{"gene":"PYGO2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2009,"finding":"Pygo2 facilitates trimethylation of histone H3 at K4 (H3K4me3), both globally and at Wnt/β-catenin target loci, via direct binding to K4-methyl histone H3 and recruiting histone H3 K4 methyltransferase complexes, thereby expanding mammary epithelial progenitor cells.","method":"Gene ablation (complete and epithelia-specific knockout in mice), chromatin immunoprecipitation, direct binding assays to K4-methyl H3, recruitment of H3K4 methyltransferase complexes, mammary transplantation/regeneration assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (in vivo KO, ChIP, direct binding, functional rescue), replicated across normal development and Wnt signaling contexts","pmids":["19487454"],"is_preprint":false},{"year":2008,"finding":"Pygo2 is expressed in elongating spermatids during chromatin remodeling and, independently of β-catenin, controls histone H3 hyperacetylation patterning and expression of post-meiotic genes (protamines, transition protein 2, H1fnt) required for chromatin condensation during spermiogenesis; loss of Pygo2 function causes spermiogenesis arrest and male infertility.","method":"Hypomorphic allele mouse model, histological analysis of spermiogenesis, immunostaining for histone H3 hyperacetylation, RT-PCR/expression analysis of post-meiotic genes","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo hypomorphic loss-of-function with defined molecular phenotype (histone acetylation, gene expression), multiple readouts in single study","pmids":["18614164"],"is_preprint":false},{"year":2007,"finding":"Pygo1 and Pygo2 function as quantitative modulators (not absolute requirements) of canonical Wnt signaling during kidney development; double knockout reduces BAT-gal Wnt reporter activity in a tissue-specific manner and disrupts ureteric bud branching morphogenesis.","method":"Targeted gene deletion (>80% coding sequence including PHD domain) in mice, BAT-gal Wnt reporter assay, confocal analysis, microarray expression profiling","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo double-null genetic epistasis with direct Wnt reporter readout, multiple tissue analyses","pmids":["17425782"],"is_preprint":false},{"year":2013,"finding":"Pygo2 acts as a histone methylation reader and context-dependent Wnt/β-catenin coactivator that suppresses luminal/alveolar differentiation of mammary stem/basal cells by binding to the Notch3 locus, recruiting β-catenin, and maintaining a poised/repressed chromatin state at the Notch3 locus; loss of Pygo2 elevates Notch signaling and luminal differentiation markers.","method":"Epithelia-specific Pygo2 knockout, mammary transplantation, Notch/Wnt pharmacological inhibition/activation, ChIP for β-catenin and chromatin state at Notch3 locus, gene expression profiling","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and pharmacological epistasis, ChIP at specific locus, in vivo transplantation readout, multiple orthogonal methods","pmids":["23684539"],"is_preprint":false},{"year":2013,"finding":"Epithelial ablation of Pygo2 in MMTV-Wnt1 mice significantly delays mammary tumor onset and reduces tumor-initiating capability upon transplantation, placing Pygo2 downstream of mammary stem cell accumulation in the transformation step and showing it modulates lineage potential of tumor-initiating cells.","method":"Epithelia-specific conditional knockout in MMTV-Wnt1 transgenic mice, tumor transplantation assay, lineage analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with quantitative tumor onset and transplantation functional readout","pmids":["23334328"],"is_preprint":false},{"year":2014,"finding":"Pygo2 in epithelial cells facilitates β-catenin-induced activation of hair follicle stem/early progenitor cells and trichofolliculoma-like skin hyperplasia; β-catenin and Pygo2 converge to induce accumulation and acetylation of p53 upon cell cycle entry of hair follicle early progenitor cells and in cultured keratinocytes.","method":"Conditional epithelial Pygo2 knockout, depilation-induced hair regeneration assay, β-catenin gain-of-function mouse model, immunostaining for p53 acetylation, cell culture experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO combined with β-catenin GOF epistasis and molecular readout (p53 acetylation) in multiple model systems","pmids":["24982158"],"is_preprint":false},{"year":2015,"finding":"Pygo2 protein is degraded via the ubiquitin/proteasome pathway through a Cullin 4 (Cul4)-DDB1 E3 ubiquitin ligase complex; Akt-mediated phosphorylation of Pygo2 at serine 48 reduces its ubiquitylation and increases its stability, thus acting downstream of PI3K/Akt and Wnt signaling to stabilize Pygo2.","method":"Proteasome inhibitor treatment, co-immunoprecipitation of Cul4/DDB1 with Pygo2, site-directed mutagenesis at S48, Akt kinase assays, ubiquitylation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase/ubiquitylation assays with mutagenesis, co-IP of E3 components, multiple orthogonal methods in one study","pmids":["26170450"],"is_preprint":false},{"year":2016,"finding":"Pygo2 activates MDR1 (ABCB1) expression in breast cancer cells via the Wnt/β-catenin pathway; Pygo2 is identified as the most upregulated Wnt pathway component in chemoresistant breast cancer cells, and its inhibition restores drug sensitivity and reduces cancer stem cell populations.","method":"Wnt pathway-specific PCR array screening, siRNA knockdown, MDR1 reporter assays, cell viability assays, mouse xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PCR array plus functional KD experiments with in vivo xenograft confirmation, but direct ChIP at MDR1 locus not described in abstract","pmids":["26876203"],"is_preprint":false},{"year":2016,"finding":"Pygo2 is required as a co-activator in the nuclear β-catenin/BCL9/BCL9-2 complex for Wnt target gene transcription (specifically c-Myc); in vivo loss of Pygo2 reduces chemically induced colon tumor development and rescues early tumorigenesis in Ctnnb1 gain-of-function mice, but does not prevent tumor development in Apc loss-of-function mice.","method":"Pygo2 knockout mice, chemically-induced colon tumor model, conditional intestinal Ctnnb1 GOF and Apc LOF mouse models, target gene expression analysis","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in multiple in vivo models with defined molecular target (c-Myc), demonstrating context-dependence","pmids":["27811361"],"is_preprint":false},{"year":2016,"finding":"Pygo2 is transiently acetylated