A critical role of the histone lysine demethylase JmjC1 in regulating severe malaria-associated virulence genes in Plasmodium falciparum.

Cerebral malaria involves the expression of a particular var subgroup, termed upsA, in Plasmodium falciparum, which encodes a subset of PfEMP1 variants that avidly bind to human receptors on endothelial cells, resulting in obstruction of microvasculature in the brain and severe pathogenesis. Despite the clinical importance of the upsA var genes, the mechanism of their low-frequency activation in asymptomatic or uncomplicated malaria cases remains poorly understood. Here, we identify a JmjC-domain-containing histone demethylase PfJmjC1 as a vital transcriptional silencer of upsA var genes, which may negatively regulate malaria pathogenesis. Genome-wide profiling reveals that PfJmjC1 localizes to heterochromatic loci including the entire var gene family, and interacts with canonical heterochromatin factors such as HP1 at the schizont stage. However, PfJmjC1 preferentially binds to the promoter regions of upsA var loci in ring-stage parasites in which non-upsA vars are activated. Genetic deletion or conditional knockdown of PfJmjC1 selectively derepresses upsA var and disrupts the var expression "counting" mechanism, accompanied by increased H3K4me3 and H3K9ac, as well as decreased H3K9me3 modification at upsA var loci. The altered PfEMP1 expression patterns and acquisition of multiple endothelial receptor-binding phenotypes are experimentally verified at the single-cell level. Additionally, Hi-C-seq and three-dimensional genome modeling show that PfJmjC1 deficiency reorganizes nuclear heterochromatin architecture, repositioning upsA var loci toward a euchromatic environment. Together, these findings not only uncover a mechanism controlling the transcriptional activity of severe malaria-associated virulence genes but also provide a potential therapeutic target against severe malaria.