{"gene":"PHF20","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2012,"finding":"The Tudor domain 2 of PHF20 directly binds p53 dimethylated at Lys370 or Lys382; a homodimeric form of this Tudor domain associates with both dimethylated sites on p53 with enhanced (multivalent) affinity. PHF20 binding to methylated p53 diminishes Mdm2-mediated p53 ubiquitylation and degradation, thereby stabilizing and activating p53.","method":"Biochemical and biophysical binding assays (multivalent Tudor domain interaction), cellular stabilization assays, p53 ubiquitylation assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical, biophysical, and cellular methods in a single rigorous study establishing direct mechanism","pmids":["22864287"],"is_preprint":false},{"year":2012,"finding":"Crystal structures of both N-terminal Tudor domains of PHF20 reveal novel structural variations; Tudor domain 2 exhibits preference for dimethylated histone substrates (confirmed biochemically).","method":"X-ray crystallography; biochemical binding assays confirming dimethyl-lysine preference","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with biochemical validation in a single study","pmids":["22449972"],"is_preprint":false},{"year":2013,"finding":"Jmjd3 targets PHF20 for ubiquitination and proteasomal degradation via recruitment of the E3 ubiquitin ligase Trim26, representing a histone demethylase-independent mechanism by which Jmjd3 inhibits somatic cell reprogramming. PHF20 is required for full reprogramming to iPSCs, as PHF20-deficient MEFs cannot be converted to fully reprogrammed iPSCs even with knockdown of Jmjd3, Ink4a, or p21.","method":"Co-immunoprecipitation, ubiquitination assays, Jmjd3/Trim26 E3 ligase recruitment assay, PHF20-knockout MEFs, iPSC reprogramming assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, E3 ligase recruitment assay, and genetic rescue experiments in a single rigorous study","pmids":["23452852"],"is_preprint":false},{"year":2013,"finding":"PHF20 maintains NF-κB in an active state by binding methylated lysine residues on p65, which prevents PP2A from associating with p65 and thereby sustains p65 phosphorylation and NF-κB DNA-binding activity.","method":"Co-immunoprecipitation, p65 phosphorylation assays, DNA-binding (EMSA/reporter) assays, TNF-induced NF-κB activation assays in PHF20-overexpressing cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, phosphorylation assay, DNA-binding assay, functional NF-κB reporter) in a single rigorous study","pmids":["23797602"],"is_preprint":false},{"year":2012,"finding":"Akt/PKB directly phosphorylates PHF20 at Ser291 in vitro and in vivo; this phosphorylation causes translocation of PHF20 from the nucleus to the cytoplasm and attenuates its ability to induce p53 transcription.","method":"In vitro kinase assay, in vivo phosphorylation, subcellular fractionation/localization, p53 transcription reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase reconstitution, in vivo phosphorylation, and localization with functional (transcriptional) consequence, single lab","pmids":["22334668"],"is_preprint":false},{"year":2012,"finding":"PKB/Akt-mediated PHF20 phosphorylation at Ser291 inhibits p53 induction following UV-induced DNA damage, reducing p21 transcriptional activity.","method":"In vitro and in vivo phosphorylation assays, UV-damage experiments, p21 transcription reporter assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay and UV-damage cellular assay with functional readout, single lab; partially overlapping with PMID:22334668","pmids":["22975685"],"is_preprint":false},{"year":2016,"finding":"The PHD finger of PHF20 directly recognizes H3K4me2 (dimethylated lysine 4 on histone H3); this interaction is required for histone acetylation by the MOF-NSL complex, accumulation of PHF20 at target gene loci, and transcriptional activation. Structural analysis explains selectivity for H3K4me2 over other methylation states.","method":"Biochemical binding assays, structural analysis (crystallography/NMR referenced), chromatin immunoprecipitation, transcriptional activation assays with PHD finger mutants","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — structural and biochemical analyses plus ChIP and functional transcriptional readout in a single rigorous study","pmids":["27760318"],"is_preprint":false},{"year":2011,"finding":"PHF20 is a component of the MOF histone acetyltransferase complex but is not required for maintaining global or locus-specific H4K16 acetylation levels; instead, PHF20 acts downstream in transcriptional regulation of MOF target genes. PHF20-knockout mice die shortly after birth with skeletal and hematopoietic phenotypes.","method":"PHF20-knockout mouse generation; H4K16 acetylation ChIP; gene expression analysis of MOF target genes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout model with ChIP and expression analysis, single lab","pmids":["22072714"],"is_preprint":false},{"year":2018,"finding":"PHF20 interacts with PARP1 and directly binds the promoter regions of OCT4 and SOX2, modulating the H3K4me3 histone mark at these loci to sustain stem cell-like properties in neuroblastoma cells.","method":"Co-immunoprecipitation (PHF20-PARP1 interaction), ChIP (PHF20 promoter occupancy, H3K4me3), CRISPR/Cas9 PHF20 knockout with phenotypic rescue by OCT4/SOX2 overexpression","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and genetic rescue experiments, single lab","pmids":["29452418"],"is_preprint":false},{"year":2020,"finding":"PHF20 interacts with WDR5 and directly binds to the promoter region of WISP1 to drive its expression; WISP1 and BGN then act together to regulate β-Catenin degradation in glioblastoma cells.","method":"Co-immunoprecipitation (PHF20-WDR5), ChIP (PHF20 at WISP1 promoter), PHF20 knockout with WISP1/BGN/β-Catenin pathway analysis","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ChIP with functional pathway readout, single lab","pmids":["33117706"],"is_preprint":false},{"year":2022,"finding":"PHF20 recognizes H3K36me2 at enhancer regions, and this binding is associated