{"gene":"PHF12","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2001,"finding":"PHF12 (Pf1) was identified as a novel PHD zinc finger protein that physically associates with the mSin3A histone deacetylase corepressor complex in vivo and recruits it to repress transcription. PHF12 contains two independent Sin3 interaction domains (SID1 and SID2): SID1 binds the PAH2 domain of mSin3A (with sequence similarity to the Mad SID), while SID2 binds the PAH1 domain of mSin3A and represents a novel Sin3-binding module.","method":"Co-immunoprecipitation, GST pulldown/mapping experiments, Gal4-fusion transcriptional repression assays in mammalian cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and domain mapping with multiple binding constructs, supported by functional repression assay; single lab but multiple orthogonal methods","pmids":["11390640"],"is_preprint":false},{"year":2001,"finding":"PHF12 (Pf1) also interacts with the mammalian Groucho homolog TLE (transducin-like enhancer of split) corepressor in an mSin3A-independent manner and recruits functional TLE complexes to repress transcription, suggesting PHF12 bridges two global corepressor networks.","method":"Co-immunoprecipitation, Gal4-fusion transcriptional repression assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and functional reporter assay, single lab, single paper","pmids":["11390640"],"is_preprint":false},{"year":2002,"finding":"PHF12 (Pf1) selectively interacts with MRG15 (but not MRGX or MORF4) among the MORF family of transcriptional regulators. PHF12 has independent binding sites for MRG15 and mSin3A, and MRG15 and PHF12 bind different domains on mSin3A, forming a trimeric MRG15/Pf1/mSin3A complex. PHF12 reduces transcriptional repression by Gal4-MRG15 but has no effect on MRGX or MORF4-mediated repression.","method":"Co-immunoprecipitation, GST pulldown domain mapping, Gal4-fusion luciferase reporter repression assays, dominant-negative TLE experiments","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus domain mapping plus functional reporter assays, single lab with multiple orthogonal methods","pmids":["12391155"],"is_preprint":false},{"year":2006,"finding":"The PHD1 domain of PHF12 (Pf1), together with a polybasic region immediately C-terminal to PHD1, binds phosphoinositides, most strongly PI(3)P. The polybasic region alone is necessary and sufficient for specific PI(3)P binding when fused to heterologous proteins or as an isolated peptide; swapping polybasic regions between PHD fingers transfers PI-binding specificity.","method":"Lipid-protein binding assays (PI strip/dot blot), GST/MBP fusion pulldowns with phosphoinositides, peptide binding experiments, domain-swap experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstituted lipid-binding assays with mutagenesis/domain-swap validation; single lab but multiple orthogonal approaches","pmids":["16893883"],"is_preprint":false},{"year":2011,"finding":"The NMR solution structure of the mSin3A PAH2 domain bound to the PHF12 SID1 motif was determined, revealing a Mad1/Mxd1-like interaction mode. Unexpectedly, MRG15 competes with Sin3 PAH2 for the same PHF12 segment encompassing SID1 and a conserved adjacent motif, implying competitive rather than cooperative binding between two subunits of the same Rpd3S/Sin3S complex for PHF12.","method":"NMR structure determination, isothermal titration calorimetry (ITC), competitive binding assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution NMR structure plus ITC quantitative binding, functional competition shown; single lab","pmids":["21440557"],"is_preprint":false},{"year":2012,"finding":"The PHD1 domain of PHF12 binds preferentially to the unmodified extreme N-terminus of histone H3 (H3K4me0) but not to H3K4me2/3. PHF12 PHD1 and MRG15 chromodomain each bind their respective histone H3 targets with >100 µM affinity, requiring bivalent (not cooperative) co-engagement to achieve biologically significant chromatin targeting of the Rpd3S/Sin3S complex. PHF12 PHD1 also engages the MRG15 MRG domain in a PHF12 MRG-binding-domain-dependent manner.","method":"Fluorescence polarization binding assays, isothermal titration calorimetry, peptide pulldowns, mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — quantitative in vitro binding assays (ITC, FP) plus mutagenesis, multiple orthogonal methods, single lab","pmids":["22728643"],"is_preprint":false},{"year":2015,"finding":"Disruption of the SIN3A–PHF12 interaction (via a competitive Tat-SID peptide mimicking the SIN3 interaction domain of MAD) blocked PHF12 binding to SIN3A PAH2, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. PHF12 knockdown phenocopied Tat-SID treatment, reducing primary tumor growth and metastasis in vivo, establishing PHF12 as required for maintenance of the stem cell phenotype and EMT in triple-negative breast cancer.","method":"Competitive peptide displacement of SIN3A-PHF12 interaction, PHF12 shRNA knockdown, in vitro functional assays (proliferation, sphere formation), in vivo xenograft tumor model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — peptide competition plus genetic KD with functional readouts in vitro and in vivo, single lab","pmids":["26460951"],"is_preprint":false},{"year":2017,"finding":"Genetic inactivation of Phf12 (Pf1) in mice causes mid-to-late gestation lethality. In mouse embryonic fibroblasts, Phf12 loss impairs proliferation, increases senescence-associated β-galactosidase activity (cellular senescence), elevates γ-H2A.X (DNA double-strand break marker), and disrupts nucleolar morphology. Proteomic analysis of PHF12-interacting complexes revealed enrichment of ribosome biogenesis factors, and transcript profiling showed PHF12 impacts multiple ribosome biogenesis regulatory pathways.","method":"Conditional/constitutive knockout mouse generation, MEF proliferation assays (BrdU incorporation), SA-β-Gal senescence assay, γ-H2A.X immunostaining, nucleolar morphology analysis, mass spectrometry-based proteomics of PHF12 complexes, transcriptomic profiling","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic KO with multiple orthogonal cellular phenotype readouts plus proteomic complex characterization; single lab but highly rigorous multi-method study","pmids":["27956701"],"is_preprint":false},{"year":2021,"finding":"Disruption of the PF1/SIN3A interaction (via PF1-SID expression) leads to increased occupancy of SIN3A and