{"gene":"PHF11","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2008,"finding":"PHF11 physically and functionally interacts with the p65 subunit of NF-κB, and knockdown of PHF11 reduces expression of the Th1-type cytokines IFN-γ and IL-2 in primary CD4+ T cells and Jurkat T cells, while overexpression increases their transcription; PHF11 was also shown by EMSA to bind DNA.","method":"siRNA knockdown, overexpression, luciferase reporter assays, electrophoretic mobility shift assay (EMSA), co-immunoprecipitation (physical interaction with p65/NF-κB)","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple orthogonal methods (siRNA, OE, reporter assay, EMSA, co-IP) in a single lab; no independent replication reported","pmids":["18405956"],"is_preprint":false},{"year":2010,"finding":"PHF11 is constitutively localized in the cytoplasm of T cells and translocates to the nucleus upon T-cell activation; in the nucleus it is recruited to the IFNG promoter, enhances NF-κB binding to the IFNG promoter and IFNG transcription; PHF11 knockdown decreases CD28 surface expression, reduces NF-κB nuclear import and DNA binding, decreases cell viability, and reduces expression of GIMAP4/5.","method":"Subcellular fractionation and immunofluorescence microscopy (localization), chromatin immunoprecipitation (ChIP; recruitment to IFNG promoter), siRNA knockdown, overexpression, flow cytometry (CD28), NF-κB reporter assay","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple orthogonal methods (fractionation, ChIP, siRNA, OE, reporter) in single lab; no independent replication","pmids":["20421878"],"is_preprint":false},{"year":2017,"finding":"PHF11 promotes 5' end resection at DNA double-strand breaks (DSBs), ATR signaling, and homologous recombination (HR). PHF11 associates with deprotected telomeres and localizes to sites of DNA damage in S phase. PHF11 depletion diminishes ATR signaling, reduces end resection, compromises HR, causes misrejoining of S-phase DSBs, and increases sensitivity to DNA-damaging agents. PHF11 physically interacts with RPA (ssDNA-binding protein) and forms a complex with nucleases including the 5' dsDNA exonuclease EXO1. Biochemically, PHF11 stimulates EXO1 by overcoming its inhibition by RPA.","method":"PICh (proteomics of isolated chromatin segments) for telomere association, siRNA depletion with ATR signaling assays, resection assays, HR reporter assays, co-immunoprecipitation (PHF11–RPA, PHF11–EXO1 complex), in vitro biochemical reconstitution (PHF11 stimulation of EXO1 in the presence of RPA), sensitivity assays to DNA-damaging agents","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — includes in vitro biochemical reconstitution with EXO1 and RPA, multiple orthogonal cellular assays (resection, ATR signaling, HR), and co-IP; rigorous single study with multiple methods","pmids":["28115467"],"is_preprint":false},{"year":2011,"finding":"The asthma-associated SNP rs1046295 in PHF11 modulates allele-specific binding by octamer-binding transcription factor 1 (Oct-1), and the A allele shows preferentially higher expression; this identifies a regulatory mechanism by which Oct-1 binding affects PHF11 transcription level in an allele-dependent manner.","method":"Electrophoretic mobility shift assay (EMSA) for transcription factor binding, allele-specific expression allelotyping","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — EMSA plus allele-specific expression in multiple cell lines; no functional rescue or mutagenesis confirming causality","pmids":["21320718"],"is_preprint":false},{"year":2015,"finding":"In keratinocytes, PHF11 undergoes nuclear localization following poly(I:C) (TLR3 ligand) treatment; PHF11 knockdown increases IL-8 expression and secretion, alters claudin-1 cellular distribution, reduces cell density, and decreases the proportion of cells in G1 phase, indicating a role for PHF11 in the innate immune response and cell cycle regulation in keratinocytes.","method":"siRNA knockdown, immunofluorescence microscopy (nuclear localization), RT-qPCR and ELISA (IL-8, ISG15, PHF11 RNA), flow cytometry (cell cycle analysis), poly(I:C) stimulation model","journal":"BMC immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple readouts (localization, gene expression, ELISA, cell cycle) in a single lab with siRNA; no independent replication","pmids":["26573531"],"is_preprint":false},{"year":2014,"finding":"A point mutation (valine to alanine) in the PHD zinc finger domain of mouse Phf11 leads to