PHF10

PHF10/BAF45a is a dedicated subunit of the PBAF chromatin remodeling complex that exists as four mutually exclusive isoforms — distinguished by the presence or absence of tandem PHD fingers — whose differential incorporation into PBAF modulates Pol II recruitment, gene transcription, and chromatin accessibility at target loci (PMID:24763304, PMID:35046892). PHF10 is recruited to specific gene promoters through direct interaction with transcriptional activators MYC, c-FOS, and NRF2, thereby coupling PBAF remodeling activity to proliferation, neuronal plasticity, anti-oxidative stress, and osteoblast differentiation programs (PMID:34465901, PMID:34837706, PMID:41197527, PMID:35046892). PHF10 protein levels are tightly controlled by two E3 ubiquitin ligase pathways — β-TrCP and Keap1 — whose activities are modulated by CK-1–dependent phosphorylation and cancer-associated mutations, respectively, and by isoform-specific phosphorylation cascades that govern nuclear import and PBAF incorporation rates (PMID:28717195, PMID:41197527, PMID:31911482). PHF10 also functions in DNA damage responses, where its loss reduces homologous recombination repair efficiency, and is essential for hematopoietic stem cell maintenance in vivo (PMID:35033590, PMID:27931852).

1. 2010 Medium

   Establishing that PHF10 is required for cell proliferation addressed the basic question of whether this PBAF subunit has a non-redundant cellular function.

   Evidence RNAi knockdown and dominant-negative overexpression in human fibroblasts with proliferation readouts

   PMID:20068294

   Open questions at the time

   • Mechanism by which PHF10 promotes proliferation was not defined
   • Whether the proliferation role is PBAF-dependent was not tested
2. 2014 High

   Discovery that PHF10 encodes mutually exclusive isoforms (PHD-containing vs. PDSM-containing) that are differentially incorporated into PBAF resolved how a single gene diversifies PBAF function, showing that isoform identity determines Pol II recruitment and transcriptional output at shared target promoters.

   Evidence Biochemical fractionation, Co-IP, promoter binding assays, and proliferation assays

   PMID:24763304

   Open questions at the time

   • Identity of downstream gene targets differentially regulated by each isoform class was not comprehensively mapped
   • Structural basis for mutually exclusive incorporation unknown
3. 2016 High

   Two advances defined PHF10's in vivo importance and post-translational regulation: conditional knockout revealed PHF10 is essential for adult HSC maintenance and myeloid development, while phosphorylation profiling showed all four isoforms are extensively and cell-type-dependently phosphorylated within PBAF.

   Evidence Conditional KO mouse with bone marrow chimera transplantation (HSC); phosphorylation analysis of PBAF-associated PHF10 across cell lines

   PMID:27239853 PMID:27931852

   Open questions at the time

   • Kinases responsible for cell-type-specific phosphorylation were not identified
   • Whether HSC loss reflects impaired self-renewal, survival, or differentiation was not resolved
4. 2017 High

   Identification of β-TrCP as a degradation-promoting E3 ligase for PHF10, operating through non-canonical degrons where CK-1 phosphorylation paradoxically stabilizes the protein, revealed a previously unknown proteostatic control mechanism for the entire PBAF complex.

   Evidence β-TrCP knockdown, half-life measurements, molecular docking, phosphorylation assays

   PMID:28717195

   Open questions at the time

   • Whether β-TrCP targets PHF10 for degradation within or outside the assembled PBAF complex was not determined
   • Physiological signals that toggle CK-1 activity toward PHF10 were not identified
5. 2020 High

   Dissection of the X-cluster phosphorylation hierarchy — where serine 327 acts as a gatekeeper for a secondary phosphorylation cascade and an embedded NLS differentially affects stability of PHD-containing vs. PHD-lacking isoforms — explained how phosphorylation quantitatively controls isoform-specific PBAF incorporation rates.