the transcriptional repressor KLF9 on the promoters of ITGA6 and ITGB1, reducing their expression. KLF9 knockdown restores ITGA6/ITGB1 expression and the invasive phenotype, placing KLF9 downstream of the SIN3A-PHF12 complex in suppression of invasion and migration in TNBC.","method":"ChIP assay (SIN3A and KLF9 promoter occupancy), RNA-seq transcriptomics, KLF9 knockdown rescue experiments, invasion/migration assays","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus epistasis rescue experiment (KLF9 KD) plus genome-wide transcriptomics; single lab, multiple orthogonal methods","pmids":["34968869"],"is_preprint":false},{"year":2024,"finding":"PHF12 transcriptionally regulates HDAC1 expression: ChIP assay showed PHF12 binds the HDAC1 promoter region. PHF12 knockdown reduces HDAC1 mRNA and protein levels, and HDAC1 overexpression rescues proliferation and migration in PHF12-knockdown NSCLC cells. The PHF12-HDAC1 axis activates the EGFR/AKT signaling pathway in non-small cell lung cancer.","method":"ChIP assay (PHF12 binding at HDAC1 promoter), qRT-PCR/Western blot (HDAC1 mRNA and protein), siRNA knockdown, HDAC1 overexpression rescue, RNA-seq + GSEA pathway analysis, in vivo xenograft model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP plus rescue experiment with functional readouts; single lab, single paper","pmids":["39075515"],"is_preprint":false}],"current_model":"PHF12 (Pf1/KIAA1523) is a dual-PHD zinc finger adaptor protein that scaffolds the Rpd3S/Sin3S histone deacetylase corepressor complex: it uses two independent Sin3-interaction domains (SID1 binding mSin3A PAH2 in a Mad-like mode, SID2 binding PAH1) to recruit mSin3A-HDAC, interacts selectively with MRG15 (not MRGX/MORF4), and together with MRG15 bivalently engages histone H3 chromatin (PHD1 binding unmodified H3K4me0, MRG15 chromodomain binding H3K36me2/3) to suppress cryptic transcription; its PHD1 polybasic region also binds PI(3)P, linking it to phosphoinositide signaling; PHF12 additionally transcriptionally upregulates HDAC1 and activates EGFR/AKT signaling in cancer cells; and genetic loss of Phf12 in mice causes embryonic lethality, cellular senescence, nucleolar disruption, and impaired ribosome biogenesis."},"narrative":{"mechanistic_narrative":"PHF12 (Pf1) is a dual-PHD zinc finger adaptor protein that scaffolds the Rpd3S/Sin3S histone deacetylase corepressor complex and directs it to chromatin to repress transcription [PMID:11390640, PMID:12391155]. It engages mSin3A through two independent Sin3-interaction domains: SID1 binds the PAH2 domain in a Mad/Mxd1-like mode (resolved by NMR), while SID2 binds PAH1 as a distinct novel module [PMID:11390640, PMID:21440557]. Within the MORF family, PHF12 selectively binds MRG15 (not MRGX or MORF4), and because PHF12 and MRG15 contact different surfaces of mSin3A it assembles a trimeric MRG15/PHF12/mSin3A complex [PMID:12391155]; notably, MRG15 and the Sin3 PAH2 domain compete for an overlapping PHF12 segment, indicating dynamic rather than simultaneous engagement of these subunits [PMID:21440557]. Chromatin targeting is achieved bivalently: the PHF12 PHD1 domain binds the unmodified histone H3 N-terminus (H3K4me0) while the MRG15 chromodomain reads a separate H3 mark, each at low affinity, so that co-engagement is required for stable recruitment [PMID:22728643]. A polybasic region immediately C-terminal to PHD1 additionally binds phosphoinositides, most strongly PI(3)P [PMID:16893883]. Beyond corepression, PHF12 sustains proliferative and invasive programs in cancer: it is required for maintenance of stem-cell and EMT phenotypes in triple-negative breast cancer via the SIN3A-PHF12 interaction and downstream KLF9-mediated control of ITGA6/ITGB1 [PMID:26460951, PMID:34968869], and it transcriptionally upregulates HDAC1 to activate EGFR/AKT signaling in non-small cell lung cancer [PMID:39075515]. Genetic inactivation of Phf12 in mice causes mid-to-late gestation lethality, and Phf12-null fibroblasts display impaired proliferation, cellular senescence, elevated DNA-damage marking, disrupted nucleolar morphology, and impaired ribosome biogenesis, with PHF12 complexes enriched for ribosome biogenesis factors [PMID:27956701].","teleology":[{"year":2001,"claim":"Established PHF12 as a transcriptional corepressor adaptor by showing it physically recruits the mSin3A HDAC complex through two independent Sin3-interaction domains, defining its core repressive function.","evidence":"Co-IP, GST pulldown domain mapping, and Gal4-fusion repression assays in mammalian cells","pmids":["11390640"],"confidence":"High","gaps":["Did not resolve how SID1/SID2 dual binding affects complex stoichiometry","No chromatin target genes identified","TLE bridging (same paper) rests on Co-IP/reporter assay only"]},{"year":2002,"claim":"Defined the selectivity of PHF12 within the MORF family and showed it forms a defined trimeric complex, clarifying which corepressor module it assembles.","evidence":"Reciprocal Co-IP, GST pulldown domain mapping, and Gal4-luciferase repression assays","pmids":["12391155"],"confidence":"High","gaps":["Structural basis of MRG15 selectivity over MRGX/MORF4 not resolved","Endogenous complex composition in chromatin context not shown"]},{"year":2006,"claim":"Revealed an unexpected lipid-binding activity for PHF12, showing a polybasic region adjacent to PHD1 confers specific PI(3)P binding and linking the protein to phosphoinositide signaling.","evidence":"In vitro lipid-protein binding assays, fusion pulldowns, and domain-swap experiments","pmids":["16893883"],"confidence":"High","gaps":["Cellular function of PI(3)P binding for PHF12 not established","Whether lipid and histone binding by PHD1 are mutually exclusive unknown"]},{"year":2011,"claim":"Provided atomic-resolution detail of the PHF12 SID1–mSin3A PAH2 interface and uncovered competition between MRG15 and PAH2 for PHF12, reframing how the complex subunits engage the adaptor.","evidence":"NMR solution structure, ITC, and competitive binding assays","pmids":["21440557"],"confidence":"High","gaps":["Functional consequence of MRG15/PAH2 competition in vivo untested","Did not address the SID2-PAH1 interaction structurally"]},{"year":2012,"claim":"Demonstrated that PHF12 PHD1 and MRG15 chromodomain co-read distinct H3 marks with low individual affinity, establishing bivalent recognition as the mechanism for targeting Rpd3S/Sin3S to