{"gene":"PHF14","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2021,"finding":"PHF14 reads unmodified histone H3(1-34) through an integrated PHD1-ZnK-PHD2 (PZP) cassette using bipartite recognition: two distinct surfaces simultaneously engage H3-Nter (residues 1-15) and H3-middle (residues 14-34). A PHF14-unique insertion loop in PHD1 (not the core β-strands) dominates H3K4 readout. Binding is sensitive to modifications at H3 R2, T3, K4, R8, and K23 but not K9 or K27, indicating a 'ground state' (unmodified H3) reader that is negatively regulated by active marks.","method":"X-ray crystallography, HDX-MS, ITC/binding assays, mutagenesis","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with HDX-MS, binding assays, and mutagenesis in a single study","pmids":["34365506"],"is_preprint":false},{"year":2012,"finding":"Phf14 acts as a transcriptional repressor that directly represses PDGFRα expression in mesenchymal cells; Phf14-null mice show elevated PDGFRα and mesenchymal cell hyperproliferation leading to lung interstitial hyperplasia and neonatal lethality.","method":"Mouse knockout (gene targeting), ChIP/transcription assays, histology, antibody rescue experiment","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined cellular phenotype plus direct transcription factor assays, replicated in renal fibrosis study","pmids":["22730381"],"is_preprint":false},{"year":2013,"finding":"PHF14α (major isoform) localizes to the nucleus, associates with chromatin during cell division, and binds histones via its PHD fingers, as demonstrated by co-immunoprecipitation.","method":"Co-immunoprecipitation, subcellular fractionation/live imaging, reverse transcriptase PCR isoform cloning","journal":"Acta Biochimica et Biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP for histone binding plus localization; neonatal lethality phenotype confirmed","pmids":["23688586"],"is_preprint":false},{"year":2023,"finding":"PHF14 binds DNMT3B and serves as a DNA CpG motif reader, recruiting DNMT3B to the SMAD7 gene locus to drive DNA methylation and transcriptional silencing of SMAD7, thereby promoting TGF-β signaling and lung adenocarcinoma metastasis.","method":"Co-immunoprecipitation, ChIP, bisulfite sequencing, in vitro and in vivo metastasis assays, DNMT3B knockdown epistasis","journal":"Cell Discovery","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, bisulfite sequencing, and in vivo rescue experiments across multiple orthogonal methods","pmids":["37072414"],"is_preprint":false},{"year":2022,"finding":"PHF14 forms a protein complex with HMG20A via a two-stranded alpha-helical coiled-coil interaction; the PHF14-HMG20A complex modulates the Hippo pathway through direct interaction with the TEAD1 transcription factor and is required for TGF-β-triggered epithelial-to-mesenchymal transition and cell migration/invasion.","method":"Proteomics (AP-MS), deletion analysis, structural modeling (AlphaFold2/coiled-coil), Co-IP, siRNA knockdown with transcriptomic and functional readouts, TEAD1 interaction assay","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with proteomic validation, structural modeling, transcriptomics, and functional phenotype across multiple orthogonal methods","pmids":["36124662"],"is_preprint":false},{"year":2023,"finding":"PHF14 is a physical component of an RNA polymerase-associated PHF5A-PHF14-HMG20A-RAI1 protein subcomplex that associates with the histone methyltransferase KMT2A; this complex epigenetically regulates pancreatic cancer stem cell self-renewal and tumorigenicity.","method":"Co-immunoprecipitation, proteomic mass spectrometry, KMT2A-WDR5 inhibitor functional assay, in vivo tumorigenicity","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with MS-identified subcomplex, functional inhibition rescue, and in vivo data","pmids":["37709746"],"is_preprint":false},{"year":2017,"finding":"In renal fibrosis, PHF14 expression is upregulated by TGF-β/SMAD3 signaling: phospho-SMAD3 acts as a transcription factor binding the PHF14 promoter to enhance PHF14 expression (ChIP assay). PHF14 in turn represses PDGFRα transcription, establishing a TGF-β/SMAD3/PHF14/PDGFRα self-limiting feedback circuit in renal fibrosis.","method":"ChIP assay, mouse kidney fibrosis model (PHF14-null mice), TGF-β stimulation in fibroblasts, SMAD3 inhibitor epistasis","journal":"Scientific Reports","confidence":"High","confidence_rationale":"Tier 2 — ChIP for direct promoter binding, knockout mice, and epistasis with SMAD3 inhibitor across orthogonal methods","pmids":["28045076"],"is_preprint":false},{"year":2022,"finding":"PHF14 loss-of-function (shRNA knockdown or CRISPR/Cas9 knockout) upregulates PDGFRα mRNA and protein in neuroblastoma cells and mesenchymal cell lines, increases proliferation, and sensitizes cells to the PDGFR inhibitor Sunitinib, confirming PHF14's role as a negative regulator of PDGFRα.","method":"shRNA knockdown, CRISPR/Cas9 KO, RT-PCR/western blot for PDGFRα, drug sensitivity assay, nude mouse xenograft","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined molecular readout (PDGFRα upregulation) and in vivo confirmation, single lab","pmids":["36359362"],"is_preprint":false},{"year":2022,"finding":"PHF14 interacts with KIF4A and contributes to the formation of BRCA2/RAD51 foci at DNA damage sites; PHF14 knockdown causes DNA damage, activates