by CBP/p300 (but not GCN5/PCAF) at specific lysine residues in its N-terminal homology domain when bound to the active TCF/β-catenin transcription complex; p300-mediated acetylation of Pygo2 at lysines in its nuclear localization sequence displaces Pygo2 from the nucleus to the cytoplasm, consistent with a recycling mechanism post-target gene activation; CBP/p300 presence also increases Pygo2 association with GCN5 independently of Pygo2 acetylation status.","method":"Co-immunoprecipitation, mutagenesis of lysine residues, subcellular fractionation/localization, Axin2 reporter assays, in vitro acetylation assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — site-directed mutagenesis combined with co-IP and functional localization readout, multiple orthogonal methods in single study","pmids":["27647933"],"is_preprint":false},{"year":2018,"finding":"PYGO2, located in the 1q21.3 amplicon, functions as a driver oncogene in prostate cancer; PYGO2 overexpression enhances primary tumor growth and lymph node invasion, PYGO2 depletion inhibits invasion in vitro and tumor progression/metastasis in vivo, and PYGO2 is necessary for transcriptional activation in response to ligand-induced Wnt/β-catenin signaling.","method":"In vivo gain-of-function tumorigenesis screen, PYGO2 overexpression and shRNA depletion in cell lines and mouse models, patient-derived xenograft models, Wnt reporter assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional genomics screen validated by multiple orthogonal in vivo models (xenograft, PDX) plus Wnt reporter mechanistic assay","pmids":["29769196"],"is_preprint":false},{"year":2018,"finding":"Pygo2 inhibition during adipocyte differentiation leads to downregulation of Axin2 in the cytoplasm, releasing Axin2-bound GSK3β to translocate to the nucleus, where it phosphorylates C/EBPβ and Snail, increasing C/EBPβ DNA binding activity and decreasing Snail stability, thereby activating C/EBPα and PPARγ expression and promoting adipogenesis; adipocyte precursor-specific Pygo2 knockout mice show increased adiposity and impaired glucose tolerance.","method":"Pygo2 conditional knockout mice, primary adipocyte differentiation assays, nuclear/cytoplasmic fractionation, GSK3β nuclear translocation analysis, co-immunoprecipitation, phosphorylation assays, metabolic phenotyping","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with metabolic phenotype combined with detailed molecular mechanism (Axin2/GSK3β/C/EBPβ axis) using multiple biochemical methods","pmids":["30279163"],"is_preprint":false},{"year":2023,"finding":"Pygo2 orchestrates a p53/Sp1/Kit/Ido1 signaling network in prostate cancer cells to create an immune microenvironment hostile to cytotoxic T lymphocytes (CTLs); Pygo2 deletion augments CTL activation and infiltration, sensitizes tumor cells to T cell killing, and enhances efficacy of immune checkpoint blockade, adoptive cell transfer, and MDSC-targeting therapies.","method":"Transgenic mouse models of metastatic prostate adenocarcinoma, Pygo2 deletion, flow cytometry of CTLs, mechanistic dissection of p53/Sp1/Kit/Ido1 pathway, pharmacological inhibition, immune checkpoint blockade combination experiments","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo transgenic models with immune phenotyping, pathway epistasis (p53/Sp1/Kit/Ido1), and therapeutic intervention experiments","pmids":["36897957"],"is_preprint":false},{"year":2023,"finding":"Pygo2 coordinates with H3K4me2/3 modifications to activate BRPF1 transcription by binding to the BRPF1 promoter; Pygo2-driven colon cancer cell proliferation, migration, stemness, and in vivo tumor growth depend on BRPF1 as a downstream effector, and BRPF1 inhibition selectively suppresses Pygo2-high tumor growth.","method":"Luciferase reporter assay, ChIP-qPCR at BRPF1 promoter, siRNA knockdown, overexpression, in vivo subcutaneous tumor model, GSK5959 pharmacological inhibition","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays establish direct promoter binding, functional epistasis via rescue experiments, but single lab study","pmids":["37423512"],"is_preprint":false},{"year":2015,"finding":"Pygo2 knockdown in glioma U251 cells inhibits cell proliferation, increases apoptosis, and reduces glioma cancer stem-like cell sphere number and size, linked mechanistically to decreased H3K4me3 levels, establishing Pygo2's role in histone H3K4 trimethylation as a driver of glioma cell survival.","method":"Lentiviral siRNA knockdown, cell proliferation assay, apoptosis assay, neurosphere assay, H3K4me3 immunostaining/western blot","journal":"Journal of molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA KD with defined molecular readout (H3K4me3), consistent with established Pygo2 mechanism, single lab","pmids":["25869613"],"is_preprint":false},{"year":2022,"finding":"EFNA4 (Ephrin A4) physically interacts with PYGO2 and positively regulates PYGO2 protein expression; EFNA4 knockdown blocks Wnt/β-catenin signaling in HCC cells in a PYGO2-dependent manner, as PYGO2 overexpression rescues the signaling and tumor phenotypes caused by EFNA4 loss.","method":"Co-immunoprecipitation (EFNA4-PYGO2 interaction), siRNA knockdown, overexpression rescue experiments, Wnt/β-catenin pathway readouts, cell proliferation/invasion/angiogenesis assays","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus epistasis rescue, single lab, but mechanistic claim supported by two orthogonal approaches","pmids":["36404439"],"is_preprint":false},{"year":2021,"finding":"Pygo2 directly binds to the MDR1 promoter region and promotes MDR1 transcriptional activation in gastric cancer; Pygo2 knockdown in drug-resistant gastric cancer cells downregulates MDR1 and restores sensitivity to cisplatin.","method":"ChIP/promoter binding assay for Pygo2 at MDR1 promoter, siRNA knockdown, MDR1 expression analysis, drug sensitivity assay","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct promoter binding assay plus functional KD, but single lab and limited mechanistic depth in abstract","pmids":["33854595"],"is_preprint":false}],"current_model":"PYGO2 is an evolutionarily conserved PHD finger-containing chromatin effector and context-dependent coactivator of Wnt/β-catenin signaling that directly binds H3K4-methylated histone H3, recruits H3K4 methyltransferase complexes to facilitate H3K4me3 at target loci, is transiently acetylated by CBP/p300 at TCF/β-catenin target sites (promoting nuclear export as a recycling mechanism), and is stabilized by Akt-mediated phosphorylation at Ser48 that antagonizes Cul4-DDB1-mediated ubiquitin/proteasome degradation; it acts as a quantitative modulator of Wnt output in development (kidney, mammary gland, hair follicle, spermiogenesis), suppresses luminal differentiation of mammary stem cells by maintaining a repressed chromatin state at Notch3, regulates adipogenesis via an Axin2/GSK3β/C/EBPβ axis, drives prostate cancer metastasis through a p53/Sp1/Kit/Ido1 immune-suppressive network, and transcriptionally activates MDR1 to confer chemoresistance."