with increased H3K4me1/2 levels at those enhancers; PHF20 deficiency impairs chromatin accessibility at enhancers and reduces autophagy gene expression under glucose starvation.","method":"ATAC-seq (chromatin accessibility), ChIP-seq (H3K36me2, H3K4me1/2), RNA-seq, Phf20 knockdown/KO with autophagic flux assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — integrated epigenomic and transcriptomic approach with functional autophagy readout, single lab","pmids":["35821310"],"is_preprint":false},{"year":2022,"finding":"ALKBH5-mediated demethylation of m6A on PHF20 mRNA 3'UTR reduces PHF20 mRNA stability; thus ALKBH5 suppresses PHF20 protein expression post-transcriptionally via m6A modification.","method":"MeRIP-seq and RNA-seq joint analysis, m6A site mapping, mRNA stability assays, ALKBH5 knockdown/overexpression","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq, RNA stability assay, and functional cell assays, single lab","pmids":["35979628"],"is_preprint":false},{"year":2017,"finding":"PHF20 directly associates with Runx2 at osteogenic gene promoters and increases H3K4me3 enrichment at the Runx2 promoter, thereby activating Runx2 expression and downstream osteoblast differentiation genes.","method":"Co-immunoprecipitation (PHF20-Runx2), ChIP (H3K4me3 at Runx2 promoter), promoter reporter assays, PHF20 overexpression/knockdown with differentiation markers","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ChIP, and promoter reporter with functional differentiation readout, single lab","pmids":["28808306"],"is_preprint":false},{"year":2025,"finding":"PHF20 elevates METTL14 expression by enhancing H3K4me3 enrichment on the METTL14 promoter; METTL14 in turn promotes m6A methylation of HOXA13 mRNA, which is recognized by IGF2BP3 to stabilize HOXA13 mRNA, facilitating osteogenic differentiation of mesenchymal stem cells.","method":"ChIP (H3K4me3 at METTL14 promoter), RIP (IGF2BP3/m6A enrichment on HOXA13 mRNA), mRNA stability assays (actinomycin D), PHF20 knockdown with differentiation readouts","journal":"Functional & integrative genomics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP, RIP, and mRNA stability assay with functional differentiation readout, single lab","pmids":["39757292"],"is_preprint":false},{"year":2026,"finding":"PHF20 interacts with GAS7 and promotes its ubiquitin-mediated proteasomal degradation; loss of PHF20 stabilizes GAS7, which is associated with enhanced nuclear F-actin assembly and increased DNA damage accumulation, implicating PHF20 in DNA damage repair regulation.","method":"Co-immunoprecipitation, ubiquitination assays, PHF20 knockdown/KO with GAS7 stability, nuclear F-actin imaging, DNA damage assays (γH2AX), in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, and functional DDR readouts, single lab, single study","pmids":["42215448"],"is_preprint":false},{"year":2025,"finding":"Homozygous deletion of PHF20 in humans leads to a neurodevelopmental syndrome; loss of PHF20 causes reduction of H4K16 acetylation at genes involved in neuronal development and cell projection, without altering levels of other NSL complex subunits.","method":"Western blot (PHF20 and NSL subunit levels in patient cells), transcriptomic analysis (RNA-seq), epigenomic analysis (H4K16ac ChIP or CUT&RUN), chromosomal microarray and exome sequencing","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cells with molecular phenotyping, transcriptomic and epigenomic readout; single case series","pmids":["41438488"],"is_preprint":false}],"current_model":"PHF20 is a multidomain epigenetic reader protein and core component of the MOF-NSL lysine acetyltransferase complex that uses its Tudor domains to recognize dimethylated lysines on p53 (K370me2, K382me2) and histones (H3K4me2, H3K36me2), and its PHD finger to bind H3K4me2, thereby linking methylation readout to H4K16 acetylation, transcriptional activation of target genes (including SOX2, OCT4, WISP1, autophagy genes, and osteogenic genes), and p53 stabilization by blocking Mdm2-mediated ubiquitination; PHF20 activity is modulated by Akt-mediated phosphorylation at Ser291 (causing nuclear-to-cytoplasmic shuttling and attenuated p53 induction), by Jmjd3/Trim26-mediated ubiquitination and degradation, and by ALKBH5-mediated m6A demethylation of its mRNA, while PHF20 itself can promote NF-κB activity by blocking PP2A-p65 interaction and can promote ubiquitin-mediated degradation of GAS7 to modulate DNA damage repair."},"narrative":{"mechanistic_narrative":"PHF20 is a multidomain epigenetic reader and core subunit of the MOF (MYST1)/NSL lysine acetyltransferase complex that couples recognition of methylated lysines on histones and non-histone proteins to transcriptional activation and protein stabilization [PMID:22864287, PMID:22072714]. Its tandem Tudor domains, particularly Tudor domain 2, directly engage dimethyl-lysine marks: a homodimeric form binds p53 dimethylated at Lys370 and Lys382 with multivalent affinity, and this binding blocks Mdm2-mediated ubiquitylation to stabilize and activate p53 [PMID:22864287, PMID:22449972]. Its PHD finger selectively recognizes H3K4me2, an interaction required for MOF-NSL-dependent histone acetylation, chromatin recruitment, and target-gene activation [PMID:27760318]; PHF20 also reads H3K36me2 at enhancers to sustain chromatin accessibility and autophagy gene expression under glucose starvation [PMID:35821310]. Through these readout activities PHF20 occupies and activates a range of target loci, driving stem-cell genes OCT4/SOX2 via PARP1 association [PMID:29452418], the WISP1/β-Catenin axis via WDR5 [PMID:33117706], and osteogenic programs through Runx2 and a METTL14–HOXA13 m6A cascade [PMID:28808306, PMID:39757292]. Beyond chromatin, PHF20 sustains NF-κB activity by binding methylated p65 and excluding PP2A to maintain p65 phosphorylation [PMID:23797602], and promotes ubiquitin-mediated degradation of GAS7 to limit nuclear F-actin assembly and DNA damage [PMID:42215448]. PHF20 abundance and activity are tightly controlled: Akt phosphorylates Ser291 to drive nuclear-to-cytoplasmic