Molecular basis for bipartite recognition of histone H3 by the PZP domain of PHF14

Abstract

Histone recognition constitutes a key epigenetic mechanism in gene regulation and cell fate decision. PHF14 is a conserved multi-PHD finger protein that has been implicated in organ development, tissue homeostasis, and tumorigenesis. Here we show that PHF14 reads unmodified histone H3(1–34) through an integrated PHD1-ZnK-PHD2 cassette (PHF14PZP). Our binding, structural and HDX-MS analyses revealed a feature of bipartite recognition, in which PHF14PZP utilizes two distinct surfaces for concurrent yet separable engagement of segments H3-Nter (e.g. 1–15) and H3-middle (e.g. 14–34) of H3(1–34). Structural studies revealed a novel histone H3 binding mode by PHD1 of PHF14PZP, in which a PHF14-unique insertion loop but not the core β-strands of a PHD finger dominates H3K4 readout. Binding studies showed that H3-PHF14PZP engagement is sensitive to modifications occurring to H3 R2, T3, K4, R8 and K23 but not K9 and K27, suggesting multiple layers of modification switch. Collectively, our work calls attention to PHF14 as a ‘ground’ state (unmodified) H3(1–34) reader that can be negatively regulated by active marks, thus providing molecular insights into a repressive function of PHF14 and its derepression.

The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways

“…Early mass spectrometry analysis of proteins associated with nucleosomes whose histones presented specific posttranslational modifications demonstrated that PHF14 and HMG20A were among the few proteins excluded from nucleosomes containing the H3K4me3 modification, but associated with H3K4-unmodified nucleosomes ( 59 , 60 ). This is consistent with very recent structural studies demonstrating that a module of PHF14, denoted as the PZP domain (formed by the first PHD and the ePHD domains), reads unmodified histone H3 ( 18 ). Co-purification of PHF14 with nucleosomes containing H2AX ( 61 ), H2A.Z ( 57 , 62–64 ) or macroH2A ( 65 ) has also been reported.…”

“…The mechanism by which the PHF14/HMG20A complex helps to activate the YAP/TAZ-TEAD targets is unknown. Indeed, as discussed above, the histone binding preferences of PHF14 suggest that the PHF14/HMG20A complex might be associated with poised regions ( 18 ). It is commonly accepted that TEAD factors bind to their DNA targets regardless of the presence or absence of YAP/TAZ coactivators—and therefore also under non-activation conditions ( 48 , 49 , 85 ).…”

“…Zheng et al. have shown that the PZP module (PHD1 + ePHD) of PHF14 binds unmodified histone H3, and that this interaction is abolished by some active histone marks, such as H3K4me3, H3K18ac and H3K23ac, but not by repressive marks, such as H3K9me3 and H3K27me3 ( 18 ). Further, they have proposed that PHF14 may associate to a chromatin ‘ground state’ that defines a repressive or poised state.…”

Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders

“…It is possible that patients who manifest phenotypes upon LoF of one PHF14 allele express slightly less PHF14 protein from their WT allele in the brain than those who do not manifest disease. Moreover, putative PHF14 orthologs, such as BRPF1 that also harbors a tandem PHD finger (PZP) domain ( 70 ), could functionally compensate for the loss of PHF14 in mice and humans. In fact, mutations in BRPF1 , including a missense mutation within the PZP domain, also cause syndromic intellectual disability ( 71 ).…”

Comprehensive analysis of histone methylation modification regulators for predicting prognosis and drug sensitivity in lung adenocarcinoma

“…However, the histone methylation-specific recognition sites of PHF14 have remained indeterminate in the past few years. Recently, a study conducted by Zheng et al revealed that PHF14 was able to recognize H3K4me3 and H3R8me2a to exert its repressive functions ( Zheng et al, 2021 ). In colorectal cancer, downregulation of PHF14 could reduce carcinogenesis, and our study also indicated that PHF14 was enriched in tumor samples and was associated with poor prognosis, while the molecular mechanisms were not clear.…”