chromatin.","evidence":"Fluorescence polarization, ITC, peptide pulldowns, and mutagenesis","pmids":["22728643"],"confidence":"High","gaps":["In vivo genome-wide chromatin occupancy not mapped","Link between bivalent reading and suppression of specific transcripts not directly shown"]},{"year":2017,"claim":"Defined the organismal and cellular requirement for PHF12, showing it is essential for embryonic viability and for preventing senescence, and linked it unexpectedly to nucleolar integrity and ribosome biogenesis.","evidence":"Knockout mouse, MEF phenotyping (proliferation, SA-β-Gal, γ-H2A.X, nucleolar morphology), proteomics, and transcriptomics","pmids":["27956701"],"confidence":"High","gaps":["Mechanistic link between corepressor scaffolding and ribosome biogenesis not resolved","Whether nucleolar phenotype is direct or downstream of senescence unclear"]},{"year":2021,"claim":"Placed the SIN3A-PHF12 complex in a defined oncogenic circuit, showing it represses KLF9-controlled integrin genes to govern invasion in triple-negative breast cancer.","evidence":"ChIP for SIN3A/KLF9 occupancy, RNA-seq, KLF9 knockdown rescue, and invasion/migration assays","pmids":["34968869"],"confidence":"Medium","gaps":["Direct PHF12 promoter binding at ITGA6/ITGB1 not shown","Generality beyond TNBC untested"]},{"year":2024,"claim":"Identified a transcriptional output of PHF12 in lung cancer, showing it binds the HDAC1 promoter to upregulate HDAC1 and activate EGFR/AKT signaling, distinct from its classical corepressor role.","evidence":"ChIP at HDAC1 promoter, knockdown/overexpression rescue, RNA-seq/GSEA, and xenograft model","pmids":["39075515"],"confidence":"Medium","gaps":["Single lab, single paper without reciprocal validation","How a corepressor adaptor activates HDAC1 transcription mechanistically unresolved","Direct versus indirect effect on EGFR/AKT not separated"]},{"year":null,"claim":"How PHF12's chromatin-corepressor scaffolding function mechanistically connects to ribosome biogenesis, embryonic viability, and its context-dependent oncogenic roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking corepression to nucleolar/ribosome phenotypes","Physiological role of PI(3)P binding undefined","Genome-wide direct target catalogue lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[5]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,8,9]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[7]}],"complexes":["Rpd3S/Sin3S HDAC corepressor complex","MRG15/PHF12/mSin3A trimeric complex"],"partners":["SIN3A","MRG15","TLE","HDAC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96QT6","full_name":"PHD finger protein 12","aliases":["PHD factor 1","Pf1"],"length_aa":1004,"mass_kda":109.7,"function":"Transcriptional repressor acting as key scaffolding subunit of SIN3 complexes which contributes to complex assembly by contacting each core subunit domain, stabilizes the complex and constitutes the substrate receptor by recruiting the H3 histone tail (PubMed:37137925). SIN3 complexes are composed of a SIN3 scaffold subunit, one catalytic core (HDAC1 or HDAC2) and 2 chromatin targeting modules (PubMed:11390640, PubMed:37137925). SIN3B complex represses transcription and counteracts the histone acetyltransferase activity of EP300 through the recognition H3K27ac marks by PHF12 and the activity of the histone deacetylase HDAC2 (PubMed:37137925). SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription (PubMed:21041482). May also repress transcription in a SIN3A-independent manner through recruitment of functional TLE5 complexes to DNA (PubMed:11390640). May also play a role in ribosomal biogenesis (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96QT6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PHF12","classification":"Common Essential","n_dependent_lines":721,"n_total_lines":1208,"dependency_fraction":0.5968543046357616},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GATAD1","stoichiometry":4.0},{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PHF12","total_profiled":1310},"omim":[{"mim_id":"618645","title":"PHD FINGER PROTEIN 12; PHF12","url":"https://www.omim.org/entry/618645"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHF12"},"hgnc":{"alias_symbol":["PF1","KIAA1523"],"prev_symbol":[]},"alphafold":{"accession":"Q96QT6","domains":[{"cath_id":"3.30.40.10","chopping":"55-112","consensus_level":"medium","plddt":82.195,"start":55,"end":112},{"cath_id":"3.30.40.10","chopping":"272-306","consensus_level":"medium","plddt":87.4743,"start":272,"end":306},{"cath_id":"2.60.200.20","chopping":"793-874_928-967","consensus_level":"medium","plddt":85.9191,"start":793,"end":967}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QT6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QT6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QT6-F1-predicted_aligned_error_v6.png","plddt_mean":55.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHF12","jax_strain_url":"https://www.jax.org/strain/search?query=PHF12"},"sequence":{"accession":"Q96QT6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96QT6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96QT6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QT6"}},"corpus_meta":[{"pmid":"6405045","id":"PMC_6405045","title":"Structure similarity, difference and variability in the filamentous viruses fd, If1, IKe, Pf1 and Xf. 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Electron density distribution calculated by a maximum entropy algorithm from native fibre diffraction data to 3 A resolution and single isomorphous replacement data to 5 A resolution.","date":"1987","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3599076","citation_count":33,"is_preprint":false},{"pmid":"16453414","id":"PMC_16453414","title":"The DNA-binding protein of Pf1 filamentous bacteriophage: amino-acid sequence and structure of the gene.","date":"1982","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16453414","citation_count":32,"is_preprint":false},{"pmid":"6410396","id":"PMC_6410396","title":"Maximum-entropy calculation of the electron density at 4 A resolution of Pf1 filamentous bacteriophage.","date":"1983","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/6410396","citation_count":32,"is_preprint":false},{"pmid":"6806774","id":"PMC_6806774","title":"DNA packing in the filamentous viruses fd, Xf, Pf1 and