{"gene":"PHF19","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2012,"finding":"PHF19 Tudor domain directly binds trimethylated histone H3K36 (H3K36me3), a mark of active chromatin, as demonstrated by NMR spectroscopy and biochemical binding assays.","method":"NMR spectroscopy, biochemical histone-binding assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural evidence plus biochemical validation, independently reported in two concurrent papers (PMID:23104054 and PMID:23160351) with orthogonal methods","pmids":["23104054","23160351"],"is_preprint":false},{"year":2012,"finding":"PHF19 Tudor domain binding to H3K36me2/me3 is required for full enzymatic activity of the PRC2 complex, as shown by in vitro methyltransferase assays with Phf19 mutants.","method":"In vitro histone methyltransferase assay, NMR, mutagenesis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in vitro plus NMR structural validation and mutagenesis in a single rigorous study","pmids":["23104054"],"is_preprint":false},{"year":2012,"finding":"PHF19 is required to recruit the PRC2 complex and the H3K36me3 demethylase NO66 to stem cell genes during differentiation, leading to H3K27me3 deposition and transcriptional silencing.","method":"ChIP, knockdown rescue experiments in mouse ESCs, co-immunoprecipitation","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus ChIP plus loss-of-function with defined molecular phenotype, replicated across two independent papers","pmids":["23160351","23104054"],"is_preprint":false},{"year":2012,"finding":"PHF19 physically associates with the H3K36me3 demethylase NO66, as shown by co-immunoprecipitation.","method":"Co-immunoprecipitation","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP reported in a single study, consistent with functional data in same paper","pmids":["23160351"],"is_preprint":false},{"year":2012,"finding":"Tudor domains of both PHF1 and PHF19 selectively bind H3K36me3; the first PHD domains of PHF1 and PHF19 do not exhibit histone H3K4 binding and do not affect Tudor domain binding to histones.","method":"Biochemical histone-binding assays, structural analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with structural analysis, single lab, corroborating two other concurrent papers","pmids":["23228662"],"is_preprint":false},{"year":2012,"finding":"PHF19 silencing in melanoma cells reduces cell proliferation and increases transendothelial migration. Upstream, Akt signaling activates PHF19 expression, and phospho-Akt is part of the transcriptional complex at the PHF19 promoter.","method":"siRNA knockdown, proliferation assay, transendothelial migration assay, chromatin immunoprecipitation","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype plus ChIP demonstrating phospho-Akt at PHF19 promoter, single lab","pmids":["22487681"],"is_preprint":false},{"year":2015,"finding":"G9a promotes H3K27 methylation at the E-cadherin promoter by upregulating PCL3/PHF19, which increases PRC2 promoter recruitment; depletion of PCL3 elevates E-cadherin expression, establishing PCL3 as a downstream effector of G9a in this pathway.","method":"ChIP, knockdown, Western blot, overexpression in pancreatic cancer cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus loss-of-function with defined molecular phenotype, single lab with multiple orthogonal methods","pmids":["26688070"],"is_preprint":false},{"year":2018,"finding":"PHF19 promotes GBM cell proliferation, migration, and chemosensitivity through the SIAH1/β-catenin axis: PHF19 binds the SIAH1 promoter and represses its transcription, thereby stabilizing β-catenin; the effects of PHF19 on GBM cells are β-catenin-dependent.","method":"siRNA knockdown, ChIP, Wnt/β-catenin inhibitor (XAV-939), Western blot, proliferation/migration assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing direct promoter binding plus epistasis with β-catenin inhibitor, single lab","pmids":["30323224"],"is_preprint":false},{"year":2018,"finding":"PHF19 forms the PRC2 complex with EZH2, EED, and SUZ12 in glioma cells; PHF19 knockdown suppresses EZH2 phosphorylation and glioma cell proliferation.","method":"Co-immunoprecipitation, siRNA knockdown, proliferation assay, xenograft model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for complex formation, supported by KD phenotype across multiple cell models","pmids":["30131250"],"is_preprint":false},{"year":2019,"finding":"miR-155 enhances PRC2 activity in CD8+ T cells by promoting Phf19 expression through downregulation of the Akt inhibitor Ship1; Phf19 histone-binding capacity is required for PRC2 recruitment to target chromatin and for restraining T cell senescence.","method":"miRNA overexpression, knockdown, ChIP, functional T cell assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiments plus ChIP showing requirement for histone-binding domain, single lab","pmids":["31089138"],"is_preprint":false},{"year":2019,"finding":"PHF19 promotes multiple myeloma tumorigenicity through PRC2-interacting and chromatin-binding functions; PHF19 depletion leads to loss of broad H3K27me3 domains, impaired H3K27me3 spreading from CpG islands, and de-repression of PRC2 target genes including cell cycle inhibitors and interferon-JAK-STAT signaling genes.","method":"ChIP-seq, RNA-seq, shRNA knockdown, xenograft, overexpression in MM models","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq plus RNA-seq plus in vitro and in vivo KD phenotypes, multiple orthogonal methods in a rigorous study","pmids":["31383640"],"is_preprint":false},{"year":2020,"finding":"In prostate cancer cells, PHF19 interacts with PRC2 and binds to PRC2 targets on chromatin; PHF19 depletion triggers increased MTF2/PCL2 chromatin recruitment with genome-wide gain in PRC2 occupancy and H3K27me3, while promoting invasive growth and angiogenesis and reducing cell proliferation.","method":"Co-immunoprecipitation, ChIP-seq, RNA-seq, siRNA knockdown, invasion/angiogenesis assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP-seq, RNA-seq, and multiple functional assays; multiple orthogonal methods in single rigorous study","pmids":["32155117"],"is_preprint":false},{"year":2020,"finding":"Genetic depletion of Phf19 in mouse HSCs increases HSC identity and quiescence while causing redistribution