},"narrative":{"mechanistic_narrative":"PYGO2 is an evolutionarily conserved PHD-finger chromatin effector that reads H3K4-methylated histone H3 and acts as a context-dependent coactivator of Wnt/β-catenin signaling, coupling histone methylation reading to transcriptional output during development and tumorigenesis [PMID:19487454, PMID:23684539]. Mechanistically, PYGO2 binds K4-methyl histone H3 and recruits H3K4 methyltransferase complexes to facilitate H3K4me3 both globally and at Wnt target loci, expanding epithelial progenitor populations [PMID:19487454]. As a quantitative rather than absolute modulator of canonical Wnt signaling, PYGO2 tunes β-catenin output in a tissue-specific manner across kidney branching morphogenesis [PMID:17425782] and functions within the nuclear β-catenin/BCL9/BCL9-2 complex to activate targets such as c-Myc, with its requirement dependent on signaling context [PMID:27811361]. At target loci, PYGO2 is transiently acetylated by CBP/p300 within its N-terminal homology domain and nuclear localization sequence, displacing it from nucleus to cytoplasm as a recycling mechanism following target gene activation [PMID:27647933]. PYGO2 protein levels are controlled by Cul4-DDB1-mediated ubiquitin/proteasome degradation, which is antagonized by Akt phosphorylation at Ser48 that stabilizes the protein downstream of PI3K/Akt and Wnt signaling [PMID:26170450]. In tissue contexts PYGO2 suppresses luminal/alveolar differentiation of mammary stem cells by maintaining a poised/repressed chromatin state at the Notch3 locus [PMID:23684539], regulates adipogenesis through an Axin2/GSK3β/C/EBPβ axis [PMID:30279163], and controls post-meiotic chromatin condensation during spermiogenesis independently of β-catenin via histone H3 hyperacetylation patterning [PMID:18614164]. PYGO2 functions as a driver oncogene: it promotes mammary tumor initiation [PMID:23334328], prostate cancer growth and metastasis including orchestration of an immune-suppressive p53/Sp1/Kit/Ido1 network hostile to cytotoxic T lymphocytes [PMID:29769196, PMID:36897957], and confers chemoresistance by directly activating MDR1/ABCB1 transcription [PMID:33854595].","teleology":[{"year":2007,"claim":"Established whether PYGO proteins are absolute or quantitative requirements for canonical Wnt signaling in mammals, resolving their role as graded modulators rather than essential switches.","evidence":"Targeted Pygo1/Pygo2 double deletion in mice with BAT-gal Wnt reporter and kidney morphogenesis analysis","pmids":["17425782"],"confidence":"High","gaps":["Did not define the molecular basis of tissue-specific Wnt dependence","No biochemical mechanism for graded coactivation"]},{"year":2008,"claim":"Revealed a β-catenin-independent role for PYGO2 in chromatin remodeling, expanding its function beyond Wnt coactivation.","evidence":"Hypomorphic Pygo2 mouse model with histological and expression analysis of spermiogenesis","pmids":["18614164"],"confidence":"High","gaps":["Mechanism linking PYGO2 to histone H3 hyperacetylation patterning not resolved","Direct chromatin targets in spermatids not mapped"]},{"year":2009,"claim":"Defined the core molecular mechanism of PYGO2 as an H3K4-methyl reader that recruits H3K4 methyltransferase complexes to drive H3K4me3 at Wnt target loci.","evidence":"In vivo knockout, ChIP, direct K4-methyl H3 binding assays, and mammary regeneration assays","pmids":["19487454"],"confidence":"High","gaps":["Identity of the recruited methyltransferase complex not fully resolved","Distinction between global versus locus-specific effects incomplete"]},{"year":2013,"claim":"Showed PYGO2 enforces stem cell identity by maintaining repressed chromatin at a specific differentiation locus, linking its reader function to lineage control.","evidence":"Epithelial knockout, mammary transplantation, ChIP at Notch3 locus, and Notch/Wnt pharmacological modulation","pmids":["23684539"],"confidence":"High","gaps":["How PYGO2 establishes a poised/repressed rather than active state at Notch3 unclear","Co-repressor partners at the locus not identified"]},{"year":2013,"claim":"Placed PYGO2 functionally at the transformation step of Wnt-driven tumorigenesis, distinguishing it from stem cell accumulation.","evidence":"Conditional Pygo2 knockout in MMTV-Wnt1 mice with tumor onset and transplantation assays","pmids":["23334328"],"confidence":"High","gaps":["Molecular targets governing tumor-initiating lineage potential not defined"]},{"year":2014,"claim":"Connected PYGO2 to p53 acetylation downstream of β-catenin during progenitor cell cycle entry, integrating Wnt with a tumor-suppressor pathway.","evidence":"Conditional epithelial knockout, β-catenin gain-of-function mice, and p53 acetylation immunostaining in keratinocytes","pmids":["24982158"],"confidence":"High","gaps":["Direct versus indirect role of PYGO2 in p53 acetylation not separated","Acetyltransferase responsible not identified in this context"]},{"year":2015,"claim":"Identified the post-translational control of PYGO2 abundance, defining Cul4-DDB1 degradation antagonized by Akt phosphorylation at Ser48.","evidence":"Proteasome inhibition, Cul4/DDB1 co-IP, S48 mutagenesis, and Akt kinase/ubiquitylation assays","pmids":["26170450"],"confidence":"High","gaps":["Substrate recognition subunit of the Cul4-DDB1 complex not identified","Stoichiometry and dynamics of Akt-Wnt crosstalk not quantified"]},{"year":2015,"claim":"Extended PYGO2's H3K4me3-driven survival function to glioma, supporting a generalizable chromatin mechanism in cancer.","evidence":"Lentiviral siRNA knockdown in U251 cells with proliferation, apoptosis, neurosphere, and H3K4me3 readouts","pmids":["25869613"],"confidence":"Medium","gaps":["Single cell line, no in vivo validation","Direct chromatin targets in glioma not mapped"]},{"year":2016,"claim":"Demonstrated context-dependence of PYGO2 in colon tumorigenesis within the β-catenin/BCL9 complex, showing it is required downstream of β-catenin gain but dispensable upon APC loss.","evidence":"Pygo2 