Multiple dimensions of epigenetic gene regulation in the malaria parasite Plasmodium 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.

A Knockout Screen of ApiAP2 Genes Reveals Networks of Interacting Transcriptional Regulators Controlling the Plasmodium Life Cycle

“…Additionally, some promoters can drive expression of a transgene with an intensity and pattern comparable to their endogenous gene, even when removed from the native genomic context (Janse et al., 2006a, Laurentino et al., 2011, Sebastian et al., 2012). However, a variety of alternative control mechanisms have been described in Plasmodium , which at different life cycle stages include changes in nuclear organization, chromatin modifications (Ay et al., 2015), dynamics of RNA degradation (Shock et al., 2007), and posttranscriptional repression (Mair et al., 2006). These are also likely to contribute to both the complexity and flexibility of the gene expression network.…”

Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth

“…Thus, the discovery of novel drug targets, and new chemotherapies with novel mechanisms of action, are high priorities. Small molecules that act on epigenetic regulatory proteins, such as those responsible for post-translational modifications of histones, are of increasing interest as chemical tools for dissecting fundamental mechanisms of parasite growth and as possible new drug leads (Andrews et al., 2012b, Ay et al., 2015, Cheeseman and Weitzman, 2015). Clinically approved drugs are also attracting interest for repurposing for new uses since this can shorten time to market and reduce costs compared to de novo drug discovery for malaria or Neglected Tropical Diseases (NTDs).…”

Epigenetic regulation of Plasmodium falciparum clonally variant gene expression during development in Anopheles gambiae

“…In humans, parasite life cycle progression occurs through coordinated waves of gene expression234, and a similar transcription switch seems to occur in the mosquito host5. Experiments carried out with the blood stages of the parasite show a correlation between changes in post-translational modifications of histones (hPTMs) and stage-specific transcription programs67. In Plasmodium , like in other organisms, H3K9ac and H3K4me3 are linked to transcription and localize at active promoters, whereas H3K9me3 is a repressive modification that tends to localize in heterochromatic regions, and is associated with gene silencing.…”