A nuclear redox sensor modulates gene activation and switching in .

The virulence of , which causes the deadliest form of human malaria, is attributed to its ability to evade the human immune response. These parasites "choose" to express a single variant from a repertoire of surface antigens called PfEMP1, which are placed on the surface of the infected red cell. Immune evasion is achieved by switches in expression between genes, each encoding a different EMP1 variant. While the mechanisms that regulate mutually exclusive expression of genes are still elusive, antisense long-noncoding RNAs (lncRNAs) transcribed from the intron of the active gene were implicated in the "choice" of the single active gene. Here, we show that this lncRNA colocalizes with the site of mRNA transcription and is anchored to the locus via DNA:RNA interactions. We define the lncRNA interactome and identify a redox sensor, thioredoxin peroxidase I (TPx-1), as one of the proteins associated with the antisense lncRNA. We show that TPx-1 localizes to a nuclear subcompartment associated with active transcription on the nuclear periphery, in ring-stage parasite, when transcription occurs. In addition, TPx-1 colocalizes with S-adenosylmethionine synthetase (SAMS) in the nucleus, and its overexpression leads to activation of similar to overexpression of SAMS. Furthermore, we show that TPx-1 knockdown alters the switch rate as well as activation of additional gene subsets. Taken together, our data indicate that nuclear TPx-1 plays a role in gene activation possibly by providing a redox-controlled nuclear microenvironment ideal for active transcription.