the ATR-CHK1-H2AX pathway, and induces apoptosis in colorectal cancer cells.","method":"Co-immunoprecipitation (PHF14-KIF4A), immunofluorescence (BRCA2/RAD51 foci), siRNA knockdown, western blot (ATR-CHK1-H2AX), apoptosis assay","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP for KIF4A interaction; multiple downstream readouts from KD but pathway placement is partially indirect","pmids":["35074497"],"is_preprint":false},{"year":2020,"finding":"PHF14 conditional knockout in germinal center (GC) B cells reduces GC formation and GC B cell proliferation in vivo, and PHF14 suppresses expression of the cell cycle inhibitor Cdkn1a (p21) by regulating H3K4me3 levels at its locus.","method":"Conditional knockout mouse model (PHF14GCB KO), flow cytometry, ChIP for H3K4me3, immunization challenge (SRBC, LCMV)","journal":"Cellular Immunology","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with defined proliferation phenotype and direct ChIP evidence linking PHF14 to H3K4me3 at Cdkn1a","pmids":["33035772"],"is_preprint":false},{"year":2019,"finding":"PHF14 is identified as a hypoxia-sensitive epigenetic regulator; hypoxia-mediated inhibition of PHF14 is associated with upregulation of cell cycle inhibitors p14ARF, p15INK4b, and p16INK4a (G1-S transition) and decreased AKT-mTOR-4E-BP1/pS6K signaling, linking PHF14 to cell cycle progression and protein synthesis control.","method":"Pulsed-SILAC proteomics, PHF14 knockdown with cell cycle inhibitor/signaling readouts, xenograft in vivo model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — pulsed-SILAC discovery plus KD functional assays with defined molecular readouts, single lab","pmids":["31040906"],"is_preprint":false},{"year":2024,"finding":"PHF14 is a component of a MeCP2-interacting TCF20/PHF14 chromatin complex in the mammalian brain that also includes RAI1 and HMG20A; mutations in complex components are linked to neurodevelopmental disorders.","method":"Literature review synthesizing Co-IP and proteomic data from primary studies; complex membership inferred from interaction studies cited","journal":"Genes","confidence":"Low","confidence_rationale":"Tier 4 — review article synthesizing prior data without new primary experiments","pmids":["39766920"],"is_preprint":false},{"year":2024,"finding":"SP4 transcription factor directly binds the PHF14 promoter and activates PHF14 transcription, placing SP4 upstream of PHF14 in a pathway that activates Wnt/β-catenin signaling in esophageal squamous cell carcinoma.","method":"ChIP assay (SP4 at PHF14 promoter), luciferase reporter assay, siRNA/overexpression rescue experiments, western blot for β-catenin pathway","journal":"Molecular Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase reporter for direct promoter binding, epistasis by PHF14 overexpression rescue of SP4 KD","pmids":["37768180"],"is_preprint":false}],"current_model":"PHF14 is a nuclear epigenetic regulator that reads unmodified histone H3 (via its PZP/PHD1-ZnK-PHD2 cassette), represses transcription of PDGFRα and SMAD7 (the latter by recruiting DNMT3B for DNA methylation), operates within multi-protein complexes including PHF14-HMG20A (modulating Hippo/TGFβ/EMT via TEAD1) and the KMT2A-associated PHF5A-PHF14-HMG20A-RAI1 subcomplex, participates in DNA damage response through KIF4A and BRCA2/RAD51 foci formation, and controls cell proliferation partly through regulation of H3K4me3 at Cdkn1a/p21 loci."},"narrative":{"teleology":[{"year":2012,"claim":"Establishing PHF14 as a transcriptional repressor of PDGFRα answered how mesenchymal cell proliferation is kept in check: Phf14-null mice showed PDGFRα de-repression, hyperproliferative mesenchyme, and neonatal lethal lung disease.","evidence":"Gene-targeted Phf14-knockout mice with ChIP, transcription assays, and anti-PDGFRα antibody rescue","pmids":["22730381"],"confidence":"High","gaps":["Mechanism by which PHF14 silences the PDGFRα promoter (cofactor recruitment) was unknown","Whether PHF14 represses PDGFRα in tissues beyond lung was untested"]},{"year":2013,"claim":"Demonstrating that the major PHF14α isoform localizes to the nucleus, associates with chromatin during mitosis, and binds histones via PHD fingers established it as a bona fide chromatin-binding protein.","evidence":"Co-immunoprecipitation with histones, subcellular fractionation, live imaging in cultured cells","pmids":["23688586"],"confidence":"Medium","gaps":["Histone binding shown by single Co-IP without reciprocal validation or domain mapping","Which histone modifications are recognized or excluded was not determined"]},{"year":2017,"claim":"Identifying a TGF-β/SMAD3 → PHF14 → PDGFRα feedback loop in renal fibrosis revealed that PHF14 is itself transcriptionally induced by phospho-SMAD3 and functions as a self-limiting brake on fibrotic signaling.","evidence":"ChIP showing pSMAD3 binding at PHF14 promoter, PHF14-null kidney fibrosis model, SMAD3 inhibitor epistasis","pmids":["28045076"],"confidence":"High","gaps":["Whether additional transcription factors cooperate with SMAD3 at the PHF14 promoter was not tested","The chromatin mechanism through which PHF14 represses PDGFRα remained undefined"]},{"year":2019,"claim":"Linking PHF14 to hypoxia-responsive cell cycle control showed that PHF14 promotes proliferation partly by suppressing CDK inhibitors (p14ARF, p15, p16) and