of H3K27me3 that accumulates at blood lineage-specific genes, leading to defects in differentiation and aberrant hematopoiesis.","method":"Conditional genetic knockout, H3K27me3 ChIP-seq, flow cytometry, hematopoietic reconstitution assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with ChIP-seq and defined cellular phenotypes, multiple orthogonal methods","pmids":["32821835"],"is_preprint":false},{"year":2021,"finding":"PHF19 depletion in CML cells decreases cell proliferation and promotes differentiation; mechanistically, PHF19 directly regulates the cell cycle inhibitor p21; MTF2 (a PHF19 homolog) partially compensates for PHF19 loss at a subset of target genes, directing erythroid differentiation.","method":"siRNA knockdown, ChIP, proliferation and differentiation assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus KD with defined cellular and molecular phenotype, single lab","pmids":["33996816"],"is_preprint":false},{"year":2021,"finding":"The short isoform of PHF19 interacts with β-TrCP (the E3 ligase of Gli1), and PHF19 knockdown promotes ubiquitination of Gli1, thereby activating Hedgehog signaling and promoting HCC tumor growth.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown, xenograft and in vivo knockout HCC mouse model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction plus ubiquitination assay plus in vivo KO model, single lab","pmids":["34129846"],"is_preprint":false},{"year":2025,"finding":"WTAP-mediated m6A methylation on the 3'-UTR of PHF19 mRNA stabilizes PHF19 transcript, thereby upregulating PHF19 protein expression in t(8;21) AML; PHF19 knockdown leads to loss of H3K27me3 and enhanced chromatin accessibility, upregulating cell cycle and DNA damage checkpoint genes.","method":"m6A-seq, RNA stability assays, ChIP-seq, ATAC-seq, shRNA knockdown, in vitro and in vivo AML models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — m6A mapping plus RNA stability assays plus ChIP-seq plus ATAC-seq plus in vivo models, multiple orthogonal methods in a single rigorous study","pmids":["40038518"],"is_preprint":false},{"year":2025,"finding":"PHF19 drives formation of micron-scale nuclear PRC2 clusters in TNBC cells through an intrinsically disordered region (IDR); these clusters stabilize local PRC2 occupancy and reinforce H3K27me3 macro-domain organization. The IDR-dependent clustering is required for promoting TNBC cell motility.","method":"In situ subcellular proteomics, high-resolution imaging, functional genomics, IDR mutagenesis, cell motility assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — integrated spatial proteomics, high-resolution imaging, and mutagenesis linking clustering to cell behavior; multiple orthogonal methods in single rigorous study","pmids":["41066230"],"is_preprint":false},{"year":2025,"finding":"The long isoform PHF19L is recruited to m6A-modified nascent RNA through YTHDC1, forming a liquid-like YTHDC1-PHF19L condensate that sequesters EZH2 away from chromatin, resulting in reduced H3K27me3 deposition and activation of EZH2-repressed genes during advanced prostate cancer progression.","method":"Co-immunoprecipitation, condensate/phase separation assays, ChIP-seq, RNA-seq, knockdown and overexpression in prostate cancer models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, condensate assays, ChIP-seq, and RNA-seq with multiple orthogonal methods establishing mechanistic switch","pmids":["41129231"],"is_preprint":false},{"year":2025,"finding":"In human pluripotent stem cells, PHF19 antagonizes MTF2-PRC2.1-mediated repression; MTF2 stimulates PRC2.1 activity through its interactions with DNA and H3K36me3, while PHF19 opposes this, with the two PCL proteins having distinct and opposing roles in H3K27me3 deposition at developmental genes and cardiomyocyte differentiation.","method":"CRISPR separation-of-function mutants in hPSCs, ChIP-seq, differentiation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered separation-of-function mutants plus ChIP-seq; preprint, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2025.05.15.654236"],"is_preprint":true},{"year":2032,"finding":"BRCA1 was found to interact with PHF19-PRC2 complex components (PHF19, EZH2, EED, SUZ12, RbAp46/48) by co-immunoprecipitation; PDGF-BB treatment upregulates PHF19-PRC2 complex members while downregulating BRCA1 via miR-221 in pericytes.","method":"Co-immunoprecipitation, luciferase reporter assay, Western blot, in vivo APP/PS1 mouse model","journal":"Brain research bulletin","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for complex interaction, single lab, mechanistic context is indirect","pmids":["41825614"],"is_preprint":false}],"current_model":"PHF19 is a PRC2 accessory subunit (forming the PRC2.1 subcomplex) that uses its Tudor domain to bind H3K36me2/me3 on active chromatin, thereby recruiting PRC2 and the H3K36me3 demethylase NO66 to facilitate H3K27me3 deposition and transcriptional silencing during developmental transitions; it also forms nuclear PRC2 clusters via an intrinsically disordered region to reinforce H3K27me3 domain organization, directly represses target genes (including SIAH1 and p21) to modulate β-catenin stability and cell cycle, can form a liquid condensate with YTHDC1 that sequesters EZH2 away from chromatin to activate otherwise-silenced genes, and is post-translationally regulated at the mRNA level by WTAP-mediated m6A methylation—collectively controlling the balance between proliferation, differentiation, and invasiveness across multiple cell types."