Pf3.","date":"1982","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/6806774","citation_count":31,"is_preprint":false},{"pmid":"1906942","id":"PMC_1906942","title":"Neutron diffraction studies of the structure of filamentous bacteriophage Pf1. Demonstration that the coat protein consists of a pair of alpha-helices with an intervening, non-helical surface loop.","date":"1991","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1906942","citation_count":30,"is_preprint":false},{"pmid":"3166982","id":"PMC_3166982","title":"Sugar pucker and phosphodiester conformations in viral genomes of filamentous bacteriophages: fd, If1, IKe, Pf1, Xf, and Pf3.","date":"1988","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3166982","citation_count":29,"is_preprint":false},{"pmid":"21440557","id":"PMC_21440557","title":"Solution structure of the mSin3A PAH2-Pf1 SID1 complex: a Mad1/Mxd1-like interaction disrupted by MRG15 in the Rpd3S/Sin3S complex.","date":"2011","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21440557","citation_count":28,"is_preprint":false},{"pmid":"12549913","id":"PMC_12549913","title":"Protein and DNA residue orientations in the filamentous virus Pf1 determined by polarized Raman and polarized FTIR spectroscopy.","date":"2003","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12549913","citation_count":26,"is_preprint":false},{"pmid":"10363369","id":"PMC_10363369","title":"The HMG-I/Y protein PF1 stimulates binding of the transcriptional activator GT-2 to the PHYA gene promoter.","date":"1999","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10363369","citation_count":26,"is_preprint":false},{"pmid":"26460951","id":"PMC_26460951","title":"Targeting the SIN3A-PF1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26460951","citation_count":26,"is_preprint":false},{"pmid":"8534808","id":"PMC_8534808","title":"A Monte Carlo model of fd and Pf1 coat proteins in lipid membranes.","date":"1995","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8534808","citation_count":26,"is_preprint":false},{"pmid":"7753584","id":"PMC_7753584","title":"The effect of the nematode peptides SDPNFLRFamide (PF1) and SADPNFLRFamide (PF2) on synaptic transmission in the parasitic nematode Ascaris suum.","date":"1995","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/7753584","citation_count":25,"is_preprint":false},{"pmid":"8373820","id":"PMC_8373820","title":"Evaluation of transmembrane helix prediction methods using the recently defined NMR structures of the coat proteins from bacteriophages M13 and Pf1.","date":"1993","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8373820","citation_count":24,"is_preprint":false},{"pmid":"22728643","id":"PMC_22728643","title":"Sequence requirements for combinatorial recognition of histone H3 by the MRG15 and Pf1 subunits of the Rpd3S/Sin3S corepressor complex.","date":"2012","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22728643","citation_count":23,"is_preprint":false},{"pmid":"25494804","id":"PMC_25494804","title":"Pf1 bacteriophage hydration by magic angle spinning solid-state NMR.","date":"2014","source":"The Journal of chemical physics","url":"https://pubmed.ncbi.nlm.nih.gov/25494804","citation_count":21,"is_preprint":false},{"pmid":"3127590","id":"PMC_3127590","title":"Conformation of the coat protein of filamentous bacteriophage Pf1 determined by neutron diffraction from magnetically oriented gels of specifically deuterated virions.","date":"1988","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3127590","citation_count":21,"is_preprint":false},{"pmid":"12464423","id":"PMC_12464423","title":"Structure-activity relationships of an inhibitory nematode FMRFamide-related peptide, SDPNFLRFamide (PF1), on Ascaris suum muscle.","date":"2002","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/12464423","citation_count":21,"is_preprint":false},{"pmid":"2005618","id":"PMC_2005618","title":"Circular dichroism and fluorescence analysis of the interaction of Pf1 gene 5 protein with poly(dT).","date":"1991","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2005618","citation_count":19,"is_preprint":false},{"pmid":"26193285","id":"PMC_26193285","title":"Purification and Characterization of a Fucoidanase (FNase S) from a Marine Bacterium Sphingomonas paucimobilis PF-1.","date":"2015","source":"Marine drugs","url":"https://pubmed.ncbi.nlm.nih.gov/26193285","citation_count":19,"is_preprint":false},{"pmid":"4039662","id":"PMC_4039662","title":"Time-resolved fluorescence of bacteriophage Pf1 DNA-binding protein. Determination of oligonucleotide and polynucleotide binding parameters.","date":"1985","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/4039662","citation_count":18,"is_preprint":false},{"pmid":"20078135","id":"PMC_20078135","title":"A structural model for the single-stranded DNA genome of filamentous bacteriophage Pf1.","date":"2010","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20078135","citation_count":18,"is_preprint":false},{"pmid":"9878347","id":"PMC_9878347","title":"Analysis of X-ray diffraction from fibres of Pf1 Inovirus (filamentous bacteriophage) shows that the DNA in the virion is not highly ordered.","date":"1998","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9878347","citation_count":17,"is_preprint":false},{"pmid":"23931317","id":"PMC_23931317","title":"NMR-based simulation studies of Pf1 coat protein in explicit membranes.","date":"2013","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/23931317","citation_count":17,"is_preprint":false},{"pmid":"15476406","id":"PMC_15476406","title":"Effects of virion and salt concentrations on the Raman signatures of filamentous phages fd, Pf1, Pf3, and PH75.","date":"2004","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15476406","citation_count":17,"is_preprint":false},{"pmid":"27956701","id":"PMC_27956701","title":"The Chromatin-Associated Phf12 Protein Maintains Nucleolar Integrity and Prevents Premature Cellular Senescence.","date":"2017","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27956701","citation_count":16,"is_preprint":false},{"pmid":"34469281","id":"PMC_34469281","title":"Biodegradation of organophosphorus pesticide profenofos by the bacterium Bacillus sp. PF1 and elucidation of initial degradation pathway.","date":"2021","source":"Environmental