knockout mice with chemically induced colon tumors and intestinal Ctnnb1 GOF / Apc LOF models","pmids":["27811361"],"confidence":"High","gaps":["Basis for differential requirement between Ctnnb1 GOF and Apc LOF lesions unexplained","Complex assembly dynamics not structurally resolved"]},{"year":2016,"claim":"Uncovered a regulated recycling mechanism whereby CBP/p300 acetylation of PYGO2 at the active TCF/β-catenin complex drives its nuclear export.","evidence":"Co-IP, lysine mutagenesis, subcellular fractionation, Axin2 reporter, and in vitro acetylation assays","pmids":["27647933"],"confidence":"High","gaps":["Deacetylase that resets PYGO2 not identified","Functional consequence of acetylation-dependent GCN5 association unclear"]},{"year":2016,"claim":"Linked PYGO2 to chemoresistance by activating MDR1 expression via Wnt/β-catenin and identifying it as the top upregulated Wnt component in resistant breast cancer cells.","evidence":"Wnt PCR array screen, siRNA knockdown, MDR1 reporter assays, and xenograft model","pmids":["26876203"],"confidence":"Medium","gaps":["Direct PYGO2 binding at the MDR1 locus not demonstrated in this study","Whether effect is solely Wnt-dependent not established"]},{"year":2018,"claim":"Validated PYGO2 as an amplicon-encoded driver oncogene in prostate cancer required for ligand-induced Wnt transcriptional output.","evidence":"In vivo gain-of-function screen, overexpression/shRNA in PDX and mouse models, and Wnt reporter assays","pmids":["29769196"],"confidence":"High","gaps":["Downstream transcriptional targets driving metastasis not yet defined here"]},{"year":2018,"claim":"Defined a non-canonical PYGO2 mechanism in adipogenesis acting through an Axin2/GSK3β/C/EBPβ/Snail axis with a metabolic phenotype.","evidence":"Adipocyte precursor-specific knockout mice, fractionation, GSK3β translocation, co-IP, and metabolic phenotyping","pmids":["30279163"],"confidence":"High","gaps":["How PYGO2 controls cytoplasmic Axin2 levels not mechanistically resolved","Direct versus chromatin-mediated regulation of Axin2 unclear"]},{"year":2021,"claim":"Provided direct evidence that PYGO2 binds the MDR1 promoter to drive transcriptional activation and chemoresistance, strengthening the earlier breast cancer correlation.","evidence":"ChIP/promoter binding assay at MDR1, siRNA knockdown, and cisplatin sensitivity assays in gastric cancer cells","pmids":["33854595"],"confidence":"Medium","gaps":["Single lab, limited mechanistic depth","Cofactors at the MDR1 promoter not identified"]},{"year":2022,"claim":"Identified EFNA4 as an upstream physical partner stabilizing PYGO2 and acting through it to drive Wnt signaling in hepatocellular carcinoma.","evidence":"Co-IP, siRNA knockdown, and PYGO2 overexpression rescue with Wnt and tumor phenotype readouts","pmids":["36404439"],"confidence":"Medium","gaps":["Mechanism by which EFNA4 stabilizes PYGO2 protein unknown","Single Co-IP without structural mapping of the interaction"]},{"year":2023,"claim":"Revealed PYGO2 as an orchestrator of an immune-suppressive tumor microenvironment, linking it to immunotherapy response in prostate cancer.","evidence":"Transgenic metastatic prostate cancer models with Pygo2 deletion, CTL flow cytometry, p53/Sp1/Kit/Ido1 pathway dissection, and checkpoint blockade combinations","pmids":["36897957"],"confidence":"High","gaps":["Direct PYGO2 transcriptional targets within the p53/Sp1/Kit/Ido1 network not fully mapped","Whether the immune effect requires Wnt coactivation unclear"]},{"year":2023,"claim":"Defined BRPF1 as a direct downstream transcriptional effector of PYGO2 coordinated with H3K4me2/3 in colon cancer, offering a targeting strategy.","evidence":"Luciferase reporter, ChIP-qPCR at the BRPF1 promoter, knockdown/overexpression, and GSK5959 inhibition in tumor models","pmids":["37423512"],"confidence":"Medium","gaps":["Single lab study","Generality of PYGO2-BRPF1 axis beyond colon cancer not tested"]},{"year":null,"claim":"How PYGO2's chromatin-reading, Wnt-coactivation, and β-catenin-independent functions are mechanistically partitioned across tissues, and the identity of the H3K4 methyltransferase complexes and co-repressors it engages at specific loci, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PYGO2 within the β-catenin/BCL9 complex on chromatin","Determinants of context-dependent activation versus repression not defined","Comprehensive genome-wide direct target map lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,3,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,8,10,13,16]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[13,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8,10]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,3,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,10,13,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,12,16]}],"complexes":["β-catenin/BCL9/BCL9-2 coactivator complex","Cul4-DDB1 E3 ubiquitin ligase complex (substrate)"],"partners":["CTNNB1","BCL9","BCL9-2","CREBBP/EP300","CUL4","DDB1","EFNA4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BRQ0","full_name":"Pygopus homolog 2","aliases":[],"length_aa":406,"mass_kda":41.2,"function":"Involved in signal transduction through the Wnt pathway","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BRQ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PYGO2","classification":"Not Classified","n_dependent_lines":33,"n_total_lines":1208,"dependency_fraction":0.027317880794701987},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PYGO2","total_profiled":1310},"omim":[{"mim_id":"615452","title":"PROSTATE CANCER-ASSOCIATED NONCODING RNA 1; PRNCR1","url":"https://www.omim.org/entry/615452"},{"mim_id":"606903","title":"PYGOPUS FAMILY PHD FINGER 2; PYGO2","url":"https://www.omim.org/entry/606903"},{"mim_id":"606902","title":"PYGOPUS FAMILY PHD FINGER 1; PYGO1","url":"https://www.omim.org/entry/606902"},{"mim_id":"605443","title":"PCGEM1 PROSTATE-SPECIFIC TRANSCRIPT; PCGEM1","url":"https://www.omim.org/entry/605443"},{"mim_id":"602597","title":"B-CELL CLL/LYMPHOMA 9; BCL9","url":"https://www.omim.org/entry/602597"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PYGO2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9BRQ0","domains":[{"cath_id":"3.30.40.10","chopping":"329-403","consensus_level":"high","plddt":84.0401,"start":329,"end":403}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRQ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRQ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRQ0-F1-predicted_aligned_error_v6.png","plddt_mean":55.