PHD1

PHD1 (PF3D7_1008100) is a PHD-finger chromatin reader that functions within a divergent PfGCN5 histone acetyltransferase complex to co-activate erythrocyte invasion and virulence gene programs in Plasmodium falciparum (PMID:31728527, PMID:34403450). Its PHD domain binds the active histone marks H3K4me2/3, positioning PHD1 to mediate crosstalk between H3K4 methylation and H3K9 acetylation (PMID:31728527). PHD1 is a subunit of a PfGCN5 acetyltransferase complex that also contains PfPHD2 and PfAP2-LT, and deletion of its PHD domain causes dramatic loss of H3K9 acetylation and H3K4 trimethylation together with global transcriptional dysregulation (PMID:34403450). These chromatin defects manifest phenotypically as reduced merozoite invasion of erythrocytes, elevated sexual conversion, and disruption of mutually exclusive var gene expression, establishing PHD1 as a link between active chromatin marks and the invasion and virulence transcriptional programs (PMID:34403450). Beyond these findings, no further mechanistic detail for PF3D7_1008100 has been characterized in the available corpus.

1. 2019 Medium

   To determine what chromatin signal PHD1 recognizes, it was tested as a candidate histone mark reader, establishing that its PHD domain engages active H3K4me2/3 and may bridge to H3K9 acetylation.

   Evidence Histone peptide pull-down with quantitative proteomics in P. falciparum

   PMID:31728527

   Open questions at the time

   • Crosstalk between H3K4me2/3 and H3K9ac is inferred from binding, not shown by an orthogonal functional assay in this study
   • No structural basis for the PHD-mark interaction established
   • Direct binding affinity and specificity across the full mark repertoire not quantified
2. 2021 High

   To place PHD1 in a pathway and test its functional requirement, its complex membership and the consequences of losing its reader domain were resolved, establishing PHD1 as a PfGCN5-complex subunit needed for normal histone acetylation/methylation and for invasion, sexual conversion suppression, and var gene control.

   Evidence Interaction proteomics identifying PfPHD2 and PfAP2-LT as complex subunits, plus conditional deletion of the PHD1 PHD domain with invasion assays, ChIP for H3K9ac/H3K4me3, and transcriptomics in P. falciparum

   PMID:34403450

   Open questions at the time

   • Whether the H3K4me2/3 reading activity is directly responsible for complex recruitment to target loci is not shown mechanistically
   • The contribution of PHD1 beyond its PHD domain (full-gene knockout vs domain deletion) is not resolved
   • How loss of PHD1 mechanistically links reduced H3K9ac to specific invasion and var loci is not mapped

• How PHD1's mark-reading activity is mechanistically coupled to targeted PfGCN5 acetylation at specific invasion and virulence loci remains unresolved.
• No genome-wide occupancy map of PHD1 itself
• No structural model of the PHD domain bound to H3K4me2/3
• Individual roles of PfPHD2 and PfAP2-LT relative to PHD1 within the complex not dissected