technology","url":"https://pubmed.ncbi.nlm.nih.gov/34469281","citation_count":16,"is_preprint":false},{"pmid":"34968869","id":"PMC_34968869","title":"Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A-PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1.","date":"2021","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34968869","citation_count":15,"is_preprint":false},{"pmid":"7794893","id":"PMC_7794893","title":"FT-IR spectroscopy of the major coat protein of M13 and Pf1 in the phage and reconstituted into phospholipid systems.","date":"1995","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7794893","citation_count":15,"is_preprint":false},{"pmid":"3280025","id":"PMC_3280025","title":"Raman spectroscopy of mercury (II) binding to two filamentous viruses: Ff (fd, M13, f1) and Pf1.","date":"1988","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3280025","citation_count":15,"is_preprint":false},{"pmid":"1891463","id":"PMC_1891463","title":"The role of tyrosine residues in the DNA-binding site of the Pf1 gene 5 protein.","date":"1991","source":"Protein engineering","url":"https://pubmed.ncbi.nlm.nih.gov/1891463","citation_count":14,"is_preprint":false},{"pmid":"20829084","id":"PMC_20829084","title":"Simultaneous structure and dynamics of a membrane protein using REDCRAFT: membrane-bound form of Pf1 coat protein.","date":"2010","source":"Journal of magnetic resonance (San Diego, Calif. : 1997)","url":"https://pubmed.ncbi.nlm.nih.gov/20829084","citation_count":14,"is_preprint":false},{"pmid":"8399218","id":"PMC_8399218","title":"Biophysical studies of the Pf1 coat protein in the filamentous phage, in detergent micelles, and in a membrane environment.","date":"1993","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8399218","citation_count":14,"is_preprint":false},{"pmid":"27014207","id":"PMC_27014207","title":"Small Colony Variants and Single Nucleotide Variations in Pf1 Region of PB1 Phage-Resistant Pseudomonas aeruginosa.","date":"2016","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27014207","citation_count":14,"is_preprint":false},{"pmid":"3972429","id":"PMC_3972429","title":"Natural killer (NK) cells and graft-versus-host disease (GVHD): no correlation between the NK cell levels and GVHD in the murine P----F1 model.","date":"1985","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/3972429","citation_count":14,"is_preprint":false},{"pmid":"3663828","id":"PMC_3663828","title":"Structural responsiveness of filamentous bacteriophage Pf1: comparison of virion structure in fibers and solution. The effect of temperature and ionic strength.","date":"1987","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/3663828","citation_count":14,"is_preprint":false},{"pmid":"6297583","id":"PMC_6297583","title":"Dissociation of the Pf1 nucleoprotein assembly complex and characterisation of the DNA binding protein.","date":"1983","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/6297583","citation_count":12,"is_preprint":false},{"pmid":"24611650","id":"PMC_24611650","title":"Involvement of tumor-associated macrophage activation in vitro during development of a novel mantle cell lymphoma cell line, PF-1, derived from a typical patient with relapsed disease.","date":"2014","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/24611650","citation_count":12,"is_preprint":false},{"pmid":"22607445","id":"PMC_22607445","title":"Pf1 filamentous phage as an alignment tool for generating local and global structural information in nucleic acids.","date":"2000","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/22607445","citation_count":12,"is_preprint":false},{"pmid":"8471719","id":"PMC_8471719","title":"Molecular dynamics simulation of Pf1 coat protein.","date":"1993","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8471719","citation_count":10,"is_preprint":false},{"pmid":"9466922","id":"PMC_9466922","title":"Equilibrium and kinetic binding analysis of the N-terminal domain of the Pf1 gene 5 protein and its interaction with single-stranded DNA.","date":"1998","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9466922","citation_count":9,"is_preprint":false},{"pmid":"3924033","id":"PMC_3924033","title":"Identification of lysine residues at the binding site of bacteriophage-Pf1 DNA-binding protein.","date":"1985","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/3924033","citation_count":8,"is_preprint":false},{"pmid":"10561545","id":"PMC_10561545","title":"Conformational studies of the C-terminal domain of bacteriophage Pf1 gene 5 protein.","date":"1999","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10561545","citation_count":7,"is_preprint":false},{"pmid":"7819190","id":"PMC_7819190","title":"Comparison of Pf1 and Fd gene 5 proteins and their single-stranded DNA complexes by NMR spectroscopy and differential scanning calorimetry.","date":"1995","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7819190","citation_count":7,"is_preprint":false},{"pmid":"3309343","id":"PMC_3309343","title":"Cloning and expression of the filamentous bacteriophage Pf1 major coat protein gene in Escherichia coli. Membrane protein processing and virus assembly.","date":"1987","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3309343","citation_count":7,"is_preprint":false},{"pmid":"34500373","id":"PMC_34500373","title":"LncRNA RP11-116G8.5 promotes the progression of lung squamous cell carcinoma through sponging miR-3150b-3p/miR-6870-5p to upregulate PHF12/FOXP4.","date":"2021","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/34500373","citation_count":6,"is_preprint":false},{"pmid":"8466905","id":"PMC_8466905","title":"Identification of a compact DNA-binding domain in the gene 5 protein of Pf1 bacteriophage.","date":"1993","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8466905","citation_count":6,"is_preprint":false},{"pmid":"3136800","id":"PMC_3136800","title":"Thermal difference circular dichroism of Pf1 filamentous virus and effects of mercury(II), silver(I), and copper(II).","date":"1988","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3136800","citation_count":6,"is_preprint":false},{"pmid":"6477921","id":"PMC_6477921","title":"Estimation of tyrosine-40-DNA distance in the filamentous phage Pf1 by analysis of its intrinsic fluorescence properties.","date":"1984","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/6477921","citation_count":5,"is_preprint":false},{"pmid":"6606711","id":"PMC_6606711","title":"Pf1 bacteriophage replication--assembly complex. X-ray fibre diffraction of the high humidity