sustaining AKT-mTOR signaling.","evidence":"Pulsed-SILAC proteomics under hypoxia, PHF14 knockdown with cell cycle and signaling readouts, xenograft model","pmids":["31040906"],"confidence":"Medium","gaps":["Whether PHF14 directly binds regulatory elements at INK4 loci or acts indirectly was not resolved","Relationship between histone reading function and AKT-mTOR pathway unclear"]},{"year":2020,"claim":"Conditional knockout in germinal-center B cells showed PHF14 is required for GC formation and proliferation by regulating H3K4me3 levels at the Cdkn1a/p21 locus, providing the first direct link between PHF14 and a specific histone mark at a defined target gene.","evidence":"Conditional KO mouse (PHF14GCB), flow cytometry, ChIP for H3K4me3, SRBC/LCMV immunization","pmids":["33035772"],"confidence":"High","gaps":["Whether PHF14 recruits a specific H3K4 methyltransferase or demethylase to Cdkn1a was not shown","Generalizability beyond GC B cells not established"]},{"year":2021,"claim":"Solving the crystal structure of PHF14's PZP cassette bound to H3 revealed bipartite recognition of unmodified H3(1–34), defining PHF14 as a 'ground-state' histone reader negatively regulated by activating marks.","evidence":"X-ray crystallography, HDX-MS, ITC binding assays, systematic mutagenesis of H3 modification sites","pmids":["34365506"],"confidence":"High","gaps":["How ground-state reading is translated into transcriptional repression (effector recruitment) was not structurally resolved","No nucleosome-level structure available"]},{"year":2022,"claim":"Discovery of the PHF14–HMG20A coiled-coil complex and its modulation of Hippo/TEAD1 signaling and TGF-β-triggered EMT revealed a new transcriptional partnership beyond simple histone reading.","evidence":"AP-MS proteomics, reciprocal Co-IP, AlphaFold2 structural modeling, siRNA knockdown with transcriptomic and functional EMT readouts","pmids":["36124662"],"confidence":"High","gaps":["Whether PHF14-HMG20A acts as a TEAD1 coactivator or corepressor at specific genomic loci not determined","Structural basis of TEAD1 interaction undefined"]},{"year":2022,"claim":"Demonstrating that PHF14 interacts with KIF4A and is required for BRCA2/RAD51 foci at DNA damage sites placed PHF14 in the DNA damage response, expanding its function beyond transcriptional control.","evidence":"Co-immunoprecipitation (PHF14-KIF4A), immunofluorescence for BRCA2/RAD51 foci, siRNA knockdown, ATR-CHK1-H2AX western blots","pmids":["35074497"],"confidence":"Medium","gaps":["KIF4A interaction shown by single Co-IP without reciprocal validation","Whether PHF14 is recruited to damage sites directly or via KIF4A not resolved","No separation of DNA repair defect from cell cycle effects of PHF14 loss"]},{"year":2022,"claim":"Confirming PDGFRα de-repression in neuroblastoma and mesenchymal cells upon PHF14 KO, and showing that this sensitizes cells to Sunitinib, validated the PHF14–PDGFRα axis as a potential therapeutic vulnerability.","evidence":"CRISPR/Cas9 KO and shRNA knockdown, RT-PCR/western blot, Sunitinib drug sensitivity assay, xenograft","pmids":["36359362"],"confidence":"Medium","gaps":["Whether PHF14 loss universally sensitizes to PDGFR inhibitors across tumor types not tested","Mechanism by which PHF14 represses PDGFRα promoter still indirect"]},{"year":2023,"claim":"Showing that PHF14 recruits DNMT3B to methylate CpG sites at the SMAD7 locus provided the first mechanistic explanation for how PHF14 achieves transcriptional silencing—through DNA methylation—and linked this to TGF-β-driven metastasis.","evidence":"Reciprocal Co-IP, ChIP, bisulfite sequencing at SMAD7, DNMT3B knockdown epistasis, in vivo metastasis assays","pmids":["37072414"],"confidence":"High","gaps":["Whether DNMT3B recruitment is the general silencing mechanism at other PHF14 targets (e.g. PDGFRα) is unknown","How the PZP histone-reading activity coordinates with DNA CpG recognition not clarified"]},{"year":2023,"claim":"Identification of PHF14 as a stable subunit of the PHF5A–PHF14–HMG20A–RAI1 subcomplex associated with KMT2A positioned PHF14 within a defined chromatin-remodeling machine regulating cancer stem cell self-renewal.","evidence":"Reciprocal Co-IP, proteomic mass spectrometry, KMT2A-WDR5 inhibitor functional assay, in vivo tumorigenicity","pmids":["37709746"],"confidence":"High","gaps":["Stoichiometry and architecture of the subcomplex not structurally defined","Direct contribution of PHF14 versus other subunits to KMT2A activity not dissected"]},{"year":2024,"claim":"Showing that SP4 directly binds and activates the PHF14 promoter placed SP4 upstream of PHF14 in esophageal squamous cell carcinoma and linked PHF14 to Wnt/β-catenin pathway activation.","evidence":"ChIP assay, luciferase reporter, siRNA/overexpression rescue, western blot for β-catenin pathway","pmids":["37768180"],"confidence":"Medium","gaps":["Whether PHF14 directly regulates Wnt pathway gene promoters or acts indirectly not resolved","Relationship between PHF14 histone reading and Wnt activation unclear"]},{"year":null,"claim":"How PHF14's ground-state histone reading, DNMT3B-mediated DNA methylation activity, and participation in the KMT2A-associated complex are coordinated at individual genomic loci—and whether they represent context-dependent or integrated mechanisms—remains the central unresolved