shuttling and attenuate p53 induction [PMID:22334668, PMID:22975685], Jmjd3 recruits the E3 ligase Trim26 for its degradation [PMID:23452852], and ALKBH5 destabilizes PHF20 mRNA via m6A removal [PMID:35979628]. Homozygous PHF20 deletion in humans causes a neurodevelopmental syndrome accompanied by loss of H4K16 acetylation at neuronal-development genes, establishing PHF20 as essential for the developmental output of MOF-NSL function [PMID:41438488].","teleology":[{"year":2012,"claim":"Established that PHF20 is a methyl-lysine reader that stabilizes p53, answering how a dimethyl mark on p53 is converted into protection from degradation.","evidence":"Biochemical/biophysical binding assays of homodimeric Tudor domain 2 with p53 K370me2/K382me2, plus cellular stabilization and ubiquitylation assays; corroborated by crystal structures of both N-terminal Tudor domains showing dimethyl-lysine preference","pmids":["22864287","22449972"],"confidence":"High","gaps":["Identity of the methyltransferase generating these p53 marks in vivo not resolved by these studies","Stoichiometry and contribution within the full MOF-NSL complex not addressed"]},{"year":2012,"claim":"Defined Akt-mediated Ser291 phosphorylation as a switch that exports PHF20 to the cytoplasm and dampens its p53/p21 response, linking growth signaling to the PHF20-p53 axis.","evidence":"In vitro kinase reconstitution, in vivo phosphorylation, subcellular fractionation, and p53/p21 transcription reporter assays including UV-damage context","pmids":["22334668","22975685"],"confidence":"High","gaps":["Whether cytoplasmic PHF20 has a distinct function not addressed","Upstream signals coupling Akt to PHF20 in specific stress contexts unclear"]},{"year":2011,"claim":"Placed PHF20 within the MOF acetyltransferase complex but as a downstream transcriptional effector rather than a determinant of global H4K16 acetylation, refining its role in the complex.","evidence":"PHF20-knockout mice with H4K16ac ChIP and MOF target-gene expression analysis","pmids":["22072714"],"confidence":"Medium","gaps":["Molecular basis for transcriptional effect independent of H4K16ac not defined","Tissue-specific contributions to skeletal/hematopoietic phenotypes not dissected"]},{"year":2013,"claim":"Revealed two distinct regulatory layers: Jmjd3/Trim26 degrades PHF20 to restrain reprogramming, and PHF20 sustains NF-κB by blocking PP2A from methylated p65.","evidence":"Reciprocal Co-IP, ubiquitination and E3 ligase recruitment assays with PHF20-KO MEFs and iPSC reprogramming (Jmjd3); Co-IP, p65 phosphorylation, EMSA/reporter and TNF-induced NF-κB assays (p65)","pmids":["23452852","23797602"],"confidence":"High","gaps":["Methyltransferase generating the p65 methyl mark read by PHF20 not identified","Demethylase-independent Jmjd3 function not generalized beyond reprogramming"]},{"year":2016,"claim":"Identified the PHD finger as an H3K4me2 reader required for MOF-NSL acetylation and chromatin recruitment, defining how PHF20 couples a histone mark to transcriptional output.","evidence":"Biochemical binding assays, structural analysis, ChIP, and transcriptional activation assays with PHD finger mutants","pmids":["27760318"],"confidence":"High","gaps":["Interplay between PHD H3K4me2 reading and Tudor methyl-protein reading not integrated","Genome-wide target set of PHD-dependent recruitment incompletely mapped"]},{"year":2017,"claim":"Connected PHF20 to context-specific gene programs, showing it activates OCT4/SOX2 stemness genes and Runx2-driven osteogenic genes through promoter occupancy and H3K4 methylation.","evidence":"Co-IP (PARP1, Runx2), ChIP for promoter occupancy and H3K4me3, promoter reporters, and CRISPR/knockdown with phenotypic rescue","pmids":["29452418","28808306"],"confidence":"Medium","gaps":["Direct causal link between PHF20 catalytic-complex activity and the observed H3K4me3 changes not established","Single-lab cancer/differentiation models limit generality"]},{"year":2020,"claim":"Extended PHF20 target programs to the WISP1/BGN/β-Catenin axis via WDR5 partnership in glioblastoma.","evidence":"Co-IP (PHF20-WDR5), ChIP at WISP1 promoter, PHF20 knockout with pathway analysis","pmids":["33117706"],"confidence":"Medium","gaps":["Whether WDR5 partnership is part of MOF-NSL or a separate assembly unclear","Single tumor-context study without reciprocal validation"]},{"year":2022,"claim":"Showed PHF20 reads H3K36me2 at enhancers to maintain chromatin accessibility and autophagy gene expression, and that ALKBH5 controls PHF20 abundance post-transcriptionally via m6A.","evidence":"ATAC-seq, ChIP-seq (H3K36me2, H3K4me1/2), RNA-seq with KO/KD and autophagy flux assays; MeRIP-seq, m6A mapping and mRNA stability assays for ALKBH5 regulation","pmids":["35821310","35979628"],"confidence":"Medium","gaps":["Domain responsible for H3K36me2 reading versus PHD/Tudor not delineated","Mechanism linking enhancer accessibility to H3K4me1/2 increase not resolved"]},{"year":2025,"claim":"Linked PHF20 to a human neurodevelopmental syndrome and to an osteogenic m6A cascade, establishing developmental requirements for PHF20-dependent H4K16 acetylation.","evidence":"Patient-derived cells with Western blot of NSL subunits, RNA-seq and H4K16ac epigenomics, microarray/exome sequencing (syndrome); ChIP at METTL14 promoter, RIP for IGF2BP3/m6A on HOXA13, mRNA stability assays (osteogenesis)","pmids":["41438488","39757292"],"confidence":"Medium","gaps":["Causality of specific mutations versus deletion in patients not fully dissected","Whether neuronal H4K16ac loss is direct or secondary to NSL dysregulation unclear"]},{"year":2026,"claim":"Defined a new non-chromatin role: PHF20 drives ubiquitin-mediated GAS7 degradation to limit nuclear F-actin and DNA damage, implicating it in DNA damage repair regulation.","evidence":"Co-IP, ubiquitination assays, KD/KO with GAS7 stability, nuclear F-actin imaging, γH2AX DNA damage assays, and in vivo xenograft","pmids":["42215448"],"confidence":"Medium","gaps":["Whether PHF20 acts as or recruits an E3 ligase for GAS7 not established","Single study