form.","date":"1983","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/6606711","citation_count":5,"is_preprint":false},{"pmid":"18760280","id":"PMC_18760280","title":"Effects of SDPNFLRF-amide (PF1) on voltage-activated currents in Ascaris suum muscle.","date":"2008","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/18760280","citation_count":4,"is_preprint":false},{"pmid":"1779755","id":"PMC_1779755","title":"Export of infectious particles by Escherichia coli transfected with the RF DNA of Pf1, a virus of Pseudomonas aeruginosa strain K.","date":"1991","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/1779755","citation_count":4,"is_preprint":false},{"pmid":"7639786","id":"PMC_7639786","title":"Cloning and characterization of cDNAs encoding oat PF1: a protein that binds to the PE1 region in the oat phytochrome A3 gene promoter.","date":"1994","source":"Biochemical Society symposium","url":"https://pubmed.ncbi.nlm.nih.gov/7639786","citation_count":3,"is_preprint":false},{"pmid":"39075515","id":"PMC_39075515","title":"PHF12 regulates HDAC1 to promote tumorigenesis via EGFR/AKT signaling pathway in non-small cell lung cancer.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39075515","citation_count":2,"is_preprint":false},{"pmid":"14967240","id":"PMC_14967240","title":"Line shape analyses for water 17O NMR quintet observed in a bacteriophage Pf1 solution at different temperatures.","date":"2004","source":"Biophysical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14967240","citation_count":2,"is_preprint":false},{"pmid":"1942028","id":"PMC_1942028","title":"Structural parameters of the Pf1 gene 5 protein-DNA complex in solution by neutron scattering.","date":"1991","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1942028","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.13.653867","title":"Co-infection with  <i>Streptococcus</i>  and  <i>Rothia</i>  spp. drives prophage dynamics in  <i>Pseudomonas aeruginosa</i>  in an artificial sputum model","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.13.653867","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.10.602839","title":"Temperate bacteriophage induced in  <i>Pseudomonas aeruginosa</i>  biofilms can modulate bacteriophage and antibiotic resistance","date":"2024-07-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.10.602839","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":39554,"output_tokens":3290,"usd":0.084006,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10456,"output_tokens":3418,"usd":0.068865,"stage2_stop_reason":"end_turn"},"total_usd":0.152871,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the human/mammalian PHF12 (also known as PF1/KIAA1523) gene, which encodes a PHD zinc finger protein involved in transcriptional repression complexes. The vast majority of papers in this corpus are about bacteriophage Pf1, nematode peptide PF1, rice/plant PF1, or other unrelated proteins sharing the \"PF1\" symbol. I will only extract from papers describing the mammalian PHF12/Pf1 protein.\n\nRelevant papers: PMIDs 11390640, 12391155, 16893883, 21440557, 22728643, 26460951, 27956701, 39075515, 34968869\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"PHF12 (Pf1) was identified as a novel PHD zinc finger protein that physically associates with the mSin3A histone deacetylase corepressor complex in vivo and recruits it to repress transcription. PHF12 contains two independent Sin3 interaction domains (SID1 and SID2): SID1 binds the PAH2 domain of mSin3A (with sequence similarity to the Mad SID), while SID2 binds the PAH1 domain of mSin3A and represents a novel Sin3-binding module.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown/mapping experiments, Gal4-fusion transcriptional repression assays in mammalian cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and domain mapping with multiple binding constructs, supported by functional repression assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"11390640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PHF12 (Pf1) also interacts with the mammalian Groucho homolog TLE (transducin-like enhancer of split) corepressor in an mSin3A-independent manner and recruits functional TLE complexes to repress transcription, suggesting PHF12 bridges two global corepressor networks.\",\n      \"method\": \"Co-immunoprecipitation, Gal4-fusion transcriptional repression assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and functional reporter assay, single lab, single paper\",\n      \"pmids\": [\"11390640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PHF12 (Pf1) selectively interacts with MRG15 (but not MRGX or MORF4) among the MORF family of transcriptional regulators. PHF12 has independent binding sites for MRG15 and mSin3A, and MRG15 and PHF12 bind different domains on mSin3A, forming a trimeric MRG15/Pf1/mSin3A complex. PHF12 reduces transcriptional repression by Gal4-MRG15 but has no effect on MRGX or MORF4-mediated repression.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown domain mapping, Gal4-fusion luciferase reporter repression assays, dominant-negative TLE experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus domain mapping plus functional reporter assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12391155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The PHD1 domain of PHF12 (Pf1), together with a polybasic region immediately C-terminal to PHD1, binds phosphoinositides, most strongly PI(3)P. The polybasic region alone is necessary and sufficient for specific PI(3)P binding when fused to heterologous proteins or as an isolated peptide; swapping polybasic regions between PHD fingers transfers PI-binding specificity.\",\n      \"method\": \"Lipid-protein binding assays (PI strip/dot blot), GST/MBP fusion pulldowns with phosphoinositides, peptide binding experiments, domain-swap experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstituted lipid-binding assays with mutagenesis/domain-swap validation; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"16893883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The NMR solution structure of the mSin3A PAH2 domain bound to the PHF12 SID1 motif was determined, revealing a Mad1/Mxd1-like interaction mode. Unexpectedly, MRG15 competes with Sin3 PAH2 for the same PHF12 segment encompassing SID1 and a conserved adjacent motif, implying competitive rather than cooperative binding between two subunits of the same Rpd3S/Sin3S complex for PHF12.