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Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):3177-3182. doi: 10.1073/pnas.1811766116. Epub 2019 Feb 6.

DNA helicase RecQ1 regulates mutually exclusive expression of virulence genes in Plasmodium falciparum via heterochromatin alteration.

Author information

1
Unit of Human Parasite Molecular and Cell Biology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, People's Republic of China.
2
School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, People's Republic of China.
3
Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612.
4
Unit of Human Parasite Molecular and Cell Biology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, People's Republic of China; zhhuang@ips.ac.cn xydai@ips.ac.cn lbjiang@ips.ac.cn.

Abstract

The Plasmodium falciparum var gene family encodes ∼60 surface antigens by which parasites escape the host immune responses via clonal expression of var genes. However, the mechanism controlling this mutual exclusivity, associated with alterations in chromatin assembly, is not understood. Here, we determined how expression of the var gene family is regulated by two RecQ DNA helicase family members, PfRecQ1 and PfWRN, in P. falciparum Through genetic manipulation, we found that the complete var repertoire was silenced on PfRecQ1 knockout, whereas their expression did not show noticeable changes when PfWRN was knocked out. More important, mutually exclusive expression of var genes could be rescued by complementation of PfRecQ1. In addition, knocking out either of these two helicase genes changed the perinuclear cluster distribution of subtelomeres and subtelomeric var genes. Whereas deletion of PfRecQ1 increased the heterochromatin mark trimethylated (H3K9me3) at the transcription start site (TSS) of the var gene upsC1, that deletion had no effect on the global distribution of H3K9me3 over gene bodies, including those for the var genes. ChIP-seq assay showed that PfRecQ1 was enriched globally at the TSSs of all genes, whereas PfWRN-enriched regions occurred at the gene bodies of the var gene family, but not of other genes or at TSSs of all genes. On PfRecQ1 deletion, the upsC1 var gene moved from the active perinuclear transcription region to a silenced region of the upsC type. These findings imply that PfRecQ1, but not PfWRN, is essential for maintaining the clonal expression of var genes.

KEYWORDS:

DNA helicases; Plasmodium falciparum; heterochromatin; mutually exclusive expression; virulence gene

PMID:
30728298
DOI:
10.1073/pnas.1811766116

Conflict of interest statement

The authors declare no conflict of interest.

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