The Emerging Role for RNA Polymerase II in Regulating Virulence Gene Expression in Malaria Parasites

Plasmodium falciparum causes the most severe form of human malaria and is responsible for a significant public health burden in the developing world. These protozoan parasites invade circulating red blood cells (RBCs) and maintain prolonged infections through an intricate gene-expression switching mechanism that enables immune evasion through antigenic variation [1]. One of the families of genes responsible for this evasion is called var; it is made up of ~60 members, of which approximately two-thirds are found located within subtelomeric heterochromatic regions of the P. falciparum genome, with the remaining third of the family arranged in clusters located in similarly heterochromatinized areas within the internal regions of the chromosomes. The var gene family encodes P. falciparum erythrocyte membrane protein 1 (PfEMP1), a protein displayed on the surface of infected RBCs and considered the primary antigenic determinant required for cytoadherence and sequestration of infected cells, thus enabling them to avoid circulation through the spleen. Only one var gene is expressed at a time, while the other 59 remain transcriptionally silent, and which gene is active switches over the course of an infection. This process allows the parasites to maintain chronic infections through an ever-changing display of PfEMP1 antigens to the immune system. Structurally, each var gene consists of two exons flanking a single, conserved intron with a bidirectional promoter that transcribes noncoding RNAs [2–4]. Although an understanding of the mechanisms that lead to coordinated switching within the var gene family have remained elusive, it has become clear in recent years that epigenetic components, particularly histone modifications, play major roles in determining whether an individual gene will be active or silent. Many of the histone modifications involved in antigenic variation, as well as other aspects of parasite development, have been catalogued. For example, trimethylation of histone H3 at lysine 4 (H3K4me3) denotes transcriptionally active genes [5], including the single active var gene. In contrast, H3K9me3 marks the 59 silent var genes [6,7]. Interestingly, H3K9me3 and another mark, H3K36me3, are very limited in their distribution throughout the genome and are found primarily at gene families that encode variant antigens like var [5,8]. How the enzymes that deposit these marks are recruited to very limited regions of the genome is poorly understood. This short review aims to expand on recent work that sheds light on the recruitment of histone modifiers to narrow regions of chromosomes, specifically var genes, by way of the C-terminal domain of RNA polymerase II (RNA pol II CTD).