significantly increased expression of Il2, NF-κB, and Setdb2 in lung tissue after LPS stimulation, providing in vivo genetic evidence that the PHD domain of Phf11 is required for its role as a Th1 cell regulator in immune responses.","method":"ENU-induced point mutagenesis (PHD domain), congenic mouse line, LPS stimulation, RT-qPCR (Il2, NF-κB, Setdb2 expression), histology, haematology","journal":"Mammalian genome","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo domain-specific mutation with defined molecular phenotype; single lab, single study","pmids":["25091723"],"is_preprint":false}],"current_model":"PHF11 is a PHD finger-containing protein with dual mechanistic roles: in immune cells, it acts as a transcriptional co-activator of Th1 cytokine genes (IFN-γ, IL-2) by cooperating with NF-κB, translocating from cytoplasm to nucleus upon T-cell activation and recruiting to target promoters; in S-phase cells, it promotes DNA double-strand break repair by forming a complex with RPA and EXO1, stimulating 5' end resection by relieving RPA-mediated inhibition of EXO1 and thereby enabling ATR signaling and homologous recombination."},"narrative":{"mechanistic_narrative":"PHF11 is a PHD finger-containing nuclear regulator that operates in two settings: transcriptional control of Th1 immune cytokines and the DNA double-strand break repair pathway [PMID:18405956, PMID:28115467]. In T cells PHF11 resides constitutively in the cytoplasm and translocates to the nucleus upon T-cell activation, where it physically and functionally interacts with the p65 subunit of NF-κB, is recruited to the IFNG promoter, and enhances NF-κB DNA binding to drive transcription of the Th1 cytokines IFN-γ and IL-2 [PMID:18405956, PMID:20421878]. Its PHD zinc-finger domain is required for this immune-regulatory function in vivo, as a point mutation in the domain dysregulates Il2 and NF-κB expression following LPS challenge [PMID:25091723]. In a distinct genome-maintenance role, PHF11 localizes to sites of DNA damage and deprotected telomeres in S phase, where it complexes with the ssDNA-binding protein RPA and the 5' exonuclease EXO1; biochemically it stimulates EXO1 by relieving RPA-mediated inhibition, thereby promoting 5' end resection, ATR signaling, and homologous recombination, and protecting cells against DNA-damaging agents [PMID:28115467]. PHF11 also participates in innate immune responses in non-immune cells, undergoing nuclear localization after TLR3 stimulation and restraining IL-8 production in keratinocytes [PMID:26573531].","teleology":[{"year":2008,"claim":"Established PHF11 as a positive transcriptional regulator of Th1 cytokines acting through NF-κB, defining its first molecular role.","evidence":"siRNA knockdown, overexpression, luciferase reporters, EMSA, and co-IP with p65/NF-κB in primary CD4+ and Jurkat T cells","pmids":["18405956"],"confidence":"Medium","gaps":["No structure of the PHF11-p65 interaction","DNA-binding specificity from EMSA not mapped to a defined motif","No independent replication"]},{"year":2010,"claim":"Showed that PHF11 function is regulated by activation-dependent cytoplasmic-to-nuclear translocation and direct promoter recruitment, explaining how it controls IFNG transcription.","evidence":"Subcellular fractionation, immunofluorescence, ChIP at the IFNG promoter, siRNA, and NF-κB reporter assays in T cells","pmids":["20421878"],"confidence":"Medium","gaps":["Signal driving nuclear translocation not identified","Mechanism linking PHF11 to CD28 and GIMAP4/5 unresolved","Single lab"]},{"year":2011,"claim":"Identified an allele-specific cis-regulatory mechanism controlling PHF11 expression, linking a transcription factor to disease-associated variation.","evidence":"EMSA showing allele-specific Oct-1 binding at SNP rs1046295 plus allele-specific expression allelotyping","pmids":["21320718"],"confidence":"Medium","gaps":["No functional rescue or mutagenesis confirming causality","Phenotypic consequence of expression difference not established"]},{"year":2014,"claim":"Provided in vivo genetic evidence that the PHD zinc-finger domain is required for PHF11's immune-regulatory role.","evidence":"ENU-induced PHD-domain point mutation in congenic mice, LPS stimulation, and RT-qPCR of Il2/NF-κB/Setdb2 in lung","pmids":["25091723"],"confidence":"Medium","gaps":["Molecular function of the PHD domain (e.g. histone or DNA recognition) not defined","Single study"]},{"year":2015,"claim":"Extended PHF11's function beyond T cells, implicating