without reciprocal validation of the GAS7 mechanism"]},{"year":null,"claim":"How PHF20's multiple reader modules (Tudor domains, PHD finger) are coordinated on chromatin versus on non-histone substrates, and how this integrates the diverse target programs into a unified function, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of full-length PHF20 within MOF-NSL","Rules governing choice between p53/p65 reading and histone reading unknown","Relative contribution of catalytic-complex versus reader-only functions in disease unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,6,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,8,12,9]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,7,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,8,9,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,13,15]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10]}],"complexes":["MOF-NSL acetyltransferase complex"],"partners":["TP53","RELA","PARP1","WDR5","RUNX2","GAS7","KDM6B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BVI0","full_name":"PHD finger protein 20","aliases":["Glioma-expressed antigen 2","Hepatocellular carcinoma-associated antigen 58","Novel zinc finger protein","Transcription factor TZP"],"length_aa":1012,"mass_kda":115.4,"function":"Methyllysine-binding protein, component of the MOF histone acetyltransferase protein complex. Not required for maintaining the global histone H4 'Lys-16' acetylation (H4K16ac) levels or locus specific histone acetylation, but instead works downstream in transcriptional regulation of MOF target genes (By similarity). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. Contributes to methyllysine-dependent p53/TP53 stabilization and up-regulation after DNA damage","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BVI0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHF20","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PHF20","total_profiled":1310},"omim":[{"mim_id":"620050","title":"PHD FINGER PROTEIN 20-LIKE 1; PHF20L1","url":"https://www.omim.org/entry/620050"},{"mim_id":"615488","title":"KAT8 REGULATORY NSL COMPLEX, SUBUNIT 2; KANSL2","url":"https://www.omim.org/entry/615488"},{"mim_id":"610335","title":"PHD FINGER PROTEIN 20; PHF20","url":"https://www.omim.org/entry/610335"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHF20"},"hgnc":{"alias_symbol":["dJ1121G12.1","TDRD20A"],"prev_symbol":["C20orf104"]},"alphafold":{"accession":"Q9BVI0","domains":[{"cath_id":"2.30.30.140","chopping":"2-81","consensus_level":"medium","plddt":82.6481,"start":2,"end":81},{"cath_id":"2.30.30.140","chopping":"86-139","consensus_level":"medium","plddt":91.1015,"start":86,"end":139},{"cath_id":"-","chopping":"713-781_931-1012","consensus_level":"medium","plddt":77.7427,"start":713,"end":1012}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVI0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVI0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVI0-F1-predicted_aligned_error_v6.png","plddt_mean":54.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHF20","jax_strain_url":"https://www.jax.org/strain/search?query=PHF20"},"sequence":{"accession":"Q9BVI0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BVI0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BVI0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVI0"}},"corpus_meta":[{"pmid":"23452852","id":"PMC_23452852","title":"Jmjd3 inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination.","date":"2013","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/23452852","citation_count":129,"is_preprint":false},{"pmid":"22864287","id":"PMC_22864287","title":"PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53.","date":"2012","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22864287","citation_count":83,"is_preprint":false},{"pmid":"23797602","id":"PMC_23797602","title":"PHF20 regulates NF-κB signalling by disrupting recruitment of PP2A to p65.","date":"2013","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/23797602","citation_count":50,"is_preprint":false},{"pmid":"35979628","id":"PMC_35979628","title":"N6-methyladenosine demethylase ALKBH5 suppresses colorectal cancer progression potentially by decreasing PHF20 mRNA methylation.","date":"2022","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35979628","citation_count":45,"is_preprint":false},{"pmid":"27760318","id":"PMC_27760318","title":"PHF20 Readers Link Methylation of Histone H3K4 and p53 with H4K16 Acetylation.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27760318","citation_count":42,"is_preprint":false},{"pmid":"22072714","id":"PMC_22072714","title":"Loss of the methyl lysine effector protein PHF20 impacts the expression of genes regulated by the lysine acetyltransferase MOF.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22072714","citation_count":31,"is_preprint":false},{"pmid":"22975685","id":"PMC_22975685","title":"PKB-mediated PHF20 phosphorylation on Ser291 is required for p53 function in DNA damage.","date":"2012","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/22975685","citation_count":28,"is_preprint":false},{"pmid":"29452418","id":"PMC_29452418","title":"PHF20 collaborates with PARP1 to promote stemness and aggressiveness of neuroblastoma cells through activation of SOX2 and OCT4.","date":"2018","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29452418","citation_count":27,"is_preprint":false},{"pmid":"22334668","id":"PMC_22334668","title":"Identification of Akt interaction protein PHF20/TZP that transcriptionally regulates p53.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22334668","citation_count":24,"is_preprint":false},{"pmid":"22449972","id":"PMC_22449972","title":"Crystal structures of the Tudor domains of human PHF20 reveal novel structural variations on the Royal Family of proteins.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22449972","citation_count":20,"is_preprint":false},{"pmid":"28808306","id":"PMC_28808306","title":"PHF20 positively regulates osteoblast differentiation via increasing the expression and activation of Runx2 with enrichment of H3K4me3.