question.","evidence":"","pmids":[],"confidence":"High","gaps":["No genome-wide map of PHF14 occupancy correlated with histone and DNA methylation states","No reconstituted system demonstrating coupled histone reading and DNMT3B recruitment","Role of PHF14 in neurodevelopment suggested by complex membership but not tested with primary experimental data"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,3,9]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,3,9]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,5,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9,10]}],"complexes":["PHF5A-PHF14-HMG20A-RAI1 (KMT2A-associated)","PHF14-HMG20A"],"partners":["HMG20A","DNMT3B","RAI1","PHF5A","KIF4A","TEAD1","KMT2A"],"other_free_text":[]},"mechanistic_narrative":"PHF14 is a chromatin-associated transcriptional repressor that reads unmodified histone H3 through a bipartite PHD1-ZnK-PHD2 (PZP) cassette and recruits silencing machinery to specific gene loci, thereby controlling mesenchymal cell proliferation, TGF-β signaling, and DNA damage responses. Its PZP domain engages H3 residues 1–34 via two distinct surfaces, with binding abolished by active histone marks at H3R2, T3, K4, R8, and K23, establishing PHF14 as a 'ground-state' chromatin reader [PMID:34365506]. PHF14 directly represses PDGFRα transcription in mesenchymal cells—loss of PHF14 causes lethal lung interstitial hyperplasia in mice—and silences SMAD7 by recruiting DNMT3B for CpG methylation, thereby sustaining TGF-β signaling [PMID:22730381, PMID:37072414]. PHF14 operates within the PHF5A–PHF14–HMG20A–RAI1 subcomplex associated with KMT2A, modulates Hippo/TEAD1-dependent transcription through its HMG20A partnership, regulates H3K4me3 at the Cdkn1a/p21 locus to promote germinal-center B cell proliferation, and contributes to BRCA2/RAD51 focus formation at DNA damage sites via interaction with KIF4A [PMID:37709746, PMID:36124662, PMID:33035772, PMID:35074497]."},"prefetch_data":{"uniprot":{"accession":"O94880","full_name":"PHD finger protein 14","aliases":[],"length_aa":948,"mass_kda":107.0,"function":"Histone-binding protein (PubMed:23688586). Binds preferentially to unmodified histone H3 but can also bind to a lesser extent to histone H3 trimethylated at 'Lys-9' (H3K9me3) as well as to histone H3 monomethylated at 'Lys-27' (H3K27ac) and trimethylated at 'Lys-27' (H3K27me3) (By similarity). Represses PDGFRA expression, thus playing a role in regulation of mesenchymal cell proliferation (By similarity). Suppresses the expression of CDKN1A/p21 by reducing the level of trimethylation of histone H3 'Lys-4', leading to enhanced proliferation of germinal center B cells (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O94880/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHF14","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PHF14","total_profiled":1310},"omim":[{"mim_id":"619907","title":"PHD FINGER PROTEIN 14; PHF14","url":"https://www.omim.org/entry/619907"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHF14"},"hgnc":{"alias_symbol":["KIAA0783"],"prev_symbol":[]},"alphafold":{"accession":"O94880","domains":[{"cath_id":"3.30.40.10","chopping":"335-355_369-575","consensus_level":"medium","plddt":85.3247,"start":335,"end":575},{"cath_id":"3.30.40.10","chopping":"726-764","consensus_level":"medium","plddt":84.1313,"start":726,"end":764},{"cath_id":"1.20.5","chopping":"613-695","consensus_level":"medium","plddt":86.3129,"start":613,"end":695}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94880","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94880-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94880-F1-predicted_aligned_error_v6.png","plddt_mean":62.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHF14","jax_strain_url":"https://www.jax.org/strain/search?query=PHF14"},"sequence":{"accession":"O94880","fasta_url":"https://rest.uniprot.org/uniprotkb/O94880.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94880/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94880"}},"corpus_meta":[{"pmid":"30940184","id":"PMC_30940184","title":"LINC00612 enhances the proliferation and invasion ability of bladder cancer cells as ceRNA by sponging miR-590 to elevate expression of PHF14.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30940184","citation_count":50,"is_preprint":false},{"pmid":"22730381","id":"PMC_22730381","title":"Phf14, a novel regulator of mesenchyme growth via platelet-derived growth factor (PDGF) receptor-α.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22730381","citation_count":30,"is_preprint":false},{"pmid":"37072414","id":"PMC_37072414","title":"PHF14 enhances DNA methylation of SMAD7 gene to promote TGF-β-driven lung adenocarcinoma metastasis.","date":"2023","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37072414","citation_count":25,"is_preprint":false},{"pmid":"23688586","id":"PMC_23688586","title":"Depletion of PHF14, a novel histone-binding protein gene, causes neonatal lethality in mice due to respiratory failure.","date":"2013","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/23688586","citation_count":24,"is_preprint":false},{"pmid":"35074497","id":"PMC_35074497","title":"PHF14 knockdown causes apoptosis by inducing DNA damage and impairing the activity of the damage response complex in colorectal cancer.","date":"2022","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/35074497","citation_count":23,"is_preprint":false},{"pmid":"34365506","id":"PMC_34365506","title":"Molecular basis for bipartite recognition of histone H3 by the PZP domain of PHF14.