},"narrative":{"mechanistic_narrative":"PHF19 (PCL3) is a Polycomb-like accessory subunit of PRC2 that couples recognition of active-chromatin marks to deposition of the repressive H3K27me3 modification, thereby controlling the balance between proliferation and differentiation across stem cells and multiple cancers [PMID:23104054, PMID:23160351, PMID:31383640]. Its Tudor domain selectively binds H3K36me2/me3, an interaction required for full PRC2 methyltransferase activity and for recruiting both PRC2 and the H3K36me3 demethylase NO66 to target genes during differentiation [PMID:23104054, PMID:23160351]. Genome-wide, PHF19 promotes H3K27me3 spreading from CpG islands and the organization of broad H3K27me3 domains, and its loss de-represses PRC2 target genes including cell-cycle inhibitors and interferon-JAK-STAT genes [PMID:31383640, PMID:32821835]; in triple-negative breast cancer cells it drives micron-scale nuclear PRC2 clusters through an intrinsically disordered region that stabilizes local PRC2 occupancy and reinforces H3K27me3 macro-domains [PMID:41066230]. PHF19 also directly represses individual target promoters, repressing SIAH1 to stabilize β-catenin and regulating the cell-cycle inhibitor p21 to promote proliferation [PMID:30323224, PMID:33996816]. Its activity is antagonized or redirected by related PCL proteins MTF2/PCL2, whose chromatin recruitment increases upon PHF19 loss [PMID:32155117, PMID:bio_10.1101_2025.05.15.654236], and it is regulated through RNA-based mechanisms: WTAP-deposited m6A on the PHF19 3'-UTR stabilizes its transcript [PMID:40038518], while the long isoform PHF19L is recruited to m6A-modified nascent RNA via YTHDC1 to form a liquid condensate that sequesters EZH2 away from chromatin and activates otherwise-silenced genes [PMID:41129231].","teleology":[{"year":2012,"claim":"Establishing how a Polycomb-like protein reads active chromatin, the Tudor domain of PHF19 was shown to directly and selectively bind H3K36me3, defining the molecular basis for targeting PRC2 to active-mark chromatin.","evidence":"NMR spectroscopy and biochemical histone-binding assays, replicated across two concurrent papers","pmids":["23104054","23160351","23228662"],"confidence":"High","gaps":["Does not establish in vivo genome-wide consequences of the binding","PHD-domain function not resolved"]},{"year":2012,"claim":"Linking the histone-reading activity to enzymatic output, Tudor binding to H3K36me2/me3 was shown to be required for full PRC2 methyltransferase activity, connecting mark recognition to catalysis.","evidence":"In vitro reconstituted methyltransferase assays with Phf19 mutants plus NMR and mutagenesis","pmids":["23104054"],"confidence":"High","gaps":["Quantitative contribution relative to other PRC2 cofactors not defined"]},{"year":2012,"claim":"Defining the developmental function, PHF19 was shown to recruit PRC2 and the H3K36me3 demethylase NO66 to stem-cell genes during differentiation, providing a model for converting active to repressive chromatin.","evidence":"ChIP, knockdown-rescue in mouse ESCs and co-immunoprecipitation","pmids":["23160351","23104054"],"confidence":"High","gaps":["NO66 association rests on Co-IP without reciprocal structural validation","Order of NO66 vs PRC2 recruitment not resolved"]},{"year":2012,"claim":"Connecting PHF19 to cancer signaling, Akt was shown to activate PHF19 expression in melanoma where PHF19 silencing reduces proliferation but increases transendothelial migration, hinting at context-dependent roles.","evidence":"siRNA knockdown, proliferation and transendothelial migration assays, ChIP at the PHF19 promoter","pmids":["22487681"],"confidence":"Medium","gaps":["Mechanism linking PHF19 to migration not defined","Single lab, single cancer type"]},{"year":2015,"claim":"Placing PHF19 in an upstream signaling cascade, G9a was shown to upregulate PCL3/PHF19 to increase PRC2 recruitment and H3K27 methylation at the E-cadherin promoter, positioning PHF19 as a downstream effector controlling an EMT-relevant gene.","evidence":"ChIP, knockdown, overexpression and Western blot in pancreatic cancer cells","pmids":["26688070"],"confidence":"Medium","gaps":["Direct vs indirect transcriptional control of PHF19 by G9a unresolved","Generality beyond E-cadherin not tested"]},{"year":2018,"claim":"Identifying a direct target-gene mechanism, PHF19 was shown to bind the SIAH1 promoter and repress it to stabilize β-catenin in glioma, establishing a β-catenin-dependent route to proliferation and migration.","evidence":"siRNA knockdown, ChIP, Wnt/β-catenin inhibitor epistasis, proliferation/migration assays; separate Co-IP confirming PRC2 (EZH2/EED/SUZ12) assembly","pmids":["30323224","30131250"],"confidence":"Medium","gaps":["Whether SIAH1 repression is PRC2/H3K27me3-dependent not shown","Single-lab tumor models"]},{"year":2019,"claim":"Demonstrating genome-scale chromatin function, PHF19 was shown to drive H3K27me3 spreading from CpG islands and organization of broad repressive domains in multiple myeloma, with loss de-repressing cell-cycle and interferon-JAK-STAT genes; a parallel study showed miR-155/Ship1/Akt signaling promotes Phf19 to restrain T-cell senescence in a histone-binding-dependent manner.","evidence":"ChIP-seq, RNA-seq, shRNA, xenograft in MM; miRNA gain/loss, ChIP and T-cell assays","pmids":["31383640","31089138"],"confidence":"High","gaps":["Mechanism of domain spreading not biochemically reconstituted","Direct vs secondary targets of de-repression not fully separated"]},{"year":2020,"claim":"Revealing functional interplay among PCL proteins, PHF19 depletion in prostate cancer was shown to increase MTF2/PCL2 recruitment and genome-wide gain of PRC2/H3K27me3, while in HSCs Phf19 loss redistributed H3K27me3 and enhanced quiescence, indicating PHF19 shapes where, not simply how much, H3K27me3 is deposited.","evidence":"Co-IP, ChIP-seq, RNA-seq and functional assays in prostate cancer; conditional knockout, H3K27me3 ChIP-seq and reconstitution assays in mouse HSCs","pmids":["32155117","32821835"],"confidence":"High","gaps":["Molecular basis of MTF2/PHF19 competition not structurally defined","Tissue-specificity of redistribution outcomes unexplained"]},{"year":2021,"claim":"Extending the proliferation-differentiation axis, PHF19 was shown to directly regulate p21 in CML with MTF2 partially compensating to direct erythroid differentiation, and a short PHF19 isoform was found to bind β-TrCP to suppress Gli1 ubiquitination and activate Hedgehog signaling in HCC, revealing isoform- and PRC2-independent functions.","evidence":"siRNA, ChIP, differentiation assays in CML; Co-IP, ubiquitination assay, xenograft and in vivo KO in HCC","pmids":["33996816","34129846"],"confidence":"Medium","gaps":["β-TrCP/Gli1 mechanism rests on single-lab Co-IP and ubiquitination assays","Isoform expression patterns across tissues not mapped"]},{"year":2025,"claim":"Defining higher-order and RNA-coupled regulation, studies showed PHF19 forms IDR-dependent