Expression of P. falciparum var Genes Involves Exchange of the Histone Variant H2A.Z at the Promoter

PLoS Pathogens

Stuart A. Ralph¹  Graham V. Brown²  Katja E. Boysen³  Michaela Petter³  Timothy J. Byrne³  Michael F. Duffy³  Chin Chin Lee³  Alan F. Cowman⁴  Jennifer Volz⁴ 

[1] Department of Biochemistry and Molecular Biology, Bio21 Molecular Sciences and Biotechnology Institute, University of Melbourne, Melbourne, Australia;Department of Medical Biology, University of Melbourne, Melbourne, Australia;Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia;The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

关键词: Histones;    Plasmodium;    Nucleosomes;    Chromatin;    Gene expression;    Gene regulation;    DNA transcription;    Introns;   

DOI  :  10.1371/journal.ppat.1001292

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Plasmodium falciparum employs antigenic variation to evade the human immune response by switching the expression of different variant surface antigens encoded by the var gene family. Epigenetic mechanisms including histone modifications and sub-nuclear compartmentalization contribute to transcriptional regulation in the malaria parasite, in particular to control antigenic variation. Another mechanism of epigenetic control is the exchange of canonical histones with alternative variants to generate functionally specialized chromatin domains. Here we demonstrate that the alternative histone PfH2A.Z is associated with the epigenetic regulation of var genes. In many eukaryotic organisms the histone variant H2A.Z mediates an open chromatin structure at promoters and facilitates diverse levels of regulation, including transcriptional activation. Throughout the asexual, intraerythrocytic lifecycle of P. falciparum we found that the P. falciparum ortholog of H2A.Z (PfH2A.Z) colocalizes with histone modifications that are characteristic of transcriptionally-permissive euchromatin, but not with markers of heterochromatin. Consistent with this finding, antibodies to PfH2A.Z co-precipitate the permissive modification H3K4me3. By chromatin-immunoprecipitation we show that PfH2A.Z is enriched in nucleosomes around the transcription start site (TSS) in both transcriptionally active and silent stage-specific genes. In var genes, however, PfH2A.Z is enriched at the TSS only during active transcription in ring stage parasites. Thus, in contrast to other genes, temporal var gene regulation involves histone variant exchange at promoter nucleosomes. Sir2 histone deacetylases are important for var gene silencing and their yeast ortholog antagonises H2A.Z function in subtelomeric yeast genes. In immature P. falciparum parasites lacking Sir2A or Sir2B high var transcription levels correlate with enrichment of PfH2A.Z at the TSS. As Sir2A knock out parasites mature the var genes are silenced, but PfH2A.Z remains enriched at the TSS of var genes; in contrast, PfH2A.Z is lost from the TSS of de-repressed var genes in mature Sir2B knock out parasites. This result indicates that PfH2A.Z occupancy at the active var promoter is antagonized by PfSir2A during the intraerythrocytic life cycle. We conclude that PfH2A.Z contributes to the nucleosome architecture at promoters and is regulated dynamically in active var genes.

【 授权许可】

CC BY