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28808306","citation_count":18,"is_preprint":false},{"pmid":"35821310","id":"PMC_35821310","title":"PHF20 is crucial for epigenetic control of starvation-induced autophagy through enhancer activation.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/35821310","citation_count":16,"is_preprint":false},{"pmid":"33117706","id":"PMC_33117706","title":"PHF20 Promotes Glioblastoma Cell Malignancies Through a WISP1/BGN-Dependent Pathway.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33117706","citation_count":14,"is_preprint":false},{"pmid":"33982773","id":"PMC_33982773","title":"PHF20 inhibition promotes apoptosis and cisplatin chemosensitivity via the OCT4‑p‑STAT3‑MCL1 signaling pathway in hypopharyngeal squamous cell carcinoma.","date":"2021","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33982773","citation_count":12,"is_preprint":false},{"pmid":"33655888","id":"PMC_33655888","title":"circCUX1 promotes neuroblastoma progression and glycolysis by regulating the miR-338-3p/PHF20 axis.","date":"2021","source":"General physiology and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/33655888","citation_count":8,"is_preprint":false},{"pmid":"31208361","id":"PMC_31208361","title":"Molecular genetic characterization reveals linear tumor evolution in a pulmonary sarcomatoid carcinomas patient with a novel PHF20-NTRK1 fusion: a case report.","date":"2019","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31208361","citation_count":7,"is_preprint":false},{"pmid":"38046167","id":"PMC_38046167","title":"Long non-coding RNA PCAT5 regulates the progression of Esophageal Squamous Cell Carcinoma via miR-4295/PHF20.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38046167","citation_count":5,"is_preprint":false},{"pmid":"39757292","id":"PMC_39757292","title":"Epigenetic modification mediated by PHF20/METTL14/HOXA13 signaling axis modulates osteogenic differentiation of mesenchymal stem cells.","date":"2025","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39757292","citation_count":3,"is_preprint":false},{"pmid":"26999840","id":"PMC_26999840","title":"[The expression and clinical significance of Bax and PHF20 in laryngeal squamous cell carcinoma].","date":"2015","source":"Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/26999840","citation_count":2,"is_preprint":false},{"pmid":"37035210","id":"PMC_37035210","title":"Corrigendum: PHF20 promotes glioblastoma cell malignancies through a WISP1/BGN-dependent pathway.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37035210","citation_count":2,"is_preprint":false},{"pmid":"39802116","id":"PMC_39802116","title":"Enhancement of renal fibrosis in PHF20 transgenic mice.","date":"2024","source":"Toxicological research","url":"https://pubmed.ncbi.nlm.nih.gov/39802116","citation_count":2,"is_preprint":false},{"pmid":"42215448","id":"PMC_42215448","title":"PHF20 stabilizes the GAS7-F-actin axis to drive DNA damage repair and chemoresistance in cutaneous squamous cell carcinoma.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/42215448","citation_count":0,"is_preprint":false},{"pmid":"41438488","id":"PMC_41438488","title":"Homozygous Deletion of the Epigenetic Regulator PHF20 in Individuals With Neurodevelopmental Disorder.","date":"2025","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/41438488","citation_count":0,"is_preprint":false},{"pmid":"31223206","id":"PMC_31223206","title":"Structure-based analysis of curcumin and conventionaldrugs targeting tumor-inducing protein PHF20.","date":"2018","source":"Bioinformation","url":"https://pubmed.ncbi.nlm.nih.gov/31223206","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.08.669278","title":"Unveiling the Role of PHF20 in TBC1D4-Mediated Glucose Uptake During  <i>Toxoplasma gondii</i>  Infection","date":"2025-08-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.08.669278","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12753,"output_tokens":3961,"usd":0.048837,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11667,"output_tokens":4266,"usd":0.082492,"stage2_stop_reason":"end_turn"},"total_usd":0.131329,"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\": \"The Tudor domain 2 of PHF20 directly binds p53 dimethylated at Lys370 or Lys382; a homodimeric form of this Tudor domain associates with both dimethylated sites on p53 with enhanced (multivalent) affinity. PHF20 binding to methylated p53 diminishes Mdm2-mediated p53 ubiquitylation and degradation, thereby stabilizing and activating p53.\",\n      \"method\": \"Biochemical and biophysical binding assays (multivalent Tudor domain interaction), cellular stabilization assays, p53 ubiquitylation assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical, biophysical, and cellular methods in a single rigorous study establishing direct mechanism\",\n      \"pmids\": [\"22864287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structures of both N-terminal Tudor domains of PHF20 reveal novel structural variations; Tudor domain 2 exhibits preference for dimethylated histone substrates (confirmed biochemically).\",\n      \"method\": \"X-ray crystallography; biochemical binding assays confirming dimethyl-lysine preference\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with biochemical validation in a single study\",\n      \"pmids\": [\"22449972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Jmjd3 targets PHF20 for ubiquitination and proteasomal degradation via recruitment of the E3 ubiquitin ligase Trim26, representing a histone demethylase-independent mechanism by which Jmjd3 inhibits somatic cell reprogramming. PHF20 is required for full reprogramming to iPSCs, as PHF20-deficient MEFs cannot be converted to fully reprogrammed iPSCs even with knockdown of Jmjd3, Ink4a, or p21.