Malaria Epigenetics

Abstract

Organisms with identical genome sequences can show substantial differences in their phenotypes owing to epigenetic changes that result in different use of their genes. Epigenetic regulation of gene expression plays a key role in the control of several fundamental processes in the biology of malaria parasites, including antigenic variation and sexual differentiation. Some of the histone modifications and chromatin-modifying enzymes that control the epigenetic states of malaria genes have been characterized, and their functions are beginning to be unraveled. The fundamental principles of epigenetic regulation of gene expression appear to be conserved between malaria parasites and model eukaryotes, but important peculiarities exist. Here, we review the current knowledge of malaria epigenetics and discuss how it can be exploited for the development of new molecular markers and new types of drugs that may contribute to malaria eradication efforts.

Figure 1.

Clonally variant gene expression during the blood stages of the Plasmodium falciparum life cycle. Asexual replication occurs within human erythrocytes and progresses through different morphological stages, including rings, trophozoites, schizonts, and merozoites (cycle at top of figure). In trophozoites, several clonally variant proteins involved in erythrocyte modification, antigenic variation, and cell permeability are expressed. Similarly, in schizonts/merozoites, clonally variant proteins that determine alternative erythrocyte invasion pathways are expressed. In a small proportion of cells, the sexual differentiation process is initiated through the activation of PfAP2-G, leading to the production of male and female gametocytes (bottom).

Figure 2.

Chromatin compartments in Plasmodium falciparum. As in other eukaryotes, the chromatin of malaria parasites can be roughly divided into three separate compartments with very distinct properties. Green and red flags represent histone marks generally associated with transcriptional activation or silencing, respectively. P. falciparum constitutive heterochromatin (upper left) is generally transcriptionally silent but allows transcription of some noncoding RNAs (ncRNAs). Euchromatic regions (upper right) are typified by the incorporation of the variant histones H2A.Z and H2B.Z as well as the histone modifications H3K4me3 and H3K9ac. Stage-specific transcription largely depends on the presence of specific transcription factors (TFs), whereas in facultative heterochromatin (bottom) transcription depends on both the presence of the relevant transcription factor(s) and chromatin accessibility. The latter is determined by which of the possible chromatin states has been assembled at a specific locus in a given cell. Typically, chromatin at silent loci incorporates the histone modification H3K9me3 and is bound by HP1, whereas active genes are associated with the histone modification H3K9ac.

Figure 3.

Epigenetic factors as targets for drug development. The normal balance between the euchromatic (active) and heterochromatic (silenced) states of clonally variant genes (top panel) can be altered pharmacologically. Drugs that inhibit the factors that catalyze the transition to or the maintenance of the active state are expected to shift the balance toward the silenced state (middle panel). In contrast, drugs that inhibit the factors that catalyze the transition to or the maintenance of the silenced state are expected to shift the balance toward the active state (bottom panel). The predicted effects of chemical inhibition of enzymes that participate in the regulation of clonally variant genes in general are listed. As examples, enzymes that operate on H3K9 are shown, but inhibition of enzymes that regulate the deposition or removal of other histone modifications (e.g., H4K20me3) may have similar effects. Inhibitors of epigenetic factors that participate in the regulation of only some clonally variant gene families (e.g., var genes) are expected to have family-specific effects. The predicted histone acetyltransferases (HATs), lysine demethylases (KDMs), histone deacetylases (HDACs), and lysine methyltransferases (KMTs) that operate on H3K9 are described in Table 2.