PHF10

PHF10 (BAF45a) is a signature subunit of the PBAF SWI/SNF chromatin-remodeling complex that couples PBAF recruitment to transcriptional programs controlling proliferation, differentiation, and stress responses (PMID:24763304, PMID:35046892). It is expressed as evolutionarily conserved isoforms that are incorporated into PBAF in a mutually exclusive manner: one bears C-terminal tandem PHD fingers (DPF domain) and activates proliferation, the other replaces these with a phosphorylation-dependent SUMO-conjugation motif, and PBAF complexes carrying different isoforms bind shared promoters yet differ in their effects on Pol II recruitment and transcription (PMID:24763304). Isoform levels are set post-translationally by phosphorylation and regulated proteolysis: CK-1-dependent phosphorylation of an X-cluster of serines (organized as sequentially phosphorylated subclusters dependent on a primary Ser327 and the NLS3 element) stabilizes PHD-lacking isoforms, and the E3 ligase β-TrCP degrades PHF10 through non-canonical degrons whose phosphorylation paradoxically blocks degradation (PMID:28717195, PMID:31911482). PHF10 directs PBAF to target promoters via direct interaction with sequence-specific activators, augmenting MYC-dependent activation of cell-cycle genes, engaging E2F1 in a positive feedback loop that represses DUSP5 to elevate pERK1/2, and recruiting SMARCA2 to NRF2-binding regions to drive antioxidant transcription and ferroptosis resistance when Keap1 (which normally ubiquitinates and degrades PHF10) is lost (PMID:34465901, PMID:39127832, PMID:41197527). It also supports homologous-recombination repair of DNA double-strand breaks, its loss elevating γH2AX, RAD51, and 53BP1 foci and reducing repair efficiency (PMID:35033590). Physiologically, PHF10 is required cell-intrinsically for maintenance of long-term repopulating hematopoietic stem cells and for osteoblast/odontoblast differentiation and mineralization downstream of RUNX2 (PMID:27931852, PMID:35046892). PHF10 expression is itself constrained by repressive chromatin via EZH2-mediated H3K27me3, and PHF10 in turn cooperates with Setdb1 to deposit H3K9me3 and silence HMGB1, restraining NF-κB signaling (PMID:39904827).

1. 2010 Medium

   Established that PHF10 is functionally required for cell proliferation rather than being a passive complex subunit, by showing that both dominant-negative truncation and RNAi knockdown impair growth.

   Evidence Truncated cDNA overexpression and RNAi in human fibroblasts and cell lines with proliferation assays

   PMID:20068294

   Open questions at the time

   • Did not define the molecular target genes or PBAF-dependent mechanism
   • No isoform-resolved analysis
2. 2014 Medium

   Defined PHF10 as a PBAF-incorporated subunit existing as mutually exclusive DPF- versus PDSM-containing isoforms that confer distinct transcriptional outputs, explaining how a single gene tunes PBAF function.

   Evidence Molecular cloning, reciprocal Co-IP, promoter binding and Pol II recruitment assays, proliferation assays

   PMID:24763304

   Open questions at the time

   • Mechanism by which isoforms differentially affect Pol II not resolved
   • Endogenous promoter targets not genome-wide mapped
3. 2016 Low

   Showed that PHF10 isoforms are extensively phosphorylated while assembled in PBAF, in a cell-type-dependent manner, indicating signaling input onto the complex.

   Evidence Immunoprecipitation of PBAF and phosphorylation analysis across human cell types

   PMID:27239853

   Open questions at the time

   • Single method described without full detail in abstract
   • Kinases and functional consequences of phosphorylation not defined here
4. 2016 High

   Demonstrated a cell-intrinsic physiological requirement for PHF10 in maintaining long-term repopulating hematopoietic stem cells, distinguishing this role from a general proliferation effect.

   Evidence Conditional knockout mouse with mixed bone marrow chimeras and flow cytometry

   PMID:27931852

   Open questions at the time

   • Target genes mediating HSC maintenance not identified
   • Isoform contribution to HSC phenotype unaddressed
5. 2017 Medium

   Identified β-TrCP as the E3 ligase controlling PHF10 stability through non-canonical phospho-degrons, with the unusual feature that degron phosphorylation prevents degradation and stabilizes PHF10 and other PBAF core subunits.

   Evidence siRNA knockdown, half-life assays, phosphorylation analysis, molecular docking

   PMID:28717195

   Open questions at the time

   • Kinase generating the protective phosphorylation not pinned down here
   • Docking-based affinity claim not validated by direct binding measurement
6. 2019 Low

   Placed PHF10 downstream of MYC transcriptionally, showing c-MYC activates PHF10 expression and hinting at a regulatory circuit.

   Evidence Reporter assays and expression analysis with c-MYC manipulation in cell lines

   PMID:31012017

   Open questions at the time

   • Limited methodological detail in abstract
   • Direct promoter occupancy not shown
7. 2020 Medium

   Resolved the phospho-code controlling PHF10 isoform levels, defining an X-cluster of serines with sequential, Ser327-dependent subcluster phosphorylation and an NLS3 element that oppositely modulates stability of PHD-lacking versus PHD-containing isoforms.