it in TLR3-driven innate immunity and cell cycle control in keratinocytes.","evidence":"siRNA, immunofluorescence, RT-qPCR/ELISA for IL-8/ISG15, and flow cytometry cell-cycle analysis after poly(I:C) stimulation","pmids":["26573531"],"confidence":"Medium","gaps":["Direct targets in keratinocytes not mapped","Mechanism connecting PHF11 to claudin-1 distribution unknown","Single lab"]},{"year":2017,"claim":"Defined a mechanistically distinct DNA repair function, showing PHF11 stimulates EXO1-mediated end resection by relieving RPA inhibition to enable HR.","evidence":"PICh telomere proteomics, siRNA with ATR/resection/HR assays, co-IP of PHF11-RPA and PHF11-EXO1, and in vitro reconstitution of EXO1 stimulation","pmids":["28115467"],"confidence":"High","gaps":["How the PHD domain contributes to the repair function not established","Recruitment to damage sites not mechanistically dissected","Relationship between the transcriptional and repair roles unknown"]},{"year":null,"claim":"How a single PHD finger protein partitions between NF-κB-dependent transcription and RPA/EXO1-dependent DNA repair, and whether these roles are functionally linked, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of PHF11 or its complexes","Ligand/mark recognized by the PHD domain unknown","Mechanism integrating immune and repair functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["RELA","RPA","EXO1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UIL8","full_name":"PHD finger protein 11","aliases":["BRCA1 C-terminus-associated protein","Renal carcinoma antigen NY-REN-34"],"length_aa":331,"mass_kda":37.6,"function":"Positive regulator of Th1-type cytokine gene expression","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UIL8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHF11","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/PHF11","total_profiled":1310},"omim":[{"mim_id":"607865","title":"SET DOMAIN PROTEIN, BIFURCATED, 2; SETDB2","url":"https://www.omim.org/entry/607865"},{"mim_id":"607796","title":"PHD FINGER PROTEIN 11; PHF11","url":"https://www.omim.org/entry/607796"},{"mim_id":"600807","title":"ASTHMA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/600807"},{"mim_id":"147050","title":"IgE RESPONSIVENESS, ATOPIC; IGER","url":"https://www.omim.org/entry/147050"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHF11"},"hgnc":{"alias_symbol":["NY-REN-34","BCAP","IGER"],"prev_symbol":[]},"alphafold":{"accession":"Q9UIL8","domains":[{"cath_id":"3.30.40.10","chopping":"40-162","consensus_level":"high","plddt":87.3903,"start":40,"end":162},{"cath_id":"-","chopping":"217-273","consensus_level":"medium","plddt":89.8023,"start":217,"end":273},{"cath_id":"1.20.5","chopping":"281-316","consensus_level":"medium","plddt":95.5933,"start":281,"end":316}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIL8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIL8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIL8-F1-predicted_aligned_error_v6.png","plddt_mean":73.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHF11","jax_strain_url":"https://www.jax.org/strain/search?query=PHF11"},"sequence":{"accession":"Q9UIL8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UIL8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UIL8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIL8"}},"corpus_meta":[{"pmid":"15674390","id":"PMC_15674390","title":"Polymorphisms within the PHF11 gene at chromosome 13q14 are associated with childhood atopic dermatitis.","date":"2005","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15674390","citation_count":39,"is_preprint":false},{"pmid":"18405956","id":"PMC_18405956","title":"Functional characterization of the atopy-associated gene PHF11.","date":"2008","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18405956","citation_count":32,"is_preprint":false},{"pmid":"20421878","id":"PMC_20421878","title":"A role for the atopy-associated gene PHF11 in T-cell activation and viability.","date":"2010","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20421878","citation_count":28,"is_preprint":false},{"pmid":"19672052","id":"PMC_19672052","title":"Polymorphisms of PHF11 and DPP10 are associated with asthma and related traits in a Chinese population.","date":"2009","source":"Respiration; international review of thoracic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19672052","citation_count":25,"is_preprint":false},{"pmid":"28115467","id":"PMC_28115467","title":"PHF11 promotes