micron-scale nuclear PRC2 clusters reinforcing H3K27me3 macro-domains and TNBC motility, that WTAP-mediated 3'-UTR m6A stabilizes PHF19 mRNA in t(8;21) AML, and that PHF19L forms a YTHDC1 condensate sequestering EZH2 from chromatin to activate genes in prostate cancer.","evidence":"Spatial proteomics, high-resolution imaging and IDR mutagenesis (TNBC); m6A-seq, RNA stability, ChIP-seq, ATAC-seq, in vivo AML models; Co-IP, condensate assays, ChIP-seq, RNA-seq (prostate)","pmids":["41066230","40038518","41129231"],"confidence":"High","gaps":["Whether clustering and condensate functions coexist in the same cells unknown","Switch between repressive PRC2-recruiting and EZH2-sequestering activities not mechanistically unified"]},{"year":2025,"claim":"Probing opposing PCL functions in development, separation-of-function mutants in human pluripotent stem cells indicated PHF19 antagonizes MTF2-PRC2.1-mediated repression at developmental genes during cardiomyocyte differentiation.","evidence":"CRISPR separation-of-function mutants in hPSCs, ChIP-seq and differentiation assays (preprint)","pmids":["bio_10.1101_2025.05.15.654236"],"confidence":"Medium","gaps":["Preprint, single lab, not yet peer-reviewed","Reconciliation with PHF19's repressive roles in other contexts unresolved"]},{"year":null,"claim":"How PHF19 switches between recruiting PRC2 to deposit H3K27me3 and sequestering EZH2 to activate genes—across isoforms, condensates, and competing PCL proteins—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating repressive and activating modes","Determinants of isoform choice and condensate formation in vivo unknown","Structural basis of PHF19 vs MTF2 chromatin partitioning not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1,4,2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,13,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,11,18]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16,2,10]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[10,12,16]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,2,10,12,16]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,10,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,12,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,10,11,14,15]}],"complexes":["PRC2","PRC2.1"],"partners":["EZH2","EED","SUZ12","NO66","MTF2","YTHDC1","WTAP","BTRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T6S3","full_name":"PHD finger protein 19","aliases":["Polycomb-like protein 3","hPCL3"],"length_aa":580,"mass_kda":65.6,"function":"Polycomb group (PcG) protein that specifically binds histone H3 trimethylated at 'Lys-36' (H3K36me3) and recruits the PRC2 complex, thus enhancing PRC2 H3K27me3 methylation activity (PubMed:15563832, PubMed:18691976, PubMed:23104054, PubMed:23160351, PubMed:23228662, PubMed:23273982, PubMed:29499137, PubMed:31959557). Probably involved in the transition from an active state to a repressed state in embryonic stem cells: acts by binding to H3K36me3, a mark for transcriptional activation, and recruiting H3K36me3 histone demethylases RIOX1 or KDM2B, leading to demethylation of H3K36 and recruitment of the PRC2 complex that mediates H3K27me3 methylation, followed by de novo silencing (PubMed:23160351). Recruits the PRC2 complex to CpG islands and contributes to embryonic stem cell self-renewal. Also binds histone H3 dimethylated at 'Lys-36' (H3K36me2) (PubMed:23104054). Isoform 1 and isoform 2 inhibit transcription from an HSV-tk promoter (PubMed:15563832)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q5T6S3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHF19","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PHF19","total_profiled":1310},"omim":[{"mim_id":"619640","title":"LYSINE DEMETHYLASE 7A; KDM7A","url":"https://www.omim.org/entry/619640"},{"mim_id":"609740","title":"PHD FINGER PROTEIN 19; PHF19","url":"https://www.omim.org/entry/609740"},{"mim_id":"604599","title":"EUCHROMATIC HISTONE-LYSINE N-METHYLTRANSFERASE 2; EHMT2","url":"https://www.omim.org/entry/604599"},{"mim_id":"192090","title":"CADHERIN 1; CDH1","url":"https://www.omim.org/entry/192090"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHF19"},"hgnc":{"alias_symbol":["DKFZP727G051","PCL3","MTF2L1","TDRD19B"],"prev_symbol":[]},"alphafold":{"accession":"Q5T6S3","domains":[{"cath_id":"2.30.30.140","chopping":"26-89","consensus_level":"medium","plddt":83.6522,"start":26,"end":89},{"cath_id":"1.10.10","chopping":"259-347","consensus_level":"high","plddt":92.4946,"start":259,"end":347}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T6S3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T6S3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T6S3-F1-predicted_aligned_error_v6.png","plddt_mean":69.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHF19","jax_strain_url":"https://www.jax.org/strain/search?query=PHF19"},"sequence":{"accession":"Q5T6S3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T6S3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T6S3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T6S3"}},"corpus_meta":[{"pmid":"23160351","id":"PMC_23160351","title":"Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation.","date":"2012","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23160351","citation_count":205,"is_preprint":false},{"pmid":"23104054","id":"PMC_23104054","title":"Phf19 links methylated Lys36 of histone H3 to regulation of Polycomb activity.","date":"2012","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23104054","citation_count":191,"is_preprint":false},{"pmid":"34737287","id":"PMC_34737287","title":"Genome-wide profiling in colorectal cancer identifies PHF19 and TBC1D16 as oncogenic super enhancers.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34737287","citation_count":86,"is_preprint":false},{"pmid":"31089138","id":"PMC_31089138","title":"miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31089138","citation_count":76,"is_preprint":false},{"pmid":"29874124","id":"PMC_29874124","title":"miR-211 sponges lncRNA MALAT1 to suppress tumor growth and progression through inhibiting PHF19 in ovarian carcinoma.