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34365506","citation_count":20,"is_preprint":false},{"pmid":"31040906","id":"PMC_31040906","title":"Pulsed SILAC-based proteomic analysis unveils hypoxia- and serum starvation-induced de novo protein synthesis with PHD finger protein 14 (PHF14) as a hypoxia 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/23833654","citation_count":13,"is_preprint":false},{"pmid":"37709746","id":"PMC_37709746","title":"KMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37709746","citation_count":12,"is_preprint":false},{"pmid":"36124662","id":"PMC_36124662","title":"The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36124662","citation_count":8,"is_preprint":false},{"pmid":"28045076","id":"PMC_28045076","title":"PHF14: an innate inhibitor against the progression of renal fibrosis following folic acid-induced kidney injury.","date":"2017","source":"Scientific 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analysis unveiling the oncogenic effect of plant homeodomain finger protein 14 (PHF14) in human tumors.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37007943","citation_count":3,"is_preprint":false},{"pmid":"28814329","id":"PMC_28814329","title":"Severe persistent pulmonary hypertension of the newborn and dysmorphic features in neonate with a deletion involving TWIST1 and PHF14: a case report.","date":"2017","source":"Journal of medical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/28814329","citation_count":3,"is_preprint":false},{"pmid":"36359362","id":"PMC_36359362","title":"Whole Exome Sequencing Identifies PHF14 Mutations in Neurocytoma and Predicts Responsivity to the PDGFR Inhibitor Sunitinib.","date":"2022","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/36359362","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10496,"output_tokens":3249,"usd":0.040112},"stage2":{"model":"claude-opus-4-6","input_tokens":6703,"output_tokens":3538,"usd":0.182948},"total_usd":0.22306,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"PHF14 reads unmodified histone H3(1-34) through an integrated PHD1-ZnK-PHD2 (PZP) cassette using bipartite recognition: two distinct surfaces simultaneously engage H3-Nter (residues 1-15) and H3-middle (residues 14-34). A PHF14-unique insertion loop in PHD1 (not the core β-strands) dominates H3K4 readout. Binding is sensitive to modifications at H3 R2, T3, K4, R8, and K23 but not K9 or K27, indicating a 'ground state' (unmodified H3) reader that is negatively regulated by active marks.\",\n      \"method\": \"X-ray crystallography, HDX-MS, ITC/binding assays, mutagenesis\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with HDX-MS, binding assays, and mutagenesis in a single study\",\n      \"pmids\": [\"34365506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Phf14 acts as a transcriptional repressor that directly represses PDGFRα expression in mesenchymal cells; Phf14-null mice show elevated PDGFRα and mesenchymal cell hyperproliferation leading to lung interstitial hyperplasia and neonatal lethality.\",\n      \"method\": \"Mouse knockout (gene targeting), ChIP/transcription assays, histology, antibody rescue experiment\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined cellular phenotype plus direct transcription factor assays, replicated in renal fibrosis study\",\n      \"pmids\": [\"22730381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PHF14α (major isoform) localizes to the nucleus, associates with chromatin during cell division, and binds histones via its PHD fingers, as demonstrated by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/live imaging, reverse transcriptase PCR isoform cloning\",\n      \"journal\": \"Acta Biochimica et Biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP for histone binding plus localization; neonatal lethality phenotype confirmed\",\n      \"pmids\": [\"23688586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHF14 binds DNMT3B and serves as a DNA CpG motif reader, recruiting DNMT3B to the SMAD7 gene locus to drive DNA methylation and transcriptional silencing of SMAD7, thereby promoting TGF-β signaling and lung adenocarcinoma metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, bisulfite sequencing, in vitro and in vivo metastasis assays, DNMT3B knockdown epistasis\",\n      \"journal\": \"Cell Discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, bisulfite sequencing, and in vivo rescue experiments across multiple orthogonal methods\",\n      \"pmids\": [\"37072414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHF14 forms a protein complex with HMG20A via a two-stranded alpha-helical coiled-coil interaction; the PHF14-HMG20A complex modulates the Hippo pathway through direct interaction with the TEAD1 transcription factor and is required for TGF-β-triggered epithelial-to-mesenchymal transition and cell migration/invasion.