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PYGO2","jax_strain_url":"https://www.jax.org/strain/search?query=PYGO2"},"sequence":{"accession":"Q9BRQ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BRQ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BRQ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRQ0"}},"corpus_meta":[{"pmid":"32727463","id":"PMC_32727463","title":"LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes.","date":"2020","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32727463","citation_count":323,"is_preprint":false},{"pmid":"19487454","id":"PMC_19487454","title":"Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19487454","citation_count":106,"is_preprint":false},{"pmid":"17425782","id":"PMC_17425782","title":"Pygo1 and Pygo2 roles in Wnt signaling in mammalian kidney development.","date":"2007","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/17425782","citation_count":78,"is_preprint":false},{"pmid":"23684539","id":"PMC_23684539","title":"Chromatin effector Pygo2 mediates Wnt-notch crosstalk to suppress luminal/alveolar potential of mammary stem and basal cells.","date":"2013","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/23684539","citation_count":76,"is_preprint":false},{"pmid":"26876203","id":"PMC_26876203","title":"Pygo2 activates MDR1 expression and mediates chemoresistance in breast cancer via the Wnt/β-catenin pathway.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/26876203","citation_count":75,"is_preprint":false},{"pmid":"18614164","id":"PMC_18614164","title":"Nuclear regulator Pygo2 controls spermiogenesis and histone H3 acetylation.","date":"2008","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18614164","citation_count":71,"is_preprint":false},{"pmid":"23456637","id":"PMC_23456637","title":"Association of PYGO2 and EGFR in esophageal squamous cell carcinoma.","date":"2013","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23456637","citation_count":37,"is_preprint":false},{"pmid":"31273950","id":"PMC_31273950","title":"miR-516a-3p inhibits breast cancer cell growth and EMT by blocking the Pygo2/Wnt signalling pathway.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31273950","citation_count":30,"is_preprint":false},{"pmid":"36897957","id":"PMC_36897957","title":"Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer.","date":"2023","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36897957","citation_count":29,"is_preprint":false},{"pmid":"26643817","id":"PMC_26643817","title":"Role of Msi1 and PYGO2 in esophageal squamous cell carcinoma depth of invasion.","date":"2015","source":"Journal of cell communication and signaling","url":"https://pubmed.ncbi.nlm.nih.gov/26643817","citation_count":29,"is_preprint":false},{"pmid":"30279163","id":"PMC_30279163","title":"Pygo2 Regulates Adiposity and Glucose Homeostasis via β-Catenin-Axin2-GSK3β Signaling Pathway.","date":"2018","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/30279163","citation_count":25,"is_preprint":false},{"pmid":"23334328","id":"PMC_23334328","title":"Chromatin effector Pygo2 regulates mammary tumor initiation and heterogeneity in MMTV-Wnt1 mice.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23334328","citation_count":25,"is_preprint":false},{"pmid":"24982158","id":"PMC_24982158","title":"Pygo2 regulates β-catenin-induced activation of hair follicle stem/progenitor cells and skin hyperplasia.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24982158","citation_count":24,"is_preprint":false},{"pmid":"27811361","id":"PMC_27811361","title":"The role of Pygo2 for Wnt/ß-catenin signaling activity during intestinal tumor initiation and progression.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27811361","citation_count":21,"is_preprint":false},{"pmid":"29769196","id":"PMC_29769196","title":"An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29769196","citation_count":17,"is_preprint":false},{"pmid":"34362407","id":"PMC_34362407","title":"Long non-coding RNA SNHG8 enhances triple-negative breast cancer cell proliferation and migration by regulating the miR-335-5p/PYGO2 axis.","date":"2021","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/34362407","citation_count":16,"is_preprint":false},{"pmid":"26170450","id":"PMC_26170450","title":"Akt Phosphorylates Wnt Coactivator and Chromatin Effector Pygo2 at Serine 48 to Antagonize Its Ubiquitin/Proteasome-mediated Degradation.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26170450","citation_count":12,"is_preprint":false},{"pmid":"36404439","id":"PMC_36404439","title":"Interference of EFNA4 suppresses cell proliferation, invasion and angiogenesis in hepatocellular carcinoma by downregulating PYGO2.","date":"2022","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36404439","citation_count":10,"is_preprint":false},{"pmid":"27647933","id":"PMC_27647933","title":"Wnt/β-catenin-dependent acetylation of Pygo2 by CBP/p300 histone acetyltransferase family members.","date":"2016","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/27647933","citation_count":10,"is_preprint":false},{"pmid":"37423512","id":"PMC_37423512","title":"Pygo2 activates BRPF1 via Pygo2-H3K4me2/3 interaction to maintain malignant progression in colon cancer.","date":"2023","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/37423512","citation_count":9,"is_preprint":false},{"pmid":"33854595","id":"PMC_33854595","title":"Pygo2 as a novel biomarker in gastric cancer for monitoring drug resistance by upregulating MDR1.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33854595","citation_count":8,"is_preprint":false},{"pmid":"38229324","id":"PMC_38229324","title":"PYGO2 increases proliferation and migration capacities through critical signaling pathways in esophageal squamous cell carcinoma.","date":"2024","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38229324","citation_count":6,"is_preprint":false},{"pmid":"31749426","id":"PMC_31749426","title":"Overexpression of Pygo2 Increases Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Cardiomyocyte-like Cells.","date":"2020","source":"Current molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31749426","citation_count":6,"is_preprint":false},{"pmid":"19487452","id":"PMC_19487452","title":"Epigenetics, Wnt signaling, and stem cells: the Pygo2 connection.