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/29874124","citation_count":74,"is_preprint":false},{"pmid":"31383640","id":"PMC_31383640","title":"PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation.","date":"2019","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/31383640","citation_count":64,"is_preprint":false},{"pmid":"25955388","id":"PMC_25955388","title":"MicroRNA-195-5p acts as an anti-oncogene by targeting PHF19 in hepatocellular carcinoma.","date":"2015","source":"Oncology 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Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22487681","citation_count":41,"is_preprint":false},{"pmid":"23228662","id":"PMC_23228662","title":"Tudor domains of the PRC2 components PHF1 and PHF19 selectively bind to histone H3K36me3.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23228662","citation_count":41,"is_preprint":false},{"pmid":"26688070","id":"PMC_26688070","title":"G9a orchestrates PCL3 and KDM7A to promote histone H3K27 methylation.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26688070","citation_count":40,"is_preprint":false},{"pmid":"32155117","id":"PMC_32155117","title":"PHF19 mediated regulation of proliferation and invasiveness in prostate cancer cells.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32155117","citation_count":32,"is_preprint":false},{"pmid":"32821835","id":"PMC_32821835","title":"The Polycomb-associated factor PHF19 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myeloma.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38755140","citation_count":9,"is_preprint":false},{"pmid":"32449434","id":"PMC_32449434","title":"Downregulation of PHF19 inhibits cell growth and migration in gastric cancer.","date":"2020","source":"Scandinavian journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/32449434","citation_count":8,"is_preprint":false},{"pmid":"34078310","id":"PMC_34078310","title":"LINC_00355 promotes gastric cancer progression by upregulating PHF19 expression through sponging miR-15a-5p.","date":"2021","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34078310","citation_count":7,"is_preprint":false},{"pmid":"33894670","id":"PMC_33894670","title":"PHF19 inhibition as a therapeutic target in multiple myeloma.","date":"2021","source":"Current research in translational 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bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/41825614","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.15.654236","title":"Macromolecular interactions dictate Polycomb-mediated epigenetic repression","date":"2025-05-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.15.654236","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.13.642950","title":"PHF19 drives PRC2 sub-nuclear compartmentalization to promote motility in TNBC cells","date":"2025-03-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.13.642950","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17425,"output_tokens":4414,"usd":0.059242,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12443,"output_tokens":4452,"usd":0.086758,"stage2_stop_reason":"end_turn"},"total_usd":0.146,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"PHF19 Tudor domain directly binds trimethylated histone H3K36 (H3K36me3), a mark of active chromatin, as demonstrated by NMR spectroscopy and biochemical binding assays.\",\n      \"method\": \"NMR spectroscopy, biochemical histone-binding assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural evidence plus biochemical validation, independently reported in two concurrent papers (PMID:23104054 and PMID:23160351) with orthogonal methods\",\n      \"pmids\": [\"23104054\", \"23160351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PHF19 Tudor domain binding to H3K36me2/me3 is required for full enzymatic activity of the PRC2 complex, as shown by in vitro methyltransferase assays with Phf19 mutants.\",\n      \"method\": \"In vitro histone methyltransferase assay, NMR, mutagenesis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in vitro plus NMR structural validation and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"23104054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PHF19 is required to recruit the PRC2 complex and the H3K36me3 demethylase NO66 to stem cell genes during differentiation, leading to H3K27me3 deposition and transcriptional silencing.\",\n      \"method\": \"ChIP, knockdown rescue experiments in mouse ESCs, co-immunoprecipitation\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus ChIP plus loss-of-function with defined molecular phenotype, replicated across two independent papers\",\n      \"pmids\": [\"23160351\", \"23104054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PHF19 physically associates with the H3K36me3 demethylase NO66, as shown by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP reported in a single study, consistent with functional data in same paper\",\n      \"pmids\": [\"23160351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tudor domains of both PHF1 and PHF19 selectively bind H3K36me3; the first PHD domains of PHF1 and PHF19 do not exhibit histone H3K4 binding and do not affect Tudor domain binding to histones.\",\n      \"method\": \"Biochemical histone-binding assays, structural analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with structural analysis, single lab, corroborating two other concurrent papers\",\n      \"pmids\": [\"23228662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PHF19 silencing in melanoma cells reduces cell proliferation and increases transendothelial migration. Upstream, Akt signaling activates PHF19 expression, and phospho-Akt is part of the transcriptional complex at the PHF19 promoter.\",\n      \"method\": \"siRNA knockdown, proliferation assay, transendothelial migration assay, chromatin immunoprecipitation\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype plus ChIP demonstrating phospho-Akt at PHF19 promoter, single lab\",\n      \"pmids\": [\"22487681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"G9a promotes H3K27 methylation at the E-cadherin promoter by upregulating PCL3/PHF19, which increases PRC2 promoter recruitment; depletion of PCL3 elevates E-cadherin expression, establishing PCL3 as a downstream effector of G9a in this pathway.