\",\n      \"method\": \"NMR structure determination, isothermal titration calorimetry (ITC), competitive binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution NMR structure plus ITC quantitative binding, functional competition shown; single lab\",\n      \"pmids\": [\"21440557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The PHD1 domain of PHF12 binds preferentially to the unmodified extreme N-terminus of histone H3 (H3K4me0) but not to H3K4me2/3. PHF12 PHD1 and MRG15 chromodomain each bind their respective histone H3 targets with >100 µM affinity, requiring bivalent (not cooperative) co-engagement to achieve biologically significant chromatin targeting of the Rpd3S/Sin3S complex. PHF12 PHD1 also engages the MRG15 MRG domain in a PHF12 MRG-binding-domain-dependent manner.\",\n      \"method\": \"Fluorescence polarization binding assays, isothermal titration calorimetry, peptide pulldowns, mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — quantitative in vitro binding assays (ITC, FP) plus mutagenesis, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22728643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Disruption of the SIN3A–PHF12 interaction (via a competitive Tat-SID peptide mimicking the SIN3 interaction domain of MAD) blocked PHF12 binding to SIN3A PAH2, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. PHF12 knockdown phenocopied Tat-SID treatment, reducing primary tumor growth and metastasis in vivo, establishing PHF12 as required for maintenance of the stem cell phenotype and EMT in triple-negative breast cancer.\",\n      \"method\": \"Competitive peptide displacement of SIN3A-PHF12 interaction, PHF12 shRNA knockdown, in vitro functional assays (proliferation, sphere formation), in vivo xenograft tumor model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — peptide competition plus genetic KD with functional readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"26460951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Genetic inactivation of Phf12 (Pf1) in mice causes mid-to-late gestation lethality. In mouse embryonic fibroblasts, Phf12 loss impairs proliferation, increases senescence-associated β-galactosidase activity (cellular senescence), elevates γ-H2A.X (DNA double-strand break marker), and disrupts nucleolar morphology. Proteomic analysis of PHF12-interacting complexes revealed enrichment of ribosome biogenesis factors, and transcript profiling showed PHF12 impacts multiple ribosome biogenesis regulatory pathways.\",\n      \"method\": \"Conditional/constitutive knockout mouse generation, MEF proliferation assays (BrdU incorporation), SA-β-Gal senescence assay, γ-H2A.X immunostaining, nucleolar morphology analysis, mass spectrometry-based proteomics of PHF12 complexes, transcriptomic profiling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic KO with multiple orthogonal cellular phenotype readouts plus proteomic complex characterization; single lab but highly rigorous multi-method study\",\n      \"pmids\": [\"27956701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Disruption of the PF1/SIN3A interaction (via PF1-SID expression) leads to increased occupancy of SIN3A and the transcriptional repressor KLF9 on the promoters of ITGA6 and ITGB1, reducing their expression. KLF9 knockdown restores ITGA6/ITGB1 expression and the invasive phenotype, placing KLF9 downstream of the SIN3A-PHF12 complex in suppression of invasion and migration in TNBC.\",\n      \"method\": \"ChIP assay (SIN3A and KLF9 promoter occupancy), RNA-seq transcriptomics, KLF9 knockdown rescue experiments, invasion/migration assays\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus epistasis rescue experiment (KLF9 KD) plus genome-wide transcriptomics; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34968869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PHF12 transcriptionally regulates HDAC1 expression: ChIP assay showed PHF12 binds the HDAC1 promoter region. PHF12 knockdown reduces HDAC1 mRNA and protein levels, and HDAC1 overexpression rescues proliferation and migration in PHF12-knockdown NSCLC cells. The PHF12-HDAC1 axis activates the EGFR/AKT signaling pathway in non-small cell lung cancer.\",\n      \"method\": \"ChIP assay (PHF12 binding at HDAC1 promoter), qRT-PCR/Western blot (HDAC1 mRNA and protein), siRNA knockdown, HDAC1 overexpression rescue, RNA-seq + GSEA pathway analysis, in vivo xenograft model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP plus rescue experiment with functional readouts; single lab, single paper\",\n      \"pmids\": [\"39075515\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHF12 (Pf1/KIAA1523) is a dual-PHD zinc finger adaptor protein that scaffolds the Rpd3S/Sin3S histone deacetylase corepressor complex: it uses two independent Sin3-interaction domains (SID1 binding mSin3A PAH2 in a Mad-like mode, SID2 binding PAH1) to recruit mSin3A-HDAC, interacts selectively with MRG15 (not MRGX/MORF4), and together with MRG15 bivalently engages histone H3 chromatin (PHD1 binding unmodified H3K4me0, MRG15 chromodomain binding H3K36me2/3) to suppress cryptic transcription; its PHD1 polybasic region also binds PI(3)P, linking it to phosphoinositide signaling; PHF12 additionally transcriptionally upregulates HDAC1 and activates EGFR/AKT signaling in cancer cells; and genetic loss of Phf12 in mice causes embryonic lethality, cellular senescence, nucleolar disruption, and impaired ribosome biogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHF12 (Pf1) is a dual-PHD zinc finger adaptor protein that scaffolds the Rpd3S/Sin3S histone deacetylase corepressor complex and directs it to chromatin to repress transcription [#0, #2]. It engages mSin3A through two independent Sin3-interaction domains: SID1 binds the PAH2 domain in a Mad/Mxd1-like mode (resolved by NMR), while SID2 binds PAH1 as a distinct novel module [#0, #4]. Within the MORF family, PHF12 selectively binds MRG15 (not MRGX or MORF4), and because PHF12 and MRG15 contact different surfaces of mSin3A it assembles a trimeric MRG15/PHF12/mSin3A complex [#2]; notably, MRG15 and the Sin3 PAH2 domain compete for an overlapping PHF12 segment, indicating dynamic rather than simultaneous engagement of these subunits [#4]. Chromatin targeting is achieved bivalently: the PHF12 PHD1 domain binds the unmodified