<i>Pf</i>GCN5 is essential for <i>Plasmodium falciparum</i> survival and transmission and regulates Pf H2B.Z acetylation and chromatin structure
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.
Authors
- Danae Schulz (ORCID: https://orcid.org/0000-0002-0392-7245)
- Mauricio Grotz
- Tania F. de Koning‐Ward (ORCID: https://orcid.org/0000-0001-5810-8063)
- Hanh H. T. Nguyen (ORCID: https://orcid.org/0000-0001-8613-4103)
- C.D. Goodman (ORCID: https://orcid.org/0000-0002-8923-7594)
- Chunhao Yu (ORCID: https://orcid.org/0009-0008-3137-6736)
- Michaela Petter (ORCID: https://orcid.org/0000-0002-1837-2756)
- Fairley McPherson
- Karen P. Day (ORCID: https://orcid.org/0000-0002-6115-6135)
- Gabrielle A. Josling (ORCID: https://orcid.org/0000-0001-6411-7812)
- Geoffrey I. McFadden (ORCID: https://orcid.org/0000-0002-5351-1627)
- Lee M. Yeoh (ORCID: https://orcid.org/0000-0001-7872-762X)
- Michael F. Duffy (ORCID: https://orcid.org/0000-0001-5635-4033)
- Anton Cozijnsen (ORCID: https://orcid.org/0000-0002-2763-2927)
- Kapil Pareek (ORCID: https://orcid.org/0000-0001-7534-2804)
- Jingyi Tang (ORCID: https://orcid.org/0000-0001-5560-1223)
- Samuel A Hustadt
Institutions
- The Royal Melbourne Hospital (AU)
- Harvey Mudd College (US)
- Burnet Institute (AU)
- Deakin University (AU)
- The University of Melbourne (AU)
- Australian Government (AU)
- Universitätsklinikum Erlangen (DE)
- Peter Doherty Institute (AU)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2025-03-20
- DOI
- https://doi.org/10.1093/nar/gkaf218
- Citations
- 4
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 7.51
Funders
- National Science Foundation
- Deutsche Forschungsgemeinschaft
- Global Health Innovative Technology Fund
- Universities Australia
- National Health and Medical Research Council