Three-dimensional modeling of the P. falciparum genome during the erythrocytic cycle reveals a strong connection between genome architecture and gene expression
- Ferhat Ay1,7,
- Evelien M. Bunnik2,7,
- Nelle Varoquaux3,4,5,7,
- Sebastiaan M. Bol2,
- Jacques Prudhomme2,
- Jean-Philippe Vert3,4,5,
- William Stafford Noble1,6,8 and
- Karine G. Le Roch2,8
- 1Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
- 2Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521, USA;
- 3Centre for Computational Biology, Mines ParisTech, Fontainebleau F-77300, France;
- 4Institut Curie, Paris F-75248, France;
- 5U900, INSERM, Paris F-75248, France;
- 6Department of Computer Science and Engineering, University of Washington, Seattle, Washington 98195, USA
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↵7 These authors contributed equally to this work.
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.
Footnotes
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↵8 Corresponding authors
E-mail william-noble{at}uw.edu
E-mail karine.leroch{at}ucr.edu
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.169417.113.
- Received November 7, 2013.
- Accepted March 26, 2014.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