\",\n      \"method\": \"Proteomics (AP-MS), deletion analysis, structural modeling (AlphaFold2/coiled-coil), Co-IP, siRNA knockdown with transcriptomic and functional readouts, TEAD1 interaction assay\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with proteomic validation, structural modeling, transcriptomics, and functional phenotype across multiple orthogonal methods\",\n      \"pmids\": [\"36124662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHF14 is a physical component of an RNA polymerase-associated PHF5A-PHF14-HMG20A-RAI1 protein subcomplex that associates with the histone methyltransferase KMT2A; this complex epigenetically regulates pancreatic cancer stem cell self-renewal and tumorigenicity.\",\n      \"method\": \"Co-immunoprecipitation, proteomic mass spectrometry, KMT2A-WDR5 inhibitor functional assay, in vivo tumorigenicity\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with MS-identified subcomplex, functional inhibition rescue, and in vivo data\",\n      \"pmids\": [\"37709746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In renal fibrosis, PHF14 expression is upregulated by TGF-β/SMAD3 signaling: phospho-SMAD3 acts as a transcription factor binding the PHF14 promoter to enhance PHF14 expression (ChIP assay). PHF14 in turn represses PDGFRα transcription, establishing a TGF-β/SMAD3/PHF14/PDGFRα self-limiting feedback circuit in renal fibrosis.\",\n      \"method\": \"ChIP assay, mouse kidney fibrosis model (PHF14-null mice), TGF-β stimulation in fibroblasts, SMAD3 inhibitor epistasis\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for direct promoter binding, knockout mice, and epistasis with SMAD3 inhibitor across orthogonal methods\",\n      \"pmids\": [\"28045076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHF14 loss-of-function (shRNA knockdown or CRISPR/Cas9 knockout) upregulates PDGFRα mRNA and protein in neuroblastoma cells and mesenchymal cell lines, increases proliferation, and sensitizes cells to the PDGFR inhibitor Sunitinib, confirming PHF14's role as a negative regulator of PDGFRα.\",\n      \"method\": \"shRNA knockdown, CRISPR/Cas9 KO, RT-PCR/western blot for PDGFRα, drug sensitivity assay, nude mouse xenograft\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined molecular readout (PDGFRα upregulation) and in vivo confirmation, single lab\",\n      \"pmids\": [\"36359362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHF14 interacts with KIF4A and contributes to the formation of BRCA2/RAD51 foci at DNA damage sites; PHF14 knockdown causes DNA damage, activates the ATR-CHK1-H2AX pathway, and induces apoptosis in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (PHF14-KIF4A), immunofluorescence (BRCA2/RAD51 foci), siRNA knockdown, western blot (ATR-CHK1-H2AX), apoptosis assay\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP for KIF4A interaction; multiple downstream readouts from KD but pathway placement is partially indirect\",\n      \"pmids\": [\"35074497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PHF14 conditional knockout in germinal center (GC) B cells reduces GC formation and GC B cell proliferation in vivo, and PHF14 suppresses expression of the cell cycle inhibitor Cdkn1a (p21) by regulating H3K4me3 levels at its locus.\",\n      \"method\": \"Conditional knockout mouse model (PHF14GCB KO), flow cytometry, ChIP for H3K4me3, immunization challenge (SRBC, LCMV)\",\n      \"journal\": \"Cellular Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined proliferation phenotype and direct ChIP evidence linking PHF14 to H3K4me3 at Cdkn1a\",\n      \"pmids\": [\"33035772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHF14 is identified as a hypoxia-sensitive epigenetic regulator; hypoxia-mediated inhibition of PHF14 is associated with upregulation of cell cycle inhibitors p14ARF, p15INK4b, and p16INK4a (G1-S transition) and decreased AKT-mTOR-4E-BP1/pS6K signaling, linking PHF14 to cell cycle progression and protein synthesis control.\",\n      \"method\": \"Pulsed-SILAC proteomics, PHF14 knockdown with cell cycle inhibitor/signaling readouts, xenograft in vivo model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pulsed-SILAC discovery plus KD functional assays with defined molecular readouts, single lab\",\n      \"pmids\": [\"31040906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PHF14 is a component of a MeCP2-interacting TCF20/PHF14 chromatin complex in the mammalian brain that also includes RAI1 and HMG20A; mutations in complex components are linked to neurodevelopmental disorders.\",\n      \"method\": \"Literature review synthesizing Co-IP and proteomic data from primary studies; complex membership inferred from interaction studies cited\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — review article synthesizing prior data without new primary experiments\",\n      \"pmids\": [\"39766920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SP4 transcription factor directly binds the PHF14 promoter and activates PHF14 transcription, placing SP4 upstream of PHF14 in a pathway that activates Wnt/β-catenin signaling in esophageal squamous cell carcinoma.