title: Three-dimensional modeling of the P. falciparum genome during the erythrocytic cycle reveals a strong connection between genome architecture and gene expression.
abstract: The development of the human malaria parasite Plasmodium falciparum is controlled by coordinated changes in gene expression throughout its complex life cycle, but the corresponding regulatory mechanisms are incompletely understood. To study the relationship between genome architecture and gene regulation in Plasmodium, we assayed the genome architecture of P. falciparum at three time points during its erythrocytic (asexual) cycle. Using chromosome conformation capture coupled with next-generation sequencing technology (Hi-C), we obtained high-resolution chromosomal contact maps, which we then used to construct a consensus three-dimensional genome structure for each time point. We observed strong clustering of centromeres, telomeres, ribosomal DNA, and virulence genes, resulting in a complex architecture that cannot be explained by a simple volume exclusion model. Internal virulence gene clusters exhibit domain-like structures in contact maps, suggesting that they play an important role in the genome architecture. Midway during the erythrocytic cycle, at the highly transcriptionally active trophozoite stage, the genome adopts a more open chromatin structure with increased chromosomal intermingling. In addition, we observed reduced expression of genes located in spatial proximity to the repressive subtelomeric center, and colocalization of distinct groups of parasite-specific genes with coordinated expression profiles. Overall, our results are indicative of a strong association between the P. falciparum spatial genome organization and gene expression. Understanding the molecular processes involved in genome conformation dynamics could contribute to the discovery of novel antimalarial strategies.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors.forename: Ferhat
authors.initials: F
authors.lastname: Ay
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521, USA;
authors.forename: Evelien M
authors.initials: EM
authors.lastname: Bunnik
authors.affiliation: Centre for Computational Biology, Mines ParisTech, Fontainebleau F-77300, France; Institut Curie, Paris F-75248, France; U900, INSERM, Paris F-75248, France;
authors.forename: Nelle
authors.initials: N
authors.lastname: Varoquaux
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521, USA;
authors.forename: Sebastiaan M
authors.initials: SM
authors.lastname: Bol
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521, USA;
authors.forename: Jacques
authors.initials: J
authors.lastname: Prudhomme
authors.affiliation: Centre for Computational Biology, Mines ParisTech, Fontainebleau F-77300, France; Institut Curie, Paris F-75248, France; U900, INSERM, Paris F-75248, France;
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Vert
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; Department of Computer Science and Engineering, University of Washington, Seattle, Washington 98195, USA.
authors.forename: William Stafford
authors.initials: WS
authors.lastname: Noble
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521, USA;
authors.forename: Karine G
authors.initials: KG
authors.lastname: Le Roch
mesh_terms: D042002:Chromatin Assembly and Disassembly; D002875:Chromosomes / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018503:Genome, Protozoan; D008957:Models, Genetic; D010963:Plasmodium falciparum / Q000235:genetics* / Q000254:growth & development; D052939:Schizonts / Q000378:metabolism; D053058:Trophozoites / Q000378:metabolism