Singh Parul, Serizay Jacques, Couble Justine, Cabahug Maureen D, Rosa Catarina, Chen Patty, Scherf Artur, Koszul Romain, Baumgarten Sebastian, Bryant Jessica M
Institut Pasteur, Université Paris Cité, INSERM U1201, CNRS EMR9195, Biology of Host-Parasite Interactions Unit, Paris, France.
Institut Pasteur, Université Paris Cité, CNRS UMR 3525, Unité Régulation Spatiale des Génomes, Paris, France.
Nat Microbiol. 2025 Jul;10(7):1665-1683. doi: 10.1038/s41564-025-02038-z. Epub 2025 Jun 30.
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.
基因组组织在使最具毒性的人类疟原虫——恶性疟原虫中紧密压缩、异染色质化的基因沉默方面发挥着重要作用。然而，这些基因如何在空间上聚集，或者活跃基因是否也以特定方式组织，仍不清楚。我们使用Micro-C技术获得了近核小体分辨率的DNA-DNA接触图谱，该图谱揭示了血液阶段疟原虫中以前未描述的染色体间和染色体内的异染色质和常染色质结构。我们观察到亚端粒折叠结构，其促进了参与抗原变异的异染色质化基因之间的相互作用。此外，我们还鉴定了活跃的阶段特异性基因之间的长距离染色体内和染色体间相互作用。这两种结构均由一种ApiAP2 DNA结合因子AP2-P和一种假定的MORC染色质重塑因子介导，并且通过与其他序列特异性DNA结合因子的组合结合实现功能特异性。本研究深入了解了这种医学上重要的真核寄生虫用于在空间上协调抗原变异相关基因并共同激活阶段特异性基因的组织机制。