\",\n      \"method\": \"ChIP assay (SP4 at PHF14 promoter), luciferase reporter assay, siRNA/overexpression rescue experiments, western blot for β-catenin pathway\",\n      \"journal\": \"Molecular Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase reporter for direct promoter binding, epistasis by PHF14 overexpression rescue of SP4 KD\",\n      \"pmids\": [\"37768180\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHF14 is a nuclear epigenetic regulator that reads unmodified histone H3 (via its PZP/PHD1-ZnK-PHD2 cassette), represses transcription of PDGFRα and SMAD7 (the latter by recruiting DNMT3B for DNA methylation), operates within multi-protein complexes including PHF14-HMG20A (modulating Hippo/TGFβ/EMT via TEAD1) and the KMT2A-associated PHF5A-PHF14-HMG20A-RAI1 subcomplex, participates in DNA damage response through KIF4A and BRCA2/RAD51 foci formation, and controls cell proliferation partly through regulation of H3K4me3 at Cdkn1a/p21 loci.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PHF14 is a chromatin-associated transcriptional repressor that reads unmodified histone H3 through a bipartite PHD1-ZnK-PHD2 (PZP) cassette and recruits silencing machinery to specific gene loci, thereby controlling mesenchymal cell proliferation, TGF-β signaling, and DNA damage responses. Its PZP domain engages H3 residues 1–34 via two distinct surfaces, with binding abolished by active histone marks at H3R2, T3, K4, R8, and K23, establishing PHF14 as a 'ground-state' chromatin reader [PMID:34365506]. PHF14 directly represses PDGFRα transcription in mesenchymal cells—loss of PHF14 causes lethal lung interstitial hyperplasia in mice—and silences SMAD7 by recruiting DNMT3B for CpG methylation, thereby sustaining TGF-β signaling [PMID:22730381, PMID:37072414]. PHF14 operates within the PHF5A–PHF14–HMG20A–RAI1 subcomplex associated with KMT2A, modulates Hippo/TEAD1-dependent transcription through its HMG20A partnership, regulates H3K4me3 at the Cdkn1a/p21 locus to promote germinal-center B cell proliferation, and contributes to BRCA2/RAD51 focus formation at DNA damage sites via interaction with KIF4A [PMID:37709746, PMID:36124662, PMID:33035772, PMID:35074497].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing PHF14 as a transcriptional repressor of PDGFRα answered how mesenchymal cell proliferation is kept in check: Phf14-null mice showed PDGFRα de-repression, hyperproliferative mesenchyme, and neonatal lethal lung disease.\",\n      \"evidence\": \"Gene-targeted Phf14-knockout mice with ChIP, transcription assays, and anti-PDGFRα antibody rescue\",\n      \"pmids\": [\"22730381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which PHF14 silences the PDGFRα promoter (cofactor recruitment) was unknown\",\n        \"Whether PHF14 represses PDGFRα in tissues beyond lung was untested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that the major PHF14α isoform localizes to the nucleus, associates with chromatin during mitosis, and binds histones via PHD fingers established it as a bona fide chromatin-binding protein.\",\n      \"evidence\": \"Co-immunoprecipitation with histones, subcellular fractionation, live imaging in cultured cells\",\n      \"pmids\": [\"23688586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Histone binding shown by single Co-IP without reciprocal validation or domain mapping\",\n        \"Which histone modifications are recognized or excluded was not determined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying a TGF-β/SMAD3 → PHF14 → PDGFRα feedback loop in renal fibrosis revealed that PHF14 is itself transcriptionally induced by phospho-SMAD3 and functions as a self-limiting brake on fibrotic signaling.\",\n      \"evidence\": \"ChIP showing pSMAD3 binding at PHF14 promoter, PHF14-null kidney fibrosis model, SMAD3 inhibitor epistasis\",\n      \"pmids\": [\"28045076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional transcription factors cooperate with SMAD3 at the PHF14 promoter was not tested\",\n        \"The chromatin mechanism through which PHF14 represses PDGFRα remained undefined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking PHF14 to hypoxia-responsive cell cycle control showed that PHF14 promotes proliferation partly by suppressing CDK inhibitors (p14ARF, p15, p16) and sustaining AKT-mTOR signaling.\",\n      \"evidence\": \"Pulsed-SILAC proteomics under hypoxia, PHF14 knockdown with cell cycle and signaling readouts, xenograft model\",\n      \"pmids\": [\"31040906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PHF14 directly binds regulatory elements at INK4 loci or acts indirectly was not resolved\",\n        \"Relationship between histone reading function and AKT-mTOR pathway unclear\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Conditional knockout in germinal-center B cells showed PHF14 is required for GC formation and proliferation by regulating H3K4me3 levels at the Cdkn1a/p21 locus, providing the first direct link between PHF14 and a specific histone mark at a defined target gene.\",\n      \"evidence\": \"Conditional KO mouse (PHF14GCB), flow cytometry, ChIP for H3K4me3, SRBC/LCMV immunization\",\n      \"pmids\": [\"33035772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PHF14 recruits a specific H3K4 methyltransferase or demethylase to Cdkn1a was not shown\",\n        \"Generalizability beyond GC B cells not established\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Solving the crystal structure of PHF14's PZP cassette bound to H3 revealed bipartite recognition of unmodified H3(1–34), defining PHF14 as a 'ground-state' histone reader negatively regulated by activating marks.