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Abstract Plasmodium falciparum causes most malaria deaths. Its developmental transitions and environmental adaptation are partially regulated by epigenetic mechanisms. Plasmodium falciparum GCN5 (PfGCN5) is an epigenetic regulator that acetylates lysines and can also bind to acetylated lysine residues on histones via its bromodomain (BRD). Here, we showed that PfGCN5 was essential for parasite transmission and survival in human blood and mosquitoes. PfGCN5 regulated genes important for metabolism and development and its BRD was required at euchromatic gene promoters for their proper expression and for acetylation of the variant histone Pf H2B.Z. However, PfGCN5 was most abundant in heterochromatin and loss of the PfGCN5 BRD de-repressed heterochromatic genes and increased levels of acetylated Pf H2B.Z in heterochromatin. The PfGCN5 BRD-binding compound L-45 phenocopied deletion of the PfGCN5 BRD, identifying PfGCN5 as a promising drug target for BRD inhibitors. Thus, PfGCN5 appears to directly contribute to activating euchromatic promoters, but PfGCN5 is also critical for maintaining repressive heterochromatin structure. 

ABSTRACT ThePlasmodium falciparumalternative histones Pf H2A.Z and Pf H2B.Z are enriched in the same nucleosomes in intergenic euchromatin but depleted from heterochromatin. They occupy most promoters but are only dynamically associated with expression atvargenes. In other organisms, acetylation of H2A.Z is important for its functions in gene expression and chromatin structure. Here, we show that acetylated Pf H2A.Z and Pf H2B.Z are dynamically associated with gene expression at promoters. In addition, acetylated Pf H2A.Z and Pf H2B.Z are antagonized by the sirtuin class III histone deacetylases (HDAC) PfSir2A and B at heterochromatin boundaries and encroach upon heterochromatin in parasites lacking PfSir2A or B. However, the majority of acetylated Pf H2A.Z and Pf H2B.Z are deacetylated by class I or II HDACs. Acetylated Pf H2A.Z and Pf H2B.Z are also dynamically associated with promoter activity of both canonical upstreamvargene promoters andvargene introns. These findings suggest that both acetylated Pf H2A.Z and Pf H2B.Z play critical roles in gene expression and contribute to maintenance of chromatin structure at the boundaries of subtelomeric, facultative heterochromatin, critical for the variegated expression of genes that enable rapid adaptation to altered host environments. IMPORTANCEThe malaria parasitePlasmodium falciparumrelies on variant expression of members of multi-gene families as a strategy for environmental adaptation to promote parasite survival and pathogenesis. These genes are located in transcriptionally silenced DNA regions. A limited number of these genes escape gene silencing, and switching between them confers variant fitness on parasite progeny. Here, we show that PfSir2 histone deacetylases antagonize DNA-interacting acetylated alternative histones at the boundaries between active and silent DNA. This finding implicates acetylated alternative histones in the mechanism regulatingP. falciparumvariant gene silencing and thus malaria pathogenesis. This work also revealed that acetylation of alternative histones at promoters is dynamically associated with promoter activity across the genome, implicating acetylation of alternative histones in gene regulation genome wide. Understanding mechanisms of gene regulation inP. falciparummay aid in the development of new therapeutic strategies for malaria, which killed 619,000 people in 2021.