GCN5 Is a Master Regulator of Gene Expression in the Malaria Parasite <i>Plasmodium falciparum</i>
GCN5-containing SAGA complex is evolutionarily conserved across yeast, plants, and humans and acts as a general transcription coactivator in the genome-wide regulation of genes. In <i>Plasmodium falciparum</i>, PfGCN5 forms a divergent complex, and the mis-localization of this complex by...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
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| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/12/876 |
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| Summary: | GCN5-containing SAGA complex is evolutionarily conserved across yeast, plants, and humans and acts as a general transcription coactivator in the genome-wide regulation of genes. In <i>Plasmodium falciparum</i>, PfGCN5 forms a divergent complex, and the mis-localization of this complex by deleting the PfGCN5 bromodomain (ΔBrd) causes a plethora of growth defects. To directly test the PfGCN5 function, we performed conditional knockdown (KD) of <i>PfGCN5</i>. Whereas <i>PfGCN5</i> KD phenotypically recapitulated the ΔBrd growth defects, it caused fewer transcriptional alterations compared to ΔBrd. To decipher the mechanism by which PfGCN5 regulates gene expression, we applied a new chromatin landscape analysis tool, CUT&Tag-seq, to map the chromatin localization of PfGCN5 and its deposited histone mark H3K9ac. Compared to ChIP-seq, CUT&Tag-seq identified substantially more H3K9ac peaks in the promoters of its target genes, with the peak intensity positively correlated with the levels of gene expression. CUT&Tag-seq analysis was remarkably more sensitive in mapping chromatin positions of PfGCN5, which colocalized with H3K9ac. The genes enriched with PfGCN5/H3K9ac signals at their promoters are involved in broad biological processes. Notably, PfGCN5′s positions overlapped with sequence motifs recognized by multiple apetela2 (AP2)-domain-containing transcription factors (AP2 TFs), suggesting that they recruited PfGCN5 to these promoters. Additionally, PfGCN5 was also colocalized with AP2-LT, further validating that AP2-LT is an integral component of the PfGCN5 complex. Collectively, these findings establish PfGCN5 as a master gene regulator in controlling general and parasite-specific cellular processes in this low-branching parasitic protist. |
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| ISSN: | 2073-4409 |