High-resolution map of the Plasmodium falciparum genome reveals MORC/ApiAP2-mediated links between distant,...

Genome organization plays an important role in silencing compacted, heterochromatinized genes in the most virulent human malaria parasite, Plasmodium falciparum. However, it remains unclear how these genes spatially cluster or whether active genes are also organized in a specific manner. We used Micro-C to achieve near-nucleosome resolution DNA-DNA contact maps, which revealed previously undescribed inter- and intrachromosomal heterochromatic and euchromatic structures in the blood-stage parasite. We observed subtelomeric fold structures that facilitate interactions among heterochromatinized genes involved in antigenic variation. In addition, we identified long-range intra- and interchromosomal interactions among active, stage-specific genes. Both structures are mediated by AP2-P, an ApiAP2 DNA-binding factor, and a putative MORC chromatin remodeler, and functional specificity is achieved via combinatorial binding with other sequence-specific DNA-binding factors. This study provides insight into the organizational machinery used by this medically important eukaryotic parasite to spatially coordinate genes underlying antigenic variation and to co-activate stage-specific genes.