\",\n      \"evidence\": \"X-ray crystallography, HDX-MS, ITC binding assays, systematic mutagenesis of H3 modification sites\",\n      \"pmids\": [\"34365506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How ground-state reading is translated into transcriptional repression (effector recruitment) was not structurally resolved\",\n        \"No nucleosome-level structure available\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery of the PHF14–HMG20A coiled-coil complex and its modulation of Hippo/TEAD1 signaling and TGF-β-triggered EMT revealed a new transcriptional partnership beyond simple histone reading.\",\n      \"evidence\": \"AP-MS proteomics, reciprocal Co-IP, AlphaFold2 structural modeling, siRNA knockdown with transcriptomic and functional EMT readouts\",\n      \"pmids\": [\"36124662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PHF14-HMG20A acts as a TEAD1 coactivator or corepressor at specific genomic loci not determined\",\n        \"Structural basis of TEAD1 interaction undefined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that PHF14 interacts with KIF4A and is required for BRCA2/RAD51 foci at DNA damage sites placed PHF14 in the DNA damage response, expanding its function beyond transcriptional control.\",\n      \"evidence\": \"Co-immunoprecipitation (PHF14-KIF4A), immunofluorescence for BRCA2/RAD51 foci, siRNA knockdown, ATR-CHK1-H2AX western blots\",\n      \"pmids\": [\"35074497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"KIF4A interaction shown by single Co-IP without reciprocal validation\",\n        \"Whether PHF14 is recruited to damage sites directly or via KIF4A not resolved\",\n        \"No separation of DNA repair defect from cell cycle effects of PHF14 loss\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirming PDGFRα de-repression in neuroblastoma and mesenchymal cells upon PHF14 KO, and showing that this sensitizes cells to Sunitinib, validated the PHF14–PDGFRα axis as a potential therapeutic vulnerability.\",\n      \"evidence\": \"CRISPR/Cas9 KO and shRNA knockdown, RT-PCR/western blot, Sunitinib drug sensitivity assay, xenograft\",\n      \"pmids\": [\"36359362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PHF14 loss universally sensitizes to PDGFR inhibitors across tumor types not tested\",\n        \"Mechanism by which PHF14 represses PDGFRα promoter still indirect\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that PHF14 recruits DNMT3B to methylate CpG sites at the SMAD7 locus provided the first mechanistic explanation for how PHF14 achieves transcriptional silencing—through DNA methylation—and linked this to TGF-β-driven metastasis.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, bisulfite sequencing at SMAD7, DNMT3B knockdown epistasis, in vivo metastasis assays\",\n      \"pmids\": [\"37072414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether DNMT3B recruitment is the general silencing mechanism at other PHF14 targets (e.g. PDGFRα) is unknown\",\n        \"How the PZP histone-reading activity coordinates with DNA CpG recognition not clarified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of PHF14 as a stable subunit of the PHF5A–PHF14–HMG20A–RAI1 subcomplex associated with KMT2A positioned PHF14 within a defined chromatin-remodeling machine regulating cancer stem cell self-renewal.\",\n      \"evidence\": \"Reciprocal Co-IP, proteomic mass spectrometry, KMT2A-WDR5 inhibitor functional assay, in vivo tumorigenicity\",\n      \"pmids\": [\"37709746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and architecture of the subcomplex not structurally defined\",\n        \"Direct contribution of PHF14 versus other subunits to KMT2A activity not dissected\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that SP4 directly binds and activates the PHF14 promoter placed SP4 upstream of PHF14 in esophageal squamous cell carcinoma and linked PHF14 to Wnt/β-catenin pathway activation.\",\n      \"evidence\": \"ChIP assay, luciferase reporter, siRNA/overexpression rescue, western blot for β-catenin pathway\",\n      \"pmids\": [\"37768180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PHF14 directly regulates Wnt pathway gene promoters or acts indirectly not resolved\",\n        \"Relationship between PHF14 histone reading and Wnt activation unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PHF14's ground-state histone reading, DNMT3B-mediated DNA methylation activity, and participation in the KMT2A-associated complex are coordinated at individual genomic loci—and whether they represent context-dependent or integrated mechanisms—remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No genome-wide map of PHF14 occupancy correlated with histone and DNA methylation states\",\n        \"No reconstituted system demonstrating coupled histone reading and DNMT3B recruitment\",\n        \"Role of PHF14 in neurodevelopment suggested by complex membership but not tested with primary experimental data\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 3, 9]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 3, 9]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [\n      \"PHF5A-PHF14-HMG20A-RAI1 (KMT2A-associated)\",\n      \"PHF14-HMG20A\"\n    ],\n    \"partners\": [\n      \"HMG20A\",\n      \"DNMT3B\",\n      \"RAI1\",\n      \"PHF5A\",\n      \"KIF4A\",\n      \"TEAD1\",\n      \"KMT2A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}