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, Jmjd3/Trim26 E3 ligase recruitment assay, PHF20-knockout MEFs, iPSC reprogramming assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, E3 ligase recruitment assay, and genetic rescue experiments in a single rigorous study\",\n      \"pmids\": [\"23452852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PHF20 maintains NF-κB in an active state by binding methylated lysine residues on p65, which prevents PP2A from associating with p65 and thereby sustains p65 phosphorylation and NF-κB DNA-binding activity.\",\n      \"method\": \"Co-immunoprecipitation, p65 phosphorylation assays, DNA-binding (EMSA/reporter) assays, TNF-induced NF-κB activation assays in PHF20-overexpressing cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, phosphorylation assay, DNA-binding assay, functional NF-κB reporter) in a single rigorous study\",\n      \"pmids\": [\"23797602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Akt/PKB directly phosphorylates PHF20 at Ser291 in vitro and in vivo; this phosphorylation causes translocation of PHF20 from the nucleus to the cytoplasm and attenuates its ability to induce p53 transcription.\",\n      \"method\": \"In vitro kinase assay, in vivo phosphorylation, subcellular fractionation/localization, p53 transcription reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase reconstitution, in vivo phosphorylation, and localization with functional (transcriptional) consequence, single lab\",\n      \"pmids\": [\"22334668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PKB/Akt-mediated PHF20 phosphorylation at Ser291 inhibits p53 induction following UV-induced DNA damage, reducing p21 transcriptional activity.\",\n      \"method\": \"In vitro and in vivo phosphorylation assays, UV-damage experiments, p21 transcription reporter assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay and UV-damage cellular assay with functional readout, single lab; partially overlapping with PMID:22334668\",\n      \"pmids\": [\"22975685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The PHD finger of PHF20 directly recognizes H3K4me2 (dimethylated lysine 4 on histone H3); this interaction is required for histone acetylation by the MOF-NSL complex, accumulation of PHF20 at target gene loci, and transcriptional activation. Structural analysis explains selectivity for H3K4me2 over other methylation states.\",\n      \"method\": \"Biochemical binding assays, structural analysis (crystallography/NMR referenced), chromatin immunoprecipitation, transcriptional activation assays with PHD finger mutants\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — structural and biochemical analyses plus ChIP and functional transcriptional readout in a single rigorous study\",\n      \"pmids\": [\"27760318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PHF20 is a component of the MOF histone acetyltransferase complex but is not required for maintaining global or locus-specific H4K16 acetylation levels; instead, PHF20 acts downstream in transcriptional regulation of MOF target genes. PHF20-knockout mice die shortly after birth with skeletal and hematopoietic phenotypes.\",\n      \"method\": \"PHF20-knockout mouse generation; H4K16 acetylation ChIP; gene expression analysis of MOF target genes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout model with ChIP and expression analysis, single lab\",\n      \"pmids\": [\"22072714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHF20 interacts with PARP1 and directly binds the promoter regions of OCT4 and SOX2, modulating the H3K4me3 histone mark at these loci to sustain stem cell-like properties in neuroblastoma cells.\",\n      \"method\": \"Co-immunoprecipitation (PHF20-PARP1 interaction), ChIP (PHF20 promoter occupancy, H3K4me3), CRISPR/Cas9 PHF20 knockout with phenotypic rescue by OCT4/SOX2 overexpression\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and genetic rescue experiments, single lab\",\n      \"pmids\": [\"29452418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PHF20 interacts with WDR5 and directly binds to the promoter region of WISP1 to drive its expression; WISP1 and BGN then act together to regulate β-Catenin degradation in glioblastoma cells.\",\n      \"method\": \"Co-immunoprecipitation (PHF20-WDR5), ChIP (PHF20 at WISP1 promoter), PHF20 knockout with WISP1/BGN/β-Catenin pathway analysis\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ChIP with functional pathway readout, single lab\",\n      \"pmids\": [\"33117706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHF20 recognizes H3K36me2 at enhancer regions, and this binding is associated with increased H3K4me1/2 levels at those enhancers; PHF20 deficiency impairs chromatin accessibility at enhancers and reduces autophagy gene expression under glucose starvation.\",\n      \"method\": \"ATAC-seq (chromatin accessibility), ChIP-seq (H3K36me2, H3K4me1/2), RNA-seq, Phf20 knockdown/KO with autophagic flux assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — integrated epigenomic and transcriptomic approach with functional autophagy readout, single lab\",\n      \"pmids\": [\"35821310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ALKBH5-mediated demethylation of m6A on PHF20 mRNA 3'UTR reduces PHF20 mRNA stability; thus ALKBH5 suppresses PHF20 protein expression post-transcriptionally via m6A modification.\",\n      \"method\": \"MeRIP-seq and RNA-seq joint analysis, m6A site mapping, mRNA stability assays, ALKBH5 knockdown/overexpression\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq, RNA stability assay, and functional cell assays, single lab\",\n      \"pmids\": [\"35979628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PHF20 directly associates with Runx2 at osteogenic gene promoters and increases H3K4me3 enrichment at the Runx2 promoter, thereby activating Runx2 expression and downstream osteoblast differentiation genes.\",\n      \"method\": \"Co-immunoprecipitation (PHF20-Runx2), ChIP (H3K4me3 at Runx2 promoter), promoter reporter assays, PHF20 overexpression/knockdown with differentiation markers\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ChIP, and promoter reporter with functional differentiation readout, single lab\",\n      \"pmids\": [\"28808306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PHF20 elevates METTL14 expression by enhancing H3K4me3 enrichment on the METTL14 promoter; METTL14 in turn promotes m6A methylation of HOXA13 mRNA, which is recognized by IGF2BP3 to stabilize HOXA13 mRNA, facilitating osteogenic differentiation of mesenchymal stem cells.