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19487452","citation_count":6,"is_preprint":false},{"pmid":"31492088","id":"PMC_31492088","title":"PYGO2 as an independent diagnostic marker expressed in a majority of colorectal cancers.","date":"2019","source":"Journal of histotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31492088","citation_count":5,"is_preprint":false},{"pmid":"26345837","id":"PMC_26345837","title":"Associations of single nucleotide polymorphisms in the Pygo2 coding sequence with idiopathic oligospermia and azoospermia.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26345837","citation_count":5,"is_preprint":false},{"pmid":"25869613","id":"PMC_25869613","title":"Pygo2 siRNA Inhibit the Growth and Increase Apoptosis of U251 Cell by Suppressing Histone H3K4 Trimethylation.","date":"2015","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/25869613","citation_count":4,"is_preprint":false},{"pmid":"26013055","id":"PMC_26013055","title":"Increased Pygo2 expression in liver of patients with hepatitis B virus-related fibrosis.","date":"2015","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/26013055","citation_count":4,"is_preprint":false},{"pmid":"35023882","id":"PMC_35023882","title":"Nuclear Expression of Pygo2 Correlates with Poorly Differentiated State Involving c-Myc, PCNA and Bcl9 in Myanmar Hepatocellular Carcinoma.","date":"2021","source":"Acta histochemica et cytochemica","url":"https://pubmed.ncbi.nlm.nih.gov/35023882","citation_count":4,"is_preprint":false},{"pmid":"34234873","id":"PMC_34234873","title":"Hypothesis: Sam68 and Pygo2 mediate cell type-specific effects of the modulation of CBP-Wnt and p300-Wnt activities in Colorectal Cancer Cells.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34234873","citation_count":4,"is_preprint":false},{"pmid":"36197138","id":"PMC_36197138","title":"Correlation of Single Nucleotide Polymorphisms of PRM1, PRM2, PYGO2, and DAZL Genes with Male Infertility in North West of Iran.","date":"2022","source":"Turkish journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/36197138","citation_count":4,"is_preprint":false},{"pmid":"36688188","id":"PMC_36688188","title":"Association of Single Nucleotide Polymorphisms in the PYGO2 and PRDM9 Genes with Idiopathic Azoospermia in Iranian Infertile Male Patients.","date":"2023","source":"Iranian journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36688188","citation_count":3,"is_preprint":false},{"pmid":"38953488","id":"PMC_38953488","title":"EFNA4 deletion suppresses the migration, invasion, stemness, and angiogenesis of gastric cancer cells through the inactivation of Pygo2/Wnt signaling.","date":"2024","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/38953488","citation_count":3,"is_preprint":false},{"pmid":"29978348","id":"PMC_29978348","title":"Immunohistochemistry analysis of Pygo2 expression in central nervous system tumors.","date":"2018","source":"Journal of cell communication and signaling","url":"https://pubmed.ncbi.nlm.nih.gov/29978348","citation_count":2,"is_preprint":false},{"pmid":"23732668","id":"PMC_23732668","title":"[Association of single nucleotide polymorphisms(SNPs) in Pygo2 coding gene with idiopathic oligospermia and azoospermia].","date":"2013","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/23732668","citation_count":2,"is_preprint":false},{"pmid":"37233752","id":"PMC_37233752","title":"Novel biphasic mechanism of the canonical Wnt signalling component PYGO2 promotes cardiomyocyte differentiation from hUC-MSCs.","date":"2023","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/37233752","citation_count":2,"is_preprint":false},{"pmid":"40301712","id":"PMC_40301712","title":"PYGO2 regulates IL10 and plays immunosuppressive role through ESCC progression.","date":"2025","source":"BMC molecular and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/40301712","citation_count":1,"is_preprint":false},{"pmid":"40034933","id":"PMC_40034933","title":"Histopathological Evaluation of PYGO2 Expression in Esophageal Squamous Cell Carcinoma.","date":"2024","source":"Iranian journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40034933","citation_count":0,"is_preprint":false},{"pmid":"40771810","id":"PMC_40771810","title":"Pygo2+ T cells possess immunosuppressive features and inferior immunotherapeutic response in gastric cancer.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40771810","citation_count":0,"is_preprint":false},{"pmid":"39808374","id":"PMC_39808374","title":"PYGO2 promotes resistance to chemotherapy via reducing apoptosis and G2/M cell cycle arrest in esophageal carcinoma cells.","date":"2025","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/39808374","citation_count":0,"is_preprint":false},{"pmid":"37193170","id":"PMC_37193170","title":"TSF/FHA induces osteogenic differentiation of Mc3t3 cells via Pygo2 dependent Wnt/β-catenin signaling pathway.","date":"2023","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/37193170","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23088,"output_tokens":4762,"usd":0.070347,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12965,"output_tokens":5389,"usd":0.099775,"stage2_stop_reason":"end_turn"},"total_usd":0.170122,"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\": 2009,\n      \"finding\": \"Pygo2 facilitates trimethylation of histone H3 at K4 (H3K4me3), both globally and at Wnt/β-catenin target loci, via direct binding to K4-methyl histone H3 and recruiting histone H3 K4 methyltransferase complexes, thereby expanding mammary epithelial progenitor cells.\",\n      \"method\": \"Gene ablation (complete and epithelia-specific knockout in mice), chromatin immunoprecipitation, direct binding assays to K4-methyl H3, recruitment of H3K4 methyltransferase complexes, mammary transplantation/regeneration assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (in vivo KO, ChIP, direct binding, functional rescue), replicated across normal development and Wnt signaling contexts\",\n      \"pmids\": [\"19487454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pygo2 is expressed in elongating spermatids during chromatin remodeling and, independently of β-catenin, controls histone H3 hyperacetylation patterning and expression of post-meiotic genes (protamines, transition protein 2, H1fnt) required for chromatin condensation during spermiogenesis; loss of Pygo2 function causes spermiogenesis arrest and male infertility.