\",\n      \"method\": \"ChIP, knockdown, Western blot, overexpression in pancreatic cancer cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus loss-of-function with defined molecular phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26688070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHF19 promotes GBM cell proliferation, migration, and chemosensitivity through the SIAH1/β-catenin axis: PHF19 binds the SIAH1 promoter and represses its transcription, thereby stabilizing β-catenin; the effects of PHF19 on GBM cells are β-catenin-dependent.\",\n      \"method\": \"siRNA knockdown, ChIP, Wnt/β-catenin inhibitor (XAV-939), Western blot, proliferation/migration assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing direct promoter binding plus epistasis with β-catenin inhibitor, single lab\",\n      \"pmids\": [\"30323224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHF19 forms the PRC2 complex with EZH2, EED, and SUZ12 in glioma cells; PHF19 knockdown suppresses EZH2 phosphorylation and glioma cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, proliferation assay, xenograft model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for complex formation, supported by KD phenotype across multiple cell models\",\n      \"pmids\": [\"30131250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-155 enhances PRC2 activity in CD8+ T cells by promoting Phf19 expression through downregulation of the Akt inhibitor Ship1; Phf19 histone-binding capacity is required for PRC2 recruitment to target chromatin and for restraining T cell senescence.\",\n      \"method\": \"miRNA overexpression, knockdown, ChIP, functional T cell assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiments plus ChIP showing requirement for histone-binding domain, single lab\",\n      \"pmids\": [\"31089138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHF19 promotes multiple myeloma tumorigenicity through PRC2-interacting and chromatin-binding functions; PHF19 depletion leads to loss of broad H3K27me3 domains, impaired H3K27me3 spreading from CpG islands, and de-repression of PRC2 target genes including cell cycle inhibitors and interferon-JAK-STAT signaling genes.\",\n      \"method\": \"ChIP-seq, RNA-seq, shRNA knockdown, xenograft, overexpression in MM models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq plus RNA-seq plus in vitro and in vivo KD phenotypes, multiple orthogonal methods in a rigorous study\",\n      \"pmids\": [\"31383640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In prostate cancer cells, PHF19 interacts with PRC2 and binds to PRC2 targets on chromatin; PHF19 depletion triggers increased MTF2/PCL2 chromatin recruitment with genome-wide gain in PRC2 occupancy and H3K27me3, while promoting invasive growth and angiogenesis and reducing cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, RNA-seq, siRNA knockdown, invasion/angiogenesis assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP-seq, RNA-seq, and multiple functional assays; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"32155117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Genetic depletion of Phf19 in mouse HSCs increases HSC identity and quiescence while causing redistribution of H3K27me3 that accumulates at blood lineage-specific genes, leading to defects in differentiation and aberrant hematopoiesis.\",\n      \"method\": \"Conditional genetic knockout, H3K27me3 ChIP-seq, flow cytometry, hematopoietic reconstitution assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with ChIP-seq and defined cellular phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"32821835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PHF19 depletion in CML cells decreases cell proliferation and promotes differentiation; mechanistically, PHF19 directly regulates the cell cycle inhibitor p21; MTF2 (a PHF19 homolog) partially compensates for PHF19 loss at a subset of target genes, directing erythroid differentiation.\",\n      \"method\": \"siRNA knockdown, ChIP, proliferation and differentiation assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus KD with defined cellular and molecular phenotype, single lab\",\n      \"pmids\": [\"33996816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The short isoform of PHF19 interacts with β-TrCP (the E3 ligase of Gli1), and PHF19 knockdown promotes ubiquitination of Gli1, thereby activating Hedgehog signaling and promoting HCC tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown, xenograft and in vivo knockout HCC mouse model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction plus ubiquitination assay plus in vivo KO model, single lab\",\n      \"pmids\": [\"34129846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WTAP-mediated m6A methylation on the 3'-UTR of PHF19 mRNA stabilizes PHF19 transcript, thereby upregulating PHF19 protein expression in t(8;21) AML; PHF19 knockdown leads to loss of H3K27me3 and enhanced chromatin accessibility, upregulating cell cycle and DNA damage checkpoint genes.\",\n      \"method\": \"m6A-seq, RNA stability assays, ChIP-seq, ATAC-seq, shRNA knockdown, in vitro and in vivo AML models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — m6A mapping plus RNA stability assays plus ChIP-seq plus ATAC-seq plus in vivo models, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"40038518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PHF19 drives formation of micron-scale nuclear PRC2 clusters in TNBC cells through an intrinsically disordered region (IDR); these clusters stabilize local PRC2 occupancy and reinforce H3K27me3 macro-domain organization. The IDR-dependent clustering is required for promoting TNBC cell motility.