DSB resection, ATR signaling, and HR.","date":"2017","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/28115467","citation_count":24,"is_preprint":false},{"pmid":"26573531","id":"PMC_26573531","title":"PHF11 expression and cellular distribution is regulated by the Toll-Like Receptor 3 Ligand Polyinosinic:Polycytidylic Acid in HaCaT keratinocytes.","date":"2015","source":"BMC immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26573531","citation_count":14,"is_preprint":false},{"pmid":"21320718","id":"PMC_21320718","title":"Allele-specific transcription of the asthma-associated PHD finger protein 11 gene (PHF11) modulated by octamer-binding transcription factor 1 (Oct-1).","date":"2011","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21320718","citation_count":14,"is_preprint":false},{"pmid":"19386584","id":"PMC_19386584","title":"The PHF11 gene is not associated with asthma or asthma phenotypes in two independent populations.","date":"2009","source":"Thorax","url":"https://pubmed.ncbi.nlm.nih.gov/19386584","citation_count":8,"is_preprint":false},{"pmid":"25091723","id":"PMC_25091723","title":"Functional analysis of a novel ENU-induced PHD finger 11 (Phf11) mouse mutant.","date":"2014","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/25091723","citation_count":8,"is_preprint":false},{"pmid":"37915596","id":"PMC_37915596","title":"Analysis of microbiota reveals the underlying mechanism of PHF11 in the development of Enterococcus-regulated endometriotic cysts.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37915596","citation_count":6,"is_preprint":false},{"pmid":"38439851","id":"PMC_38439851","title":"Moxibustion alleviates intestinal inflammation in ulcerative colitis rats by modulating long non-coding RNA LOC108352929 and inhibiting Phf11 expression.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38439851","citation_count":2,"is_preprint":false},{"pmid":"20717939","id":"PMC_20717939","title":"PHF11 is not a major candidate gene for asthma or eczema in Chinese children.","date":"2010","source":"Pediatric pulmonology","url":"https://pubmed.ncbi.nlm.nih.gov/20717939","citation_count":1,"is_preprint":false},{"pmid":"28130344","id":"PMC_28130344","title":"Putting PHDs to work: PHF11 clears the way for EXO1 in double-strand break repair.","date":"2017","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/28130344","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8723,"output_tokens":1903,"usd":0.027357,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8810,"output_tokens":2386,"usd":0.05185,"stage2_stop_reason":"end_turn"},"total_usd":0.079207,"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\": 2008,\n      \"finding\": \"PHF11 physically and functionally interacts with the p65 subunit of NF-κB, and knockdown of PHF11 reduces expression of the Th1-type cytokines IFN-γ and IL-2 in primary CD4+ T cells and Jurkat T cells, while overexpression increases their transcription; PHF11 was also shown by EMSA to bind DNA.\",\n      \"method\": \"siRNA knockdown, overexpression, luciferase reporter assays, electrophoretic mobility shift assay (EMSA), co-immunoprecipitation (physical interaction with p65/NF-κB)\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple orthogonal methods (siRNA, OE, reporter assay, EMSA, co-IP) in a single lab; no independent replication reported\",\n      \"pmids\": [\"18405956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PHF11 is constitutively localized in the cytoplasm of T cells and translocates to the nucleus upon T-cell activation; in the nucleus it is recruited to the IFNG promoter, enhances NF-κB binding to the IFNG promoter and IFNG transcription; PHF11 knockdown decreases CD28 surface expression, reduces NF-κB nuclear import and DNA binding, decreases cell viability, and reduces expression of GIMAP4/5.\",\n      \"method\": \"Subcellular fractionation and immunofluorescence microscopy (localization), chromatin immunoprecipitation (ChIP; recruitment to IFNG promoter), siRNA knockdown, overexpression, flow cytometry (CD28), NF-κB reporter assay\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple orthogonal methods (fractionation, ChIP, siRNA, OE, reporter) in single lab; no independent replication\",\n      \"pmids\": [\"20421878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PHF11 promotes 5' end resection at DNA double-strand breaks (DSBs), ATR signaling, and homologous recombination (HR). PHF11 associates with deprotected telomeres and localizes to sites of DNA damage in S phase. PHF11 depletion diminishes ATR signaling, reduces end resection, compromises HR, causes misrejoining of S-phase DSBs, and increases sensitivity to DNA-damaging agents. PHF11 physically interacts with RPA (ssDNA-binding protein) and forms a complex with nucleases including the 5' dsDNA exonuclease EXO1. Biochemically, PHF11 stimulates EXO1 by overcoming its inhibition by RPA.