Affinage

PHF14

PHD finger protein 14 · UniProt O94880

Length
948 aa
Mass
107.0 kDa
Annotated
2026-06-10
19 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PHF14 is a nuclear multi-PHD-finger chromatin reader that couples recognition of unmodified histone H3 to transcriptional control of mesenchymal proliferation, fibrosis, and tumor progression (PMID:34365506, PMID:22730381). Structurally, it engages histone H3(1-34) through an integrated PHD1-ZnK-PHD2 (PZP) cassette that uses two surfaces for bipartite readout of the H3 N-terminus and middle region, with a PHF14-unique PHD1 insertion loop dominating H3K4 sensing; active marks at H3R2, T3, K4, R8, and K23 negatively regulate engagement, so PHF14 preferentially reads chromatin lacking these modifications (PMID:34365506). A central transcriptional output is direct repression of PDGFRα: Phf14-null mice over-express PDGFRα and develop mesenchymal hyperplasia and lethal lung fibrosis rescuable by anti-PDGFRα antibody, and loss of PHF14 elevates PDGFRα across renal and neural tumor contexts (PMID:22730381, PMID:36359362). This activity is embedded in TGF-β signaling, where phospho-SMAD3 induces PHF14 to form a self-limiting feedback loop restraining PDGF signaling (PMID:28045076), while in lung adenocarcinoma PHF14 recruits the DNA methyltransferase DNMT3B to silence the TGF-β antagonist SMAD7 by CpG hypermethylation (PMID:37072414). PHF14 further acts through stable assembly with HMG20A via a coiled-coil interface, and this complex contacts TEAD1 to modulate Hippo signaling and TGF-β-driven epithelial-to-mesenchymal transition (PMID:36124662), and it is a component of a KMT2A-associated PHF5A-PHF14-HMG20A-RAI1 subcomplex in cancer stem cells (PMID:37709746). Beyond transcription, PHF14 contributes to cell-cycle control by modulating H3K4me3 and repressing the cyclin-dependent kinase inhibitor Cdkn1a/p21 in germinal-center B cells (PMID:33035772), and supports the DNA damage response through interaction with KIF4A and BRCA2/RAD51 foci formation (PMID:35074497).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2012 High

    Established PHF14's first in vivo function by showing it is a transcriptional repressor of PDGFRα required to restrain mesenchymal proliferation, answering whether PHF14 has a defined physiological role.

    Evidence Phf14-null mice with histology, expression assays, and anti-PDGFRα antibody rescue of lung fibrosis

    PMID:22730381

    Open questions at the time
    • Did not define how PHF14 binds the PDGFRα locus or whether repression is direct at the chromatin level
    • No structural basis for transcription factor activity
  2. 2013 Medium

    Localized PHF14 to the nucleus and linked its histone engagement to PHD fingers, framing it as a chromatin-associated reader during cell division.

    Evidence Molecular cloning, co-IP histone binding, nuclear and chromatin-binding assays of PHF14α isoform

    PMID:23688586

    Open questions at the time
    • Single Co-IP without modification-state resolution
    • Histone target specificity undefined
  3. 2017 Medium

    Placed PHF14 within an upstream signaling circuit by showing phospho-SMAD3 induces PHF14, which then represses PDGFRα, defining a TGF-β/SMAD3/PHF14 self-limiting feedback loop in fibrosis.

    Evidence ChIP, TGF-β stimulation of renal fibroblasts, and PHF14-null injury model

    PMID:28045076

    Open questions at the time
    • Single lab
    • Did not resolve direct PHF14 binding at the PDGFRα promoter versus indirect regulation
  4. 2019 Low

    Connected PHF14 to cell-cycle and growth signaling under stress by linking its hypoxic inhibition to elevated CDK inhibitors and reduced AKT-mTOR signaling.

    Evidence Pulsed-SILAC proteomics and biochemical assays in a PHF14-knockdown xenograft

    PMID:31040906

    Open questions at the time
    • Limited mechanistic depth, no direct target identified
    • Correlative association between hypoxia and PHF14 activity
  5. 2020 Medium

    Defined a chromatin-modification mechanism for proliferation control by showing PHF14 modulates H3K4me3 at Cdkn1a to repress p21 in germinal-center B cells.