\",\n      \"method\": \"Hypomorphic allele mouse model, histological analysis of spermiogenesis, immunostaining for histone H3 hyperacetylation, RT-PCR/expression analysis of post-meiotic genes\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo hypomorphic loss-of-function with defined molecular phenotype (histone acetylation, gene expression), multiple readouts in single study\",\n      \"pmids\": [\"18614164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Pygo1 and Pygo2 function as quantitative modulators (not absolute requirements) of canonical Wnt signaling during kidney development; double knockout reduces BAT-gal Wnt reporter activity in a tissue-specific manner and disrupts ureteric bud branching morphogenesis.\",\n      \"method\": \"Targeted gene deletion (>80% coding sequence including PHD domain) in mice, BAT-gal Wnt reporter assay, confocal analysis, microarray expression profiling\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo double-null genetic epistasis with direct Wnt reporter readout, multiple tissue analyses\",\n      \"pmids\": [\"17425782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Pygo2 acts as a histone methylation reader and context-dependent Wnt/β-catenin coactivator that suppresses luminal/alveolar differentiation of mammary stem/basal cells by binding to the Notch3 locus, recruiting β-catenin, and maintaining a poised/repressed chromatin state at the Notch3 locus; loss of Pygo2 elevates Notch signaling and luminal differentiation markers.\",\n      \"method\": \"Epithelia-specific Pygo2 knockout, mammary transplantation, Notch/Wnt pharmacological inhibition/activation, ChIP for β-catenin and chromatin state at Notch3 locus, gene expression profiling\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and pharmacological epistasis, ChIP at specific locus, in vivo transplantation readout, multiple orthogonal methods\",\n      \"pmids\": [\"23684539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Epithelial ablation of Pygo2 in MMTV-Wnt1 mice significantly delays mammary tumor onset and reduces tumor-initiating capability upon transplantation, placing Pygo2 downstream of mammary stem cell accumulation in the transformation step and showing it modulates lineage potential of tumor-initiating cells.\",\n      \"method\": \"Epithelia-specific conditional knockout in MMTV-Wnt1 transgenic mice, tumor transplantation assay, lineage analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with quantitative tumor onset and transplantation functional readout\",\n      \"pmids\": [\"23334328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Pygo2 in epithelial cells facilitates β-catenin-induced activation of hair follicle stem/early progenitor cells and trichofolliculoma-like skin hyperplasia; β-catenin and Pygo2 converge to induce accumulation and acetylation of p53 upon cell cycle entry of hair follicle early progenitor cells and in cultured keratinocytes.\",\n      \"method\": \"Conditional epithelial Pygo2 knockout, depilation-induced hair regeneration assay, β-catenin gain-of-function mouse model, immunostaining for p53 acetylation, cell culture experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO combined with β-catenin GOF epistasis and molecular readout (p53 acetylation) in multiple model systems\",\n      \"pmids\": [\"24982158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pygo2 protein is degraded via the ubiquitin/proteasome pathway through a Cullin 4 (Cul4)-DDB1 E3 ubiquitin ligase complex; Akt-mediated phosphorylation of Pygo2 at serine 48 reduces its ubiquitylation and increases its stability, thus acting downstream of PI3K/Akt and Wnt signaling to stabilize Pygo2.\",\n      \"method\": \"Proteasome inhibitor treatment, co-immunoprecipitation of Cul4/DDB1 with Pygo2, site-directed mutagenesis at S48, Akt kinase assays, ubiquitylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase/ubiquitylation assays with mutagenesis, co-IP of E3 components, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26170450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pygo2 activates MDR1 (ABCB1) expression in breast cancer cells via the Wnt/β-catenin pathway; Pygo2 is identified as the most upregulated Wnt pathway component in chemoresistant breast cancer cells, and its inhibition restores drug sensitivity and reduces cancer stem cell populations.\",\n      \"method\": \"Wnt pathway-specific PCR array screening, siRNA knockdown, MDR1 reporter assays, cell viability assays, mouse xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PCR array plus functional KD experiments with in vivo xenograft confirmation, but direct ChIP at MDR1 locus not described in abstract\",\n      \"pmids\": [\"26876203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pygo2 is required as a co-activator in the nuclear β-catenin/BCL9/BCL9-2 complex for Wnt target gene transcription (specifically c-Myc); in vivo loss of Pygo2 reduces chemically induced colon tumor development and rescues early tumorigenesis in Ctnnb1 gain-of-function mice, but does not prevent tumor development in Apc loss-of-function mice.\",\n      \"method\": \"Pygo2 knockout mice, chemically-induced colon tumor model, conditional intestinal Ctnnb1 GOF and Apc LOF mouse models, target gene expression analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in multiple in vivo models with defined molecular target (c-Myc), demonstrating context-dependence\",\n      \"pmids\": [\"27811361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pygo2 is transiently acetylated by CBP/p300 (but not GCN5/PCAF) at specific lysine residues in its N-terminal homology domain when bound to the active TCF/β-catenin transcription complex; p300-mediated acetylation of Pygo2 at lysines in its nuclear localization sequence displaces Pygo2 from the nucleus to the cytoplasm, consistent with a recycling mechanism post-target gene activation; CBP/p300 presence also increases Pygo2 association with GCN5 independently of Pygo2 acetylation status.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of lysine residues, subcellular fractionation/localization, Axin2 reporter assays, in vitro acetylation assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-directed mutagenesis combined with co-IP and functional localization readout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"27647933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PYGO2, located in the 1q21.3 amplicon, functions as a driver oncogene in prostate cancer; PYGO2 overexpression enhances primary tumor growth and lymph node invasion, PYGO2 depletion inhibits invasion in vitro and tumor progression/metastasis in vivo, and PYGO2 is necessary for transcriptional activation in response to ligand-induced Wnt/β-catenin signaling.