   Evidence Site-directed mutagenesis, stability assays, NLS deletion constructs, localization imaging

   PMID:31911482

   Open questions at the time

   • Identity of the kinase(s) phosphorylating serine 327 unknown
   • Downstream transcriptional consequences of altered isoform incorporation rates not measured
6. 2021 High

   Two studies connected PHF10 to specific transcription factor partnerships: PHF10 physically interacts with MYC to recruit PBAF to cell-cycle gene promoters (with PHF10 depletion causing G1 arrest and senescence), and PHF10 interacts with c-FOS during LTP induction, dynamically shuttling between nucleus and cytoplasm to participate in secondary response gene activation.

   Evidence Co-IP and ChIP for MYC–PHF10–PBAF at promoters with cell cycle/senescence readouts; Co-IP and live-cell imaging of PHF10–c-FOS translocation in neuronal cultures

   PMID:34465901 PMID:34837706

   Open questions at the time

   • Whether PHF10–c-FOS interaction is direct or bridged by other PBAF subunits was not resolved
   • Genome-wide targets of the PHF10–MYC module beyond candidate genes not mapped
   • c-FOS interaction confirmed only by Co-IP without reciprocal validation
7. 2022 High

   Two studies expanded PHF10's functional repertoire to DNA repair and skeletal differentiation: PHF10 loss reduced HR repair efficiency at DSBs (with its mRNA translation controlled by ZC3H13-mediated m6A modification), and ATAC-seq/ChIP-seq in Baf45a-knockout osteoblasts showed PBAF-dependent chromatin accessibility at osteoblast-specific loci and ATF4/KLF4 binding sites.

   Evidence m6A/translation assays plus γH2AX/RAD51/53BP1 immunofluorescence and HR reporter; ATAC-seq, ChIP-seq, overexpression, shRNA knockdown, and conditional KO in osteoblasts/odontoblasts

   PMID:35033590 PMID:35046892

   Open questions at the time

   • Whether PHF10 is recruited directly to DSB sites or acts indirectly through transcriptional regulation of repair factors not distinguished
   • RUNX2 crosstalk with PBAF inferred from motif analysis, not validated by direct interaction
8. 2024 Medium

   PHF10 was placed in a positive feedback loop with E2F1 and shown to repress DUSP5 via SWI/SNF, sustaining pERK1/2 signaling that impedes gastric epithelium differentiation and promotes stemness, while isoform switching during neuronal and muscle differentiation was documented.

   Evidence ChIP at DUSP5 promoter, rescue with DUSP5 overexpression, pERK readout; isoform expression analysis during differentiation

   PMID:38189889 PMID:39127832

   Open questions at the time

   • Functional consequence of the DPF-to-non-DPF isoform switch during differentiation lacks direct validation
   • DUSP5 repression mechanism (direct remodeling vs. indirect) not fully resolved
9. 2025 High

   Two studies defined PHF10 as an integration node in epigenetic repression and stress signaling: Keap1 was identified as a second E3 ligase that polyubiquitinates PHF10, with cancer-associated Keap1 mutations causing PHF10 accumulation that, through NRF2 interaction, opens chromatin at NRF2 targets and confers ferroptosis resistance; separately, PHF10 coordinates with Setdb1 to deposit H3K9me3 at the HMGB1 promoter, repressing HMGB1 in an axis governed by EZH2-mediated H3K27me3 at the PHF10 promoter itself.

   Evidence TAP-MS, Co-IP, ubiquitination assays, ATAC-seq, xenograft models (Keap1); ChIP for H3K9me3/H3K27me3, KO cells, in vivo tumor models (Setdb1–HMGB1 axis)

   PMID:39904827 PMID:41197527

   Open questions at the time

   • Whether Keap1 and β-TrCP pathways act on the same or different PHF10 isoforms is unknown
   • Direct vs. bridged nature of PHF10–Setdb1 interaction not determined
   • Whether PHF10–NRF2 interaction is independent of PBAF not tested

• A comprehensive understanding of how PHF10 isoform switching is regulated during differentiation, how its two degradation pathways are coordinated, and the structural basis for isoform-specific PBAF assembly remains unresolved.
• No high-resolution structure of PHF10 within the PBAF complex
• Signals that trigger isoform switching during differentiation uncharacterized
• Relative contributions and cross-regulation of Keap1 and β-TrCP degradation pathways unknown
• Genome-wide mapping of isoform-specific PBAF occupancy not performed