\",\n      \"method\": \"PICh (proteomics of isolated chromatin segments) for telomere association, siRNA depletion with ATR signaling assays, resection assays, HR reporter assays, co-immunoprecipitation (PHF11–RPA, PHF11–EXO1 complex), in vitro biochemical reconstitution (PHF11 stimulation of EXO1 in the presence of RPA), sensitivity assays to DNA-damaging agents\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — includes in vitro biochemical reconstitution with EXO1 and RPA, multiple orthogonal cellular assays (resection, ATR signaling, HR), and co-IP; rigorous single study with multiple methods\",\n      \"pmids\": [\"28115467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The asthma-associated SNP rs1046295 in PHF11 modulates allele-specific binding by octamer-binding transcription factor 1 (Oct-1), and the A allele shows preferentially higher expression; this identifies a regulatory mechanism by which Oct-1 binding affects PHF11 transcription level in an allele-dependent manner.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA) for transcription factor binding, allele-specific expression allelotyping\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — EMSA plus allele-specific expression in multiple cell lines; no functional rescue or mutagenesis confirming causality\",\n      \"pmids\": [\"21320718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In keratinocytes, PHF11 undergoes nuclear localization following poly(I:C) (TLR3 ligand) treatment; PHF11 knockdown increases IL-8 expression and secretion, alters claudin-1 cellular distribution, reduces cell density, and decreases the proportion of cells in G1 phase, indicating a role for PHF11 in the innate immune response and cell cycle regulation in keratinocytes.\",\n      \"method\": \"siRNA knockdown, immunofluorescence microscopy (nuclear localization), RT-qPCR and ELISA (IL-8, ISG15, PHF11 RNA), flow cytometry (cell cycle analysis), poly(I:C) stimulation model\",\n      \"journal\": \"BMC immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple readouts (localization, gene expression, ELISA, cell cycle) in a single lab with siRNA; no independent replication\",\n      \"pmids\": [\"26573531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A point mutation (valine to alanine) in the PHD zinc finger domain of mouse Phf11 leads to significantly increased expression of Il2, NF-κB, and Setdb2 in lung tissue after LPS stimulation, providing in vivo genetic evidence that the PHD domain of Phf11 is required for its role as a Th1 cell regulator in immune responses.\",\n      \"method\": \"ENU-induced point mutagenesis (PHD domain), congenic mouse line, LPS stimulation, RT-qPCR (Il2, NF-κB, Setdb2 expression), histology, haematology\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo domain-specific mutation with defined molecular phenotype; single lab, single study\",\n      \"pmids\": [\"25091723\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHF11 is a PHD finger-containing protein with dual mechanistic roles: in immune cells, it acts as a transcriptional co-activator of Th1 cytokine genes (IFN-γ, IL-2) by cooperating with NF-κB, translocating from cytoplasm to nucleus upon T-cell activation and recruiting to target promoters; in S-phase cells, it promotes DNA double-strand break repair by forming a complex with RPA and EXO1, stimulating 5' end resection by relieving RPA-mediated inhibition of EXO1 and thereby enabling ATR signaling and homologous recombination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHF11 is a PHD finger-containing nuclear regulator that operates in two settings: transcriptional control of Th1 immune cytokines and the DNA double-strand break repair pathway [#0, #2]. In T cells PHF11 resides constitutively in the cytoplasm and translocates to the nucleus upon T-cell activation, where it physically and functionally interacts with the p65 subunit of NF-κB, is recruited to the IFNG promoter, and enhances NF-κB DNA binding to drive transcription of the Th1 cytokines IFN-γ and IL-2 [#0, #1]. Its PHD zinc-finger