\",\n      \"method\": \"In vivo gain-of-function tumorigenesis screen, PYGO2 overexpression and shRNA depletion in cell lines and mouse models, patient-derived xenograft models, Wnt reporter assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional genomics screen validated by multiple orthogonal in vivo models (xenograft, PDX) plus Wnt reporter mechanistic assay\",\n      \"pmids\": [\"29769196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Pygo2 inhibition during adipocyte differentiation leads to downregulation of Axin2 in the cytoplasm, releasing Axin2-bound GSK3β to translocate to the nucleus, where it phosphorylates C/EBPβ and Snail, increasing C/EBPβ DNA binding activity and decreasing Snail stability, thereby activating C/EBPα and PPARγ expression and promoting adipogenesis; adipocyte precursor-specific Pygo2 knockout mice show increased adiposity and impaired glucose tolerance.\",\n      \"method\": \"Pygo2 conditional knockout mice, primary adipocyte differentiation assays, nuclear/cytoplasmic fractionation, GSK3β nuclear translocation analysis, co-immunoprecipitation, phosphorylation assays, metabolic phenotyping\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with metabolic phenotype combined with detailed molecular mechanism (Axin2/GSK3β/C/EBPβ axis) using multiple biochemical methods\",\n      \"pmids\": [\"30279163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pygo2 orchestrates a p53/Sp1/Kit/Ido1 signaling network in prostate cancer cells to create an immune microenvironment hostile to cytotoxic T lymphocytes (CTLs); Pygo2 deletion augments CTL activation and infiltration, sensitizes tumor cells to T cell killing, and enhances efficacy of immune checkpoint blockade, adoptive cell transfer, and MDSC-targeting therapies.\",\n      \"method\": \"Transgenic mouse models of metastatic prostate adenocarcinoma, Pygo2 deletion, flow cytometry of CTLs, mechanistic dissection of p53/Sp1/Kit/Ido1 pathway, pharmacological inhibition, immune checkpoint blockade combination experiments\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo transgenic models with immune phenotyping, pathway epistasis (p53/Sp1/Kit/Ido1), and therapeutic intervention experiments\",\n      \"pmids\": [\"36897957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pygo2 coordinates with H3K4me2/3 modifications to activate BRPF1 transcription by binding to the BRPF1 promoter; Pygo2-driven colon cancer cell proliferation, migration, stemness, and in vivo tumor growth depend on BRPF1 as a downstream effector, and BRPF1 inhibition selectively suppresses Pygo2-high tumor growth.\",\n      \"method\": \"Luciferase reporter assay, ChIP-qPCR at BRPF1 promoter, siRNA knockdown, overexpression, in vivo subcutaneous tumor model, GSK5959 pharmacological inhibition\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays establish direct promoter binding, functional epistasis via rescue experiments, but single lab study\",\n      \"pmids\": [\"37423512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pygo2 knockdown in glioma U251 cells inhibits cell proliferation, increases apoptosis, and reduces glioma cancer stem-like cell sphere number and size, linked mechanistically to decreased H3K4me3 levels, establishing Pygo2's role in histone H3K4 trimethylation as a driver of glioma cell survival.\",\n      \"method\": \"Lentiviral siRNA knockdown, cell proliferation assay, apoptosis assay, neurosphere assay, H3K4me3 immunostaining/western blot\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA KD with defined molecular readout (H3K4me3), consistent with established Pygo2 mechanism, single lab\",\n      \"pmids\": [\"25869613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EFNA4 (Ephrin A4) physically interacts with PYGO2 and positively regulates PYGO2 protein expression; EFNA4 knockdown blocks Wnt/β-catenin signaling in HCC cells in a PYGO2-dependent manner, as PYGO2 overexpression rescues the signaling and tumor phenotypes caused by EFNA4 loss.\",\n      \"method\": \"Co-immunoprecipitation (EFNA4-PYGO2 interaction), siRNA knockdown, overexpression rescue experiments, Wnt/β-catenin pathway readouts, cell proliferation/invasion/angiogenesis assays\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus epistasis rescue, single lab, but mechanistic claim supported by two orthogonal approaches\",\n      \"pmids\": [\"36404439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pygo2 directly binds to the MDR1 promoter region and promotes MDR1 transcriptional activation in gastric cancer; Pygo2 knockdown in drug-resistant gastric cancer cells downregulates MDR1 and restores sensitivity to cisplatin.\",\n      \"method\": \"ChIP/promoter binding assay for Pygo2 at MDR1 promoter, siRNA knockdown, MDR1 expression analysis, drug sensitivity assay\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct promoter binding assay plus functional KD, but single lab and limited mechanistic depth in abstract\",\n      \"pmids\": [\"33854595\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PYGO2 is an evolutionarily conserved PHD finger-containing chromatin effector and context-dependent coactivator of Wnt/β-catenin signaling that directly binds H3K4-methylated histone H3, recruits H3K4 methyltransferase complexes to facilitate H3K4me3 at target loci, is transiently acetylated by CBP/p300 at TCF/β-catenin target sites (promoting nuclear export as a recycling mechanism), and is stabilized by Akt-mediated phosphorylation at Ser48 that antagonizes Cul4-DDB1-mediated ubiquitin/proteasome degradation; it acts as a quantitative modulator of Wnt output in development (kidney, mammary gland, hair follicle, spermiogenesis), suppresses luminal differentiation of mammary stem cells by maintaining a repressed chromatin state at Notch3, regulates adipogenesis via an Axin2/GSK3β/C/EBPβ axis, drives prostate cancer metastasis through a p53/Sp1/Kit/Ido1 immune-suppressive network, and transcriptionally activates MDR1 to confer chemoresistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PYGO2 is an evolutionarily conserved PHD-finger chromatin effector that reads H3K4-methylated histone H3 and acts as a context-dependent coactivator of Wnt/\\u03b2-catenin signaling, coupling histone methylation reading to transcriptional output during development and tumorigenesis [#0, #3]. Mechanistically, PYGO2 binds K4-methyl histone H3 and recruits H3K4 methyltransferase complexes to facilitate H3K4me3 both globally and at Wnt target loci, expanding epithelial progenitor populations [