histone H3 N-terminus (H3K4me0) while the MRG15 chromodomain reads a separate H3 mark, each at low affinity, so that co-engagement is required for stable recruitment [#5]. A polybasic region immediately C-terminal to PHD1 additionally binds phosphoinositides, most strongly PI(3)P [#3]. Beyond corepression, PHF12 sustains proliferative and invasive programs in cancer: it is required for maintenance of stem-cell and EMT phenotypes in triple-negative breast cancer via the SIN3A-PHF12 interaction and downstream KLF9-mediated control of ITGA6/ITGB1 [#6, #8], and it transcriptionally upregulates HDAC1 to activate EGFR/AKT signaling in non-small cell lung cancer [#9]. Genetic inactivation of Phf12 in mice causes mid-to-late gestation lethality, and Phf12-null fibroblasts display impaired proliferation, cellular senescence, elevated DNA-damage marking, disrupted nucleolar morphology, and impaired ribosome biogenesis, with PHF12 complexes enriched for ribosome biogenesis factors [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established PHF12 as a transcriptional corepressor adaptor by showing it physically recruits the mSin3A HDAC complex through two independent Sin3-interaction domains, defining its core repressive function.\",\n      \"evidence\": \"Co-IP, GST pulldown domain mapping, and Gal4-fusion repression assays in mammalian cells\",\n      \"pmids\": [\"11390640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve how SID1/SID2 dual binding affects complex stoichiometry\",\n        \"No chromatin target genes identified\",\n        \"TLE bridging (same paper) rests on Co-IP/reporter assay only\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the selectivity of PHF12 within the MORF family and showed it forms a defined trimeric complex, clarifying which corepressor module it assembles.\",\n      \"evidence\": \"Reciprocal Co-IP, GST pulldown domain mapping, and Gal4-luciferase repression assays\",\n      \"pmids\": [\"12391155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of MRG15 selectivity over MRGX/MORF4 not resolved\",\n        \"Endogenous complex composition in chromatin context not shown\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed an unexpected lipid-binding activity for PHF12, showing a polybasic region adjacent to PHD1 confers specific PI(3)P binding and linking the protein to phosphoinositide signaling.\",\n      \"evidence\": \"In vitro lipid-protein binding assays, fusion pulldowns, and domain-swap experiments\",\n      \"pmids\": [\"16893883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cellular function of PI(3)P binding for PHF12 not established\",\n        \"Whether lipid and histone binding by PHD1 are mutually exclusive unknown\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided atomic-resolution detail of the PHF12 SID1–mSin3A PAH2 interface and uncovered competition between MRG15 and PAH2 for PHF12, reframing how the complex subunits engage the adaptor.\",\n      \"evidence\": \"NMR solution structure, ITC, and competitive binding assays\",\n      \"pmids\": [\"21440557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of MRG15/PAH2 competition in vivo untested\",\n        \"Did not address the SID2-PAH1 interaction structurally\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that PHF12 PHD1 and MRG15 chromodomain co-read distinct H3 marks with low individual affinity, establishing bivalent recognition as the mechanism for targeting Rpd3S/Sin3S to chromatin.\",\n      \"evidence\": \"Fluorescence polarization, ITC, peptide pulldowns, and mutagenesis\",\n      \"pmids\": [\"22728643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo genome-wide chromatin occupancy not mapped\",\n        \"Link between bivalent reading and suppression of specific transcripts not directly shown\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the organismal and cellular requirement for PHF12, showing it is essential for embryonic viability and for preventing senescence, and linked it unexpectedly to nucleolar integrity and ribosome biogenesis.\",\n      \"evidence\": \"Knockout mouse, MEF phenotyping (proliferation, SA-β-Gal, γ-H2A.X, nucleolar morphology), proteomics, and transcriptomics\",\n      \"pmids\": [\"27956701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanistic link between corepressor scaffolding and ribosome biogenesis not resolved\",\n        \"Whether nucleolar phenotype is direct or downstream of senescence unclear\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed the SIN3A-PHF12 complex in a defined oncogenic circuit, showing it represses KLF9-controlled integrin genes to govern invasion in triple-negative breast cancer.\",\n      \"evidence\": \"ChIP for SIN3A/KLF9 occupancy, RNA-seq, KLF9 knockdown rescue, and invasion/migration assays\",\n      \"pmids\": [\"34968869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct PHF12 promoter binding at ITGA6/ITGB1 not shown\",\n        \"Generality beyond TNBC untested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a transcriptional output of PHF12 in lung cancer, showing it binds the HDAC1 promoter to upregulate HDAC1 and activate EGFR/AKT signaling, distinct from its classical corepressor role.\",\n      \"evidence\": \"ChIP at HDAC1 promoter, knockdown/overexpression rescue, RNA-seq/GSEA, and xenograft model\",\n      \"pmids\": [\"39075515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, single paper without reciprocal validation\",\n        \"How a corepressor adaptor activates HDAC1 transcription mechanistically unresolved\",\n        \"Direct versus indirect effect on EGFR/AKT not separated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PHF12's chromatin-corepressor scaffolding function mechanistically connects to ribosome biogenesis, embryonic viability, and its context-dependent oncogenic roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unified model linking corepression to nucleolar/ribosome phenotypes\",\n        \"Physiological role of PI(3)P binding undefined\",\n        \"Genome-wide direct target catalogue lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 8, 9]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"Rpd3S/Sin3S HDAC corepressor complex\",\n      \"MRG15/PHF12/mSin3A trimeric complex\"\n    ],\n    \"partners\": [\n      \"SIN3A\",\n      \"MRG15\",\n      \"TLE\",\n      \"HDAC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}