\",\n      \"method\": \"In situ subcellular proteomics, high-resolution imaging, functional genomics, IDR mutagenesis, cell motility assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — integrated spatial proteomics, high-resolution imaging, and mutagenesis linking clustering to cell behavior; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"41066230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The long isoform PHF19L is recruited to m6A-modified nascent RNA through YTHDC1, forming a liquid-like YTHDC1-PHF19L condensate that sequesters EZH2 away from chromatin, resulting in reduced H3K27me3 deposition and activation of EZH2-repressed genes during advanced prostate cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, condensate/phase separation assays, ChIP-seq, RNA-seq, knockdown and overexpression in prostate cancer models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, condensate assays, ChIP-seq, and RNA-seq with multiple orthogonal methods establishing mechanistic switch\",\n      \"pmids\": [\"41129231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In human pluripotent stem cells, PHF19 antagonizes MTF2-PRC2.1-mediated repression; MTF2 stimulates PRC2.1 activity through its interactions with DNA and H3K36me3, while PHF19 opposes this, with the two PCL proteins having distinct and opposing roles in H3K27me3 deposition at developmental genes and cardiomyocyte differentiation.\",\n      \"method\": \"CRISPR separation-of-function mutants in hPSCs, ChIP-seq, differentiation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered separation-of-function mutants plus ChIP-seq; preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.15.654236\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2032,\n      \"finding\": \"BRCA1 was found to interact with PHF19-PRC2 complex components (PHF19, EZH2, EED, SUZ12, RbAp46/48) by co-immunoprecipitation; PDGF-BB treatment upregulates PHF19-PRC2 complex members while downregulating BRCA1 via miR-221 in pericytes.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, Western blot, in vivo APP/PS1 mouse model\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for complex interaction, single lab, mechanistic context is indirect\",\n      \"pmids\": [\"41825614\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHF19 is a PRC2 accessory subunit (forming the PRC2.1 subcomplex) that uses its Tudor domain to bind H3K36me2/me3 on active chromatin, thereby recruiting PRC2 and the H3K36me3 demethylase NO66 to facilitate H3K27me3 deposition and transcriptional silencing during developmental transitions; it also forms nuclear PRC2 clusters via an intrinsically disordered region to reinforce H3K27me3 domain organization, directly represses target genes (including SIAH1 and p21) to modulate β-catenin stability and cell cycle, can form a liquid condensate with YTHDC1 that sequesters EZH2 away from chromatin to activate otherwise-silenced genes, and is post-translationally regulated at the mRNA level by WTAP-mediated m6A methylation—collectively controlling the balance between proliferation, differentiation, and invasiveness across multiple cell types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHF19 (PCL3) is a Polycomb-like accessory subunit of PRC2 that couples recognition of active-chromatin marks to deposition of the repressive H3K27me3 modification, thereby controlling the balance between proliferation and differentiation across stem cells and multiple cancers [#0, #2, #10]. Its Tudor domain selectively binds H3K36me2/me3, an interaction required for full PRC2 methyltransferase activity and for recruiting both PRC2 and the H3K36me3 demethylase NO66 to target genes during differentiation [#0, #1, #2, #3]. Genome-wide, PHF19 promotes H3K27me3 spreading from CpG islands and the organization of broad H3K27me3 domains, and its loss de-represses PRC2 target genes including cell-cycle inhibitors and interferon-JAK-STAT genes [#10, #12]; in triple-negative breast cancer cells it drives micron-scale nuclear PRC2 clusters through an intrinsically disordered region that stabilizes local PRC2 occupancy and reinforces H3K27me3 macro-domains [#16]. PHF19 also directly represses individual target promoters, repressing SIAH1 to stabilize \\u03b2-catenin and regulating the cell-cycle inhibitor p21 to promote proliferation [#7, #13]. Its activity is antagonized or redirected by related PCL proteins MTF2/PCL2, whose chromatin recruitment increases upon PHF19 loss [#11, #18], and it is regulated through RNA-based mechanisms: WTAP-deposited m6A on the PHF19 3'-UTR stabilizes its transcript [#15], while the long isoform PHF19L is recruited to m6A-modified nascent RNA via YTHDC1 to form a liquid condensate that sequesters EZH2 away from chromatin and activates otherwise-silenced genes [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing how a Polycomb-like protein reads active chromatin, the Tudor domain of PHF19 was shown to directly and selectively bind H3K36me3, defining the molecular basis for targeting PRC2 to active-mark chromatin.\",\n      \"evidence\": \"NMR spectroscopy and biochemical histone-binding assays, replicated across two concurrent papers\",\n      \"pmids\": [\"23104054\", \"23160351\", \"23228662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish in vivo genome-wide consequences of the binding\", \"PHD-domain function not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linking the histone-reading activity to enzymatic output, Tudor binding to H3K36me2/me3 was shown to be required for full PRC2 methyltransferase activity, connecting mark recognition to catalysis.\",\n      \"evidence\": \"In vitro reconstituted methyltransferase assays with Phf19 mutants plus NMR and mutagenesis\",\n      \"pmids\": [\"23104054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution relative to other PRC2 cofactors not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining the developmental function, PHF19 was shown to recruit PRC2 and the H3K36me3 demethylase NO66 to stem-cell genes during differentiation, providing a model for converting active to repressive chromatin.\",\n      \"evidence\": \"ChIP, knockdown-rescue in mouse ESCs and co-immunoprecipitation\",\n      \"pmids\": [\"23160351\", \"23104054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NO66 association rests on Co-IP without reciprocal structural validation\", \"Order of NO66 vs PRC2 recruitment not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connecting PHF19 to cancer signaling, Akt was shown to activate PHF19 expression in melanoma where PHF19 silencing reduces proliferation but increases transendothelial migration, hinting at context-dependent roles.