\",\n      \"method\": \"ChIP (H3K4me3 at METTL14 promoter), RIP (IGF2BP3/m6A enrichment on HOXA13 mRNA), mRNA stability assays (actinomycin D), PHF20 knockdown with differentiation readouts\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP, RIP, and mRNA stability assay with functional differentiation readout, single lab\",\n      \"pmids\": [\"39757292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PHF20 interacts with GAS7 and promotes its ubiquitin-mediated proteasomal degradation; loss of PHF20 stabilizes GAS7, which is associated with enhanced nuclear F-actin assembly and increased DNA damage accumulation, implicating PHF20 in DNA damage repair regulation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, PHF20 knockdown/KO with GAS7 stability, nuclear F-actin imaging, DNA damage assays (γH2AX), in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, and functional DDR readouts, single lab, single study\",\n      \"pmids\": [\"42215448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Homozygous deletion of PHF20 in humans leads to a neurodevelopmental syndrome; loss of PHF20 causes reduction of H4K16 acetylation at genes involved in neuronal development and cell projection, without altering levels of other NSL complex subunits.\",\n      \"method\": \"Western blot (PHF20 and NSL subunit levels in patient cells), transcriptomic analysis (RNA-seq), epigenomic analysis (H4K16ac ChIP or CUT&RUN), chromosomal microarray and exome sequencing\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cells with molecular phenotyping, transcriptomic and epigenomic readout; single case series\",\n      \"pmids\": [\"41438488\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHF20 is a multidomain epigenetic reader protein and core component of the MOF-NSL lysine acetyltransferase complex that uses its Tudor domains to recognize dimethylated lysines on p53 (K370me2, K382me2) and histones (H3K4me2, H3K36me2), and its PHD finger to bind H3K4me2, thereby linking methylation readout to H4K16 acetylation, transcriptional activation of target genes (including SOX2, OCT4, WISP1, autophagy genes, and osteogenic genes), and p53 stabilization by blocking Mdm2-mediated ubiquitination; PHF20 activity is modulated by Akt-mediated phosphorylation at Ser291 (causing nuclear-to-cytoplasmic shuttling and attenuated p53 induction), by Jmjd3/Trim26-mediated ubiquitination and degradation, and by ALKBH5-mediated m6A demethylation of its mRNA, while PHF20 itself can promote NF-κB activity by blocking PP2A-p65 interaction and can promote ubiquitin-mediated degradation of GAS7 to modulate DNA damage repair.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PHF20 is a multidomain epigenetic reader and core subunit of the MOF (MYST1)/NSL lysine acetyltransferase complex that couples recognition of methylated lysines on histones and non-histone proteins to transcriptional activation and protein stabilization [#0, #7]. Its tandem Tudor domains, particularly Tudor domain 2, directly engage dimethyl-lysine marks: a homodimeric form binds p53 dimethylated at Lys370 and Lys382 with multivalent affinity, and this binding blocks Mdm2-mediated ubiquitylation to stabilize and activate p53 [#0, #1]. Its PHD finger selectively recognizes H3K4me2, an interaction required for MOF-NSL-dependent histone acetylation, chromatin recruitment, and target-gene activation [#6]; PHF20 also reads H3K36me2 at enhancers to sustain chromatin accessibility and autophagy gene expression under glucose starvation [#10]. Through these readout activities PHF20 occupies and activates a range of target loci, driving stem-cell genes OCT4/SOX2 via PARP1 association [#8], the WISP1/\\u03b2-Catenin axis via WDR5 [#9], and osteogenic programs through Runx2 and a METTL14\\u2013HOXA13 m6A cascade [#12, #13]. Beyond chromatin, PHF20 sustains NF-\\u03baB activity by binding methylated p65 and excluding PP2A to maintain p65 phosphorylation [#3], and promotes ubiquitin-mediated degradation of GAS7 to limit nuclear F-actin assembly and DNA damage [#14]. PHF20 abundance and activity are tightly controlled: Akt phosphorylates Ser291 to drive nuclear-to-cytoplasmic shuttling and attenuate p53 induction [#4, #5], Jmjd3 recruits the E3 ligase Trim26 for its degradation [#2], and ALKBH5 destabilizes PHF20 mRNA via m6A removal [#11]. Homozygous PHF20 deletion in humans causes a neurodevelopmental syndrome accompanied by loss of H4K16 acetylation at neuronal-development genes, establishing PHF20 as essential for the developmental output of MOF-NSL function [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that PHF20 is a methyl-lysine reader that stabilizes p53, answering how a dimethyl mark on p53 is converted into protection from degradation.\",\n      \"evidence\": \"Biochemical/biophysical binding assays of homodimeric Tudor domain 2 with p53 K370me2/K382me2, plus cellular stabilization and ubiquitylation assays; corroborated by crystal structures of both N-terminal Tudor domains showing dimethyl-lysine preference\",\n      \"pmids\": [\"22864287\", \"22449972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the methyltransferase generating these p53 marks in vivo not resolved by these studies\", \"Stoichiometry and contribution within the full MOF-NSL complex not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined Akt-mediated Ser291 phosphorylation as a switch that exports PHF20 to the cytoplasm and dampens its p53/p21 response, linking growth signaling to the PHF20-p53 axis.