Micro-C reveals MORC/ApiAP2-mediated links between distant, functionally related genes in the human malaria parasite

Genome organization plays a significant role in silencing heterochromatinized genes in the most virulent human malaria parasite, Plasmodium falciparum. However, it remains unclear how heterochromatinized genes spatially cluster or if active genes are also organized in a specific manner. We used Micro-C to achieve a near-nucleosome resolution DNA-DNA contact map, which revealed new inter- and intrachromosomal heterochromatic and euchromatic structures in the blood stage parasite. We observed subtelomeric fold structures that facilitate interactions amongst heterochromatinized genes involved in antigenic variation. In addition, we identified long-range intra- and interchromosomal interactions amongst active, stage-specific genes. Both structures are mediated by AP2-P, an ApiAP2 transcription 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 unprecedented 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.