\",\n      \"evidence\": \"siRNA knockdown, proliferation and transendothelial migration assays, ChIP at the PHF19 promoter\",\n      \"pmids\": [\"22487681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking PHF19 to migration not defined\", \"Single lab, single cancer type\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placing PHF19 in an upstream signaling cascade, G9a was shown to upregulate PCL3/PHF19 to increase PRC2 recruitment and H3K27 methylation at the E-cadherin promoter, positioning PHF19 as a downstream effector controlling an EMT-relevant gene.\",\n      \"evidence\": \"ChIP, knockdown, overexpression and Western blot in pancreatic cancer cells\",\n      \"pmids\": [\"26688070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcriptional control of PHF19 by G9a unresolved\", \"Generality beyond E-cadherin not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying a direct target-gene mechanism, PHF19 was shown to bind the SIAH1 promoter and repress it to stabilize \\u03b2-catenin in glioma, establishing a \\u03b2-catenin-dependent route to proliferation and migration.\",\n      \"evidence\": \"siRNA knockdown, ChIP, Wnt/\\u03b2-catenin inhibitor epistasis, proliferation/migration assays; separate Co-IP confirming PRC2 (EZH2/EED/SUZ12) assembly\",\n      \"pmids\": [\"30323224\", \"30131250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SIAH1 repression is PRC2/H3K27me3-dependent not shown\", \"Single-lab tumor models\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating genome-scale chromatin function, PHF19 was shown to drive H3K27me3 spreading from CpG islands and organization of broad repressive domains in multiple myeloma, with loss de-repressing cell-cycle and interferon-JAK-STAT genes; a parallel study showed miR-155/Ship1/Akt signaling promotes Phf19 to restrain T-cell senescence in a histone-binding-dependent manner.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, shRNA, xenograft in MM; miRNA gain/loss, ChIP and T-cell assays\",\n      \"pmids\": [\"31383640\", \"31089138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of domain spreading not biochemically reconstituted\", \"Direct vs secondary targets of de-repression not fully separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealing functional interplay among PCL proteins, PHF19 depletion in prostate cancer was shown to increase MTF2/PCL2 recruitment and genome-wide gain of PRC2/H3K27me3, while in HSCs Phf19 loss redistributed H3K27me3 and enhanced quiescence, indicating PHF19 shapes where, not simply how much, H3K27me3 is deposited.\",\n      \"evidence\": \"Co-IP, ChIP-seq, RNA-seq and functional assays in prostate cancer; conditional knockout, H3K27me3 ChIP-seq and reconstitution assays in mouse HSCs\",\n      \"pmids\": [\"32155117\", \"32821835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of MTF2/PHF19 competition not structurally defined\", \"Tissue-specificity of redistribution outcomes unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extending the proliferation-differentiation axis, PHF19 was shown to directly regulate p21 in CML with MTF2 partially compensating to direct erythroid differentiation, and a short PHF19 isoform was found to bind \\u03b2-TrCP to suppress Gli1 ubiquitination and activate Hedgehog signaling in HCC, revealing isoform- and PRC2-independent functions.\",\n      \"evidence\": \"siRNA, ChIP, differentiation assays in CML; Co-IP, ubiquitination assay, xenograft and in vivo KO in HCC\",\n      \"pmids\": [\"33996816\", \"34129846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"\\u03b2-TrCP/Gli1 mechanism rests on single-lab Co-IP and ubiquitination assays\", \"Isoform expression patterns across tissues not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining higher-order and RNA-coupled regulation, studies showed PHF19 forms IDR-dependent micron-scale nuclear PRC2 clusters reinforcing H3K27me3 macro-domains and TNBC motility, that WTAP-mediated 3'-UTR m6A stabilizes PHF19 mRNA in t(8;21) AML, and that PHF19L forms a YTHDC1 condensate sequestering EZH2 from chromatin to activate genes in prostate cancer.\",\n      \"evidence\": \"Spatial proteomics, high-resolution imaging and IDR mutagenesis (TNBC); m6A-seq, RNA stability, ChIP-seq, ATAC-seq, in vivo AML models; Co-IP, condensate assays, ChIP-seq, RNA-seq (prostate)\",\n      \"pmids\": [\"41066230\", \"40038518\", \"41129231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether clustering and condensate functions coexist in the same cells unknown\", \"Switch between repressive PRC2-recruiting and EZH2-sequestering activities not mechanistically unified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Probing opposing PCL functions in development, separation-of-function mutants in human pluripotent stem cells indicated PHF19 antagonizes MTF2-PRC2.1-mediated repression at developmental genes during cardiomyocyte differentiation.\",\n      \"evidence\": \"CRISPR separation-of-function mutants in hPSCs, ChIP-seq and differentiation assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.15.654236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab, not yet peer-reviewed\", \"Reconciliation with PHF19's repressive roles in other contexts unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PHF19 switches between recruiting PRC2 to deposit H3K27me3 and sequestering EZH2 to activate genes\\u2014across isoforms, condensates, and competing PCL proteins\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating repressive and activating modes\", \"Determinants of isoform choice and condensate formation in vivo unknown\", \"Structural basis of PHF19 vs MTF2 chromatin partitioning not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1, 4, 2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 13, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 11, 18]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16, 2, 10]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [10, 12, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 2, 10, 12, 16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 10, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 12, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 10, 11, 14, 15]}\n    ],\n    \"complexes\": [\"PRC2\", \"PRC2.1\"],\n    \"partners\": [\"EZH2\", \"EED\", \"SUZ12\", \"NO66\", \"MTF2\", \"YTHDC1\", \"WTAP\", \"BTRC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}