\",\n      \"evidence\": \"In vitro kinase reconstitution, in vivo phosphorylation, subcellular fractionation, and p53/p21 transcription reporter assays including UV-damage context\",\n      \"pmids\": [\"22334668\", \"22975685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cytoplasmic PHF20 has a distinct function not addressed\", \"Upstream signals coupling Akt to PHF20 in specific stress contexts unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed PHF20 within the MOF acetyltransferase complex but as a downstream transcriptional effector rather than a determinant of global H4K16 acetylation, refining its role in the complex.\",\n      \"evidence\": \"PHF20-knockout mice with H4K16ac ChIP and MOF target-gene expression analysis\",\n      \"pmids\": [\"22072714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for transcriptional effect independent of H4K16ac not defined\", \"Tissue-specific contributions to skeletal/hematopoietic phenotypes not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed two distinct regulatory layers: Jmjd3/Trim26 degrades PHF20 to restrain reprogramming, and PHF20 sustains NF-\\u03baB by blocking PP2A from methylated p65.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination and E3 ligase recruitment assays with PHF20-KO MEFs and iPSC reprogramming (Jmjd3); Co-IP, p65 phosphorylation, EMSA/reporter and TNF-induced NF-\\u03baB assays (p65)\",\n      \"pmids\": [\"23452852\", \"23797602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Methyltransferase generating the p65 methyl mark read by PHF20 not identified\", \"Demethylase-independent Jmjd3 function not generalized beyond reprogramming\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the PHD finger as an H3K4me2 reader required for MOF-NSL acetylation and chromatin recruitment, defining how PHF20 couples a histone mark to transcriptional output.\",\n      \"evidence\": \"Biochemical binding assays, structural analysis, ChIP, and transcriptional activation assays with PHD finger mutants\",\n      \"pmids\": [\"27760318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between PHD H3K4me2 reading and Tudor methyl-protein reading not integrated\", \"Genome-wide target set of PHD-dependent recruitment incompletely mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected PHF20 to context-specific gene programs, showing it activates OCT4/SOX2 stemness genes and Runx2-driven osteogenic genes through promoter occupancy and H3K4 methylation.\",\n      \"evidence\": \"Co-IP (PARP1, Runx2), ChIP for promoter occupancy and H3K4me3, promoter reporters, and CRISPR/knockdown with phenotypic rescue\",\n      \"pmids\": [\"29452418\", \"28808306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct causal link between PHF20 catalytic-complex activity and the observed H3K4me3 changes not established\", \"Single-lab cancer/differentiation models limit generality\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended PHF20 target programs to the WISP1/BGN/\\u03b2-Catenin axis via WDR5 partnership in glioblastoma.\",\n      \"evidence\": \"Co-IP (PHF20-WDR5), ChIP at WISP1 promoter, PHF20 knockout with pathway analysis\",\n      \"pmids\": [\"33117706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether WDR5 partnership is part of MOF-NSL or a separate assembly unclear\", \"Single tumor-context study without reciprocal validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed PHF20 reads H3K36me2 at enhancers to maintain chromatin accessibility and autophagy gene expression, and that ALKBH5 controls PHF20 abundance post-transcriptionally via m6A.\",\n      \"evidence\": \"ATAC-seq, ChIP-seq (H3K36me2, H3K4me1/2), RNA-seq with KO/KD and autophagy flux assays; MeRIP-seq, m6A mapping and mRNA stability assays for ALKBH5 regulation\",\n      \"pmids\": [\"35821310\", \"35979628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain responsible for H3K36me2 reading versus PHD/Tudor not delineated\", \"Mechanism linking enhancer accessibility to H3K4me1/2 increase not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked PHF20 to a human neurodevelopmental syndrome and to an osteogenic m6A cascade, establishing developmental requirements for PHF20-dependent H4K16 acetylation.\",\n      \"evidence\": \"Patient-derived cells with Western blot of NSL subunits, RNA-seq and H4K16ac epigenomics, microarray/exome sequencing (syndrome); ChIP at METTL14 promoter, RIP for IGF2BP3/m6A on HOXA13, mRNA stability assays (osteogenesis)\",\n      \"pmids\": [\"41438488\", \"39757292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality of specific mutations versus deletion in patients not fully dissected\", \"Whether neuronal H4K16ac loss is direct or secondary to NSL dysregulation unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a new non-chromatin role: PHF20 drives ubiquitin-mediated GAS7 degradation to limit nuclear F-actin and DNA damage, implicating it in DNA damage repair regulation.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, KD/KO with GAS7 stability, nuclear F-actin imaging, \\u03b3H2AX DNA damage assays, and in vivo xenograft\",\n      \"pmids\": [\"42215448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PHF20 acts as or recruits an E3 ligase for GAS7 not established\", \"Single study without reciprocal validation of the GAS7 mechanism\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PHF20's multiple reader modules (Tudor domains, PHD finger) are coordinated on chromatin versus on non-histone substrates, and how this integrates the diverse target programs into a unified function, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of full-length PHF20 within MOF-NSL\", \"Rules governing choice between p53/p65 reading and histone reading unknown\", \"Relative contribution of catalytic-complex versus reader-only functions in disease unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 6, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 8, 12, 9]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 7, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 8, 9, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 13, 15]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"MOF-NSL acetyltransferase complex\"],\n    \"partners\": [\"TP53\", \"RELA\", \"PARP1\", \"WDR5\", \"RUNX2\", \"GAS7\", \"KDM6B\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}