   Evidence Phospho-site mapping, serine and NLS3 mutagenesis, stability assays

   PMID:31911482

   Open questions at the time

   • Responsible kinase(s) for each subcluster not all identified
   • Link between stability code and specific gene programs untested
8. 2021 Medium

   Showed PHF10 physically binds MYC and recruits PBAF to MYC target promoters to amplify cell-cycle gene activation, with depletion causing G1 arrest and senescence-like phenotype, mechanistically connecting PHF10 to oncogenic transcription.

   Evidence Co-IP, ChIP, siRNA knockdown, cell cycle analysis in melanoma cells

   PMID:34465901

   Open questions at the time

   • Isoform specificity of the MYC interaction not resolved
   • Single cancer-cell context
9. 2021 Low

   Revealed activity-dependent regulation of PHF10 in neurons, with nuclear-cytoplasmic shuttling upon LTP induction and physical interaction with c-FOS, extending PHF10 function to neuronal stimulus responses.

   Evidence Immunofluorescence, Co-IP, KCl-induced LTP in neuronal cultures

   PMID:34837706

   Open questions at the time

   • Downstream transcriptional consequence of the c-FOS interaction not demonstrated
   • Localization shuttling not mechanistically explained
10. 2022 Medium

    Connected PHF10 to genome stability and its translational control, showing ZC3H13/YTHDF1 m6A-dependent translation of PHF10 mRNA and that PHF10 is required for efficient homologous-recombination repair of DSBs.

    Evidence m6A assays, siRNA knockdown, γH2AX/RAD51/53BP1 foci and HR repair assays in pancreatic cancer cells

    PMID:35033590

    Open questions at the time

    • Whether PHF10 acts at break sites via PBAF chromatin remodeling not directly shown
    • Isoform dependence of the HR role unknown
11. 2022 Medium

    Established PHF10 as a PBAF-specific subunit driving differentiation, demonstrating that BAF45A activates osteoblast/odontoblast maturation genes downstream of RUNX2 and that its loss reduces chromatin accessibility and mineralization in vivo.

    Evidence ChIP-seq, ATAC-seq, shRNA, overexpression, craniofacial conditional KO mouse

    PMID:35046892

    Open questions at the time

    • Isoform usage during osteogenesis not dissected
    • Direct PBAF-RUNX2 physical contact at target loci not fully mapped
12. 2024 Medium

    Defined an E2F1-PHF10-DUSP5-pERK1/2 feedback axis whereby PHF10 represses DUSP5 via SWI/SNF assembly to sustain ERK signaling, promoting stemness and inhibiting differentiation in gastric cancer.

    Evidence ChIP, Co-IP, siRNA knockdown and rescue, pERK1/2 Western blot

    PMID:39127832

    Open questions at the time

    • Mechanism of PHF10-mediated repression at DUSP5 not detailed
    • Generality beyond gastric cancer unknown
13. 2024 Low

    Linked PHF10 isoform switching to lineage commitment, showing the DPF-lacking isoform replaces the DPF-containing isoform in PBAF during neuronal and muscle differentiation.

    Evidence RT-PCR and Western blot of isoform expression during in vitro differentiation

    PMID:38189889

    Open questions at the time

    • Observation is correlative without functional perturbation
    • Target-gene consequences of the switch untested
14. 2025 Medium

    Identified Keap1 as a degrader of PHF10 and placed PHF10 in NRF2-driven antioxidant transcription, showing Keap1-mutant accumulation of PHF10 recruits SMARCA2 to NRF2 regions and confers ferroptosis resistance.

    Evidence TAP-MS, Co-IP, ubiquitination assays, ATAC-seq, xenograft models in NSCLC

    PMID:41197527

    Open questions at the time

    • Isoform involved in NRF2 cooperation not defined
    • Relationship between Keap1- and β-TrCP-mediated degradation not reconciled
15. 2025 Medium

    Showed PHF10 expression is epigenetically restrained by EZH2/H3K27me3 and that PHF10 in turn enforces H3K9me3 with Setdb1 at HMGB1 to suppress NF-κB signaling, embedding PHF10 in a repressive chromatin network in cholangiocarcinoma.

    Evidence ChIP for histone marks, transcriptome, siRNA/CRISPR KO, in vitro and in vivo assays

    PMID:39904827

    Open questions at the time

    • How a PBAF subunit directs H3K9me3 deposition mechanistically is unclear
    • Direct PHF10-Setdb1 contact not structurally defined

• How the distinct phospho-states, isoform identities, and competing degradation pathways (β-TrCP versus Keap1) are integrated to select specific PBAF target programs across tissues remains unresolved.
• No unified model linking isoform/phospho state to genome-wide target selection
• Structural basis of PHF10 isoform incorporation into PBAF not determined
• Reconciliation of opposing stabilizing/destabilizing inputs lacking