domain is required for this immune-regulatory function in vivo, as a point mutation in the domain dysregulates Il2 and NF-κB expression following LPS challenge [#5]. In a distinct genome-maintenance role, PHF11 localizes to sites of DNA damage and deprotected telomeres in S phase, where it complexes with the ssDNA-binding protein RPA and the 5' exonuclease EXO1; biochemically it stimulates EXO1 by relieving RPA-mediated inhibition, thereby promoting 5' end resection, ATR signaling, and homologous recombination, and protecting cells against DNA-damaging agents [#2]. PHF11 also participates in innate immune responses in non-immune cells, undergoing nuclear localization after TLR3 stimulation and restraining IL-8 production in keratinocytes [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established PHF11 as a positive transcriptional regulator of Th1 cytokines acting through NF-κB, defining its first molecular role.\",\n      \"evidence\": \"siRNA knockdown, overexpression, luciferase reporters, EMSA, and co-IP with p65/NF-κB in primary CD4+ and Jurkat T cells\",\n      \"pmids\": [\"18405956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the PHF11-p65 interaction\", \"DNA-binding specificity from EMSA not mapped to a defined motif\", \"No independent replication\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that PHF11 function is regulated by activation-dependent cytoplasmic-to-nuclear translocation and direct promoter recruitment, explaining how it controls IFNG transcription.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, ChIP at the IFNG promoter, siRNA, and NF-κB reporter assays in T cells\",\n      \"pmids\": [\"20421878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal driving nuclear translocation not identified\", \"Mechanism linking PHF11 to CD28 and GIMAP4/5 unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified an allele-specific cis-regulatory mechanism controlling PHF11 expression, linking a transcription factor to disease-associated variation.\",\n      \"evidence\": \"EMSA showing allele-specific Oct-1 binding at SNP rs1046295 plus allele-specific expression allelotyping\",\n      \"pmids\": [\"21320718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional rescue or mutagenesis confirming causality\", \"Phenotypic consequence of expression difference not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided in vivo genetic evidence that the PHD zinc-finger domain is required for PHF11's immune-regulatory role.\",\n      \"evidence\": \"ENU-induced PHD-domain point mutation in congenic mice, LPS stimulation, and RT-qPCR of Il2/NF-κB/Setdb2 in lung\",\n      \"pmids\": [\"25091723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular function of the PHD domain (e.g. histone or DNA recognition) not defined\", \"Single study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended PHF11's function beyond T cells, implicating it in TLR3-driven innate immunity and cell cycle control in keratinocytes.\",\n      \"evidence\": \"siRNA, immunofluorescence, RT-qPCR/ELISA for IL-8/ISG15, and flow cytometry cell-cycle analysis after poly(I:C) stimulation\",\n      \"pmids\": [\"26573531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct targets in keratinocytes not mapped\", \"Mechanism connecting PHF11 to claudin-1 distribution unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a mechanistically distinct DNA repair function, showing PHF11 stimulates EXO1-mediated end resection by relieving RPA inhibition to enable HR.\",\n      \"evidence\": \"PICh telomere proteomics, siRNA with ATR/resection/HR assays, co-IP of PHF11-RPA and PHF11-EXO1, and in vitro reconstitution of EXO1 stimulation\",\n      \"pmids\": [\"28115467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the PHD domain contributes to the repair function not established\", \"Recruitment to damage sites not mechanistically dissected\", \"Relationship between the transcriptional and repair roles unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single PHD finger protein partitions between NF-κB-dependent transcription and RPA/EXO1-dependent DNA repair, and whether these roles are functionally linked, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of PHF11 or its complexes\", \"Ligand/mark recognized by the PHD domain unknown\", \"Mechanism integrating immune and repair functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RELA\", \"RPA\", \"EXO1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}