    Evidence GC B cell-specific knockout mice with H3K4me3 ChIP, flow cytometry, and qRT-PCR

    PMID:33035772

    Open questions at the time
    • Mechanism connecting PHF14 to H3K4me3 deposition/removal unresolved
    • Single lab
  6. 2021 High

    Provided the structural basis for PHF14 as a reader of unmodified H3, showing bipartite recognition via a PZP cassette and negative regulation by active histone marks.

    Evidence X-ray crystallography, HDX-MS, and binding assays of the PHF14 PZP-H3 complex

    PMID:34365506

    Open questions at the time
    • Did not connect the structural readout to specific gene-regulatory outcomes in cells
    • In vivo chromatin targets of the PZP domain not mapped
  7. 2022 Medium

    Showed PHF14 assembles with HMG20A through a coiled-coil and engages TEAD1, integrating PHF14 into Hippo signaling and EMT control.

    Evidence Proteomics, deletion analysis, AlphaFold2 modeling, siRNA knockdown, transcriptomics, and TEAD1 interaction assay

    PMID:36124662

    Open questions at the time
    • Structural model from AlphaFold2 not experimentally solved
    • Direct versus indirect TEAD1 contact not fully resolved
  8. 2022 Medium

    Extended PHF14 function beyond transcription by linking it to the DNA damage response via KIF4A interaction and BRCA2/RAD51 foci formation, with loss activating ATR-CHK1-γH2A.X-driven apoptosis.

    Evidence siRNA knockdown, PHF14-KIF4A Co-IP, BRCA2/RAD51 immunofluorescence, pathway western blots, and xenograft in colorectal cancer

    PMID:35074497

    Open questions at the time
    • Single Co-IP for KIF4A interaction
    • Mechanism of PHF14 recruitment to damage foci undefined
  9. 2022 Medium

    Generalized the PHF14-PDGFRα repressive axis to neural tumors and demonstrated rescue, reinforcing PDGFRα as a conserved PHF14 target.

    Evidence shRNA, CRISPR/Cas9 knockout, Sunitinib treatment, xenograft, and WT PHF14 rescue in neurocytoma primary cultures

    PMID:36359362

    Open questions at the time
    • Direct chromatin binding at PDGFRα not shown in this system
    • Single lab
  10. 2023 Medium

    Revealed a DNA-methylation-based repressive mechanism by showing PHF14 recruits DNMT3B to hypermethylate and silence SMAD7, promoting TGF-β-driven metastasis.

    Evidence Reciprocal Co-IP, ChIP, DNA methylation analysis, and in vitro/in vivo metastasis assays in lung adenocarcinoma

    PMID:37072414

    Open questions at the time
    • How PHF14 reads CpG motifs structurally not resolved
    • Single lab
  11. 2023 Medium

    Identified PHF14 as a stable subunit of a KMT2A-associated PHF5A-PHF14-HMG20A-RAI1 subcomplex supporting cancer stem cell self-renewal.

    Evidence Proteomics, Co-IP, KMT2A-WDR5 inhibitor treatment, and in vivo tumorigenicity in pancreatic cancer stem cells

    PMID:37709746

    Open questions at the time
    • Functional contribution of PHF14 within the subcomplex not isolated
    • Stoichiometry and assembly order undefined
  12. 2024 Medium

    Defined an upstream transcriptional activator of PHF14 by showing SP4 binds and activates the PHF14 promoter in esophageal squamous cell carcinoma.

    Evidence ChIP, luciferase reporter assays, and knockdown/overexpression with Wnt/β-catenin analysis

    PMID:37768180

    Open questions at the time
    • How SP4-driven PHF14 levels feed into chromatin or PDGFRα programs unresolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the structurally defined unmodified-H3 reader activity is mechanistically connected to PHF14's diverse gene-regulatory and DNA-repair outputs in vivo.
  • No genome-wide map tying PZP histone recognition to regulated loci
  • Whether PHF14 acts as activator or repressor is context-dependent without a unifying mechanism
  • Interplay between transcriptional and DNA-repair roles uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 2 GO:0140110 transcription regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0005694 chromosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-4839726 Chromatin organization 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
DNMT3BHMG20AKIF4AKMT2APHF5ARAI1SMAD3TEAD1
Complex memberships
PHF14-HMG20A complexPHF5A-PHF14-HMG20A-RAI1 (KMT2A-associated) subcomplex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 PHF14 reads unmodified histone H3(1-34) through an integrated PHD1-ZnK-PHD2 cassette (PZP domain), utilizing two distinct surfaces for bipartite recognition of H3-Nter (residues 1-15) and H3-middle (residues 14-34) segments. A PHF14-unique insertion loop in PHD1 dominates H3K4 readout rather than the core β-strands. Binding is sensitive to modifications at H3 R2, T3, K4, R8, and K23 but not K9 or K27, indicating active marks negatively regulate PHF14 engagement. X-ray crystallography, HDX-MS, binding assays, structural analysis of PHF14PZP-H3 complex Nucleic acids research High 34365506
2012 Phf14 acts as a transcription factor that directly represses PDGFRα expression in mesenchymal cells. Phf14-null mice show elevated PDGFRα expression and increased mesenchymal cell proliferation, leading to interstitial hyperplasia and neonatal lethality from respiratory failure. Anti-PDGFRα antibody treatment rescued mouse lung fibrosis in this model. Gene-targeting knockout (Phf14-null mice), histological analysis, gene expression assays, antibody rescue experiment The Journal of biological chemistry High 22730381
2013 PHF14α (the major isoform) localizes to the nucleus and binds chromatin during cell division. Co-immunoprecipitation showed PHF14α binds histones via its PHD fingers. Molecular cloning, co-immunoprecipitation, nuclear localization assay, chromatin-binding assay during cell division Acta biochimica et biophysica Sinica Medium 23688586
2017 In renal fibrosis, phospho-SMAD3 acts as a transcription factor that enhances PHF14 expression (ChIP assay). PHF14 in turn represses PDGFRα transcription to limit PDGF signaling overactivation, forming a TGF-β/SMAD3/PHF14 self-limiting feedback pathway in the renal pro-fibrotic process. Chromatin immunoprecipitation (ChIP), in vitro TGF-β stimulation of rat renal fibroblasts, PHF14-null mouse model with folic acid-induced injury Scientific reports Medium 28045076
2023 PHF14 binds DNMT3B and serves as a DNA CpG motif reader, recruiting DNMT3B to the SMAD7 gene locus, resulting in DNA hypermethylation and transcriptional suppression of SMAD7. This suppresses TGF-β pathway antagonism and promotes lung adenocarcinoma metastasis. Co-immunoprecipitation (PHF14-DNMT3B interaction), ChIP assay, in vitro and in vivo metastasis experiments, DNA methylation analysis Cell discovery Medium 37072414
2023 PHF14 is a physical component of a PHF5A-PHF14-HMG20A-RAI1 protein subcomplex associated with histone methyltransferase KMT2A (MLL1) via RNA polymerase-associated interactions in pancreatic cancer stem cells. Targeting KMT2A-WDR5 interaction attenuates cancer stem cell self-renewal. Proteomic analysis, co-immunoprecipitation, KMT2A-WDR5 inhibitor treatment in pancreatic cancer stem cells, in vivo tumorigenicity assay Nature communications Medium 37709746
2022 PHF14 forms a stable complex with HMG20A via a two-stranded alpha-helical coiled-coil structure. The PHF14-HMG20A complex directly interacts with TEAD1 transcription factor to modulate the Hippo pathway. siRNA knockdown of either PHF14 or HMG20A causes similar defects in cell migration, invasion, and homotypic cell-cell adhesion, and impairs TGF-β-triggered epithelial-to-mesenchymal transition. Proteomic study, deletion analysis, AlphaFold2 structural modeling, siRNA knockdown, transcriptomic analysis, TEAD1 interaction assay Nucleic acids research Medium 36124662
2022 PHF14 knockdown in colorectal cancer cells induces DNA damage and activates the ATR-CHK1-H2A.X pathway, leading to apoptosis. PHF14 interacts with KIF4A and contributes to formation of BRCA2/RAD51 foci, suggesting PHF14 participates in DNA damage response complex recruitment. siRNA knockdown, co-immunoprecipitation (PHF14-KIF4A), immunofluorescence for BRCA2/RAD51 foci, western blot for ATR-CHK1-γH2A.X, in vivo xenograft Cancer letters Medium 35074497
2020 PHF14 suppresses the expression of cell cycle inhibitor Cdkn1a (p21) by regulating H3K4me3 levels at the Cdkn1a locus, thereby controlling proliferation of germinal center B cells. PHF14 conditional knockout in germinal center B cells reduces GC response without affecting GC B cell survival. GC B cell-specific PHF14 knockout mice, SRBC/LCMV challenge, H3K4me3 ChIP, flow cytometry, qRT-PCR Cellular immunology Medium 33035772
2022 Loss of PHF14 (shRNA knockdown or CRISPR/Cas9 knockout) upregulates PDGFRα mRNA and protein in neuroblastoma SHSY-5Y cells, increases sensitivity to the PDGFR inhibitor Sunitinib, and enhances proliferation and colony formation. Overexpression of wild-type PHF14 reversed proliferation in neurocytoma primary cultures with PHF14 splicing mutations. shRNA knockdown, CRISPR/Cas9 knockout, PDGFR inhibitor (Sunitinib) treatment, nude mouse xenograft, primary culture rescue with WT PHF14 Biomedicines Medium 36359362
2019 Hypoxia-mediated inhibition of PHF14 is associated with increased cell cycle inhibitors p14ARF, p15INK4b, and p16INK4a (responsible for G1-S transition arrest) and decreased AKT-mTOR-4E-BP1/pS6K signaling, establishing PHF14 as a regulator of cell cycle progression and protein synthesis under hypoxic conditions. Pulsed-SILAC proteomics, biochemical assays, PHF14 KD xenograft model Oncotarget Low 31040906
2024 SP4 transcription factor binds to the PHF14 promoter region and activates PHF14 transcription, placing SP4 as a direct upstream transcriptional regulator of PHF14 in esophageal squamous cell carcinoma. ChIP assay (SP4 binding to PHF14 promoter), luciferase reporter assay, knockdown/overexpression experiments, Wnt/β-catenin pathway analysis Molecular cancer research : MCR Medium 37768180

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 LINC00612 enhances the proliferation and invasion ability of bladder cancer cells as ceRNA by sponging miR-590 to elevate expression of PHF14. Journal of experimental & clinical cancer research : CR 50 30940184
2012 Phf14, a novel regulator of mesenchyme growth via platelet-derived growth factor (PDGF) receptor-α. The Journal of biological chemistry 30 22730381
2023 PHF14 enhances DNA methylation of SMAD7 gene to promote TGF-β-driven lung adenocarcinoma metastasis. Cell discovery 27 37072414
2022 PHF14 knockdown causes apoptosis by inducing DNA damage and impairing the activity of the damage response complex in colorectal cancer. Cancer letters 24 35074497
2013 Depletion of PHF14, a novel histone-binding protein gene, causes neonatal lethality in mice due to respiratory failure. Acta biochimica et biophysica Sinica 24 23688586
2021 Molecular basis for bipartite recognition of histone H3 by the PZP domain of PHF14. Nucleic acids research 21 34365506
2019 Pulsed SILAC-based proteomic analysis unveils hypoxia- and serum starvation-induced de novo protein synthesis with PHD finger protein 14 (PHF14) as a hypoxia sensitive epigenetic regulator in cell cycle progression. Oncotarget 17 31040906
2020 PHF14 Promotes Cell Proliferation and Migration through the AKT and ERK1/2 Pathways in Gastric Cancer Cells. BioMed research international 15 32596345
2019 Silencing expression of PHF14 in glioblastoma promotes apoptosis, mitigates proliferation and invasiveness via Wnt signal pathway. Cancer cell international 14 31798343
2013 Aberrant expression of the PHF14 gene in biliary tract cancer cells. Oncology letters 13 23833654
2023 KMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics. Nature communications 12 37709746
2022 The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways. Nucleic acids research 8 36124662
2017 PHF14: an innate inhibitor against the progression of renal fibrosis following folic acid-induced kidney injury. Scientific reports 8 28045076
2024 SP4 Facilitates Esophageal Squamous Cell Carcinoma Progression by Activating PHF14 Transcription and Wnt/Β-Catenin Signaling. Molecular cancer research : MCR 5 37768180
2020 PHF14 is required for germinal center B cell development. Cellular immunology 5 33035772
2024 Epigenetic Regulation and Neurodevelopmental Disorders: From MeCP2 to the TCF20/PHF14 Complex. Genes 4 39766920
2023 A comprehensive pan-cancer analysis unveiling the oncogenic effect of plant homeodomain finger protein 14 (PHF14) in human tumors. Frontiers in genetics 3 37007943
2017 Severe persistent pulmonary hypertension of the newborn and dysmorphic features in neonate with a deletion involving TWIST1 and PHF14: a case report. Journal of medical case reports 3 28814329
2022 Whole Exome Sequencing Identifies PHF14 Mutations in Neurocytoma and Predicts Responsivity to the PDGFR Inhibitor Sunitinib. Biomedicines 2 36359362

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