

Kinetic Flux Profiling Elucidates Two Independent Acetyl-CoA Biosynthetic Pathways in Plasmodium falciparum

“…The IC 50 of oxythiamine was determined, and a low dose long-term incuba-tion strategy was required to allow conversion of oxythiamine to oxythiamine pyrophosphate. [5][6][7][8][9][10][11][12][13] C]Glutamine was added to glutamine-free RPMI at a final concentration of 2 mM for [5][6][7][8][9][10][11][12][13] C]glutamine labeling experiments. [6][7][8][9][10][11][12][13] C, 15 N]leucine labeling experiments were performed in complete custom-made RPMI without leucine and supplemented with [6][7][8][9][10][11][12][13] C, 15 N]leucine at the RPMI concentration.…”

“…Most of this glucose is metabolized to pyruvate that is subsequently reduced to lactate and excreted (7)(8)(9)(10)(11). However, P. falciparum possess several metabolic pathways that are typically supplied by pyruvate-derived acetyl-CoA including the mitochondrial tricarboxylic acid cycle (TCA), cytosolic fatty acid elongation, and nuclear histone acetylation (12)(13)(14)(15)(16). In most organisms acetyl-CoA is predominantly synthesized through the action of the pyruvate dehydrogenase (PDH) 3 complex.…”

Protein Arginine Methylation in Parasitic Protozoa

“…In contrast, dynamic dimethylation of H4R3, which is mediated by PfPRMT1 in vitro, was observed during the parasite life cycle, with high levels of H4R3 observed in late trophozoites and schizonts (35). These data suggest a conserved role for histone arginine methylation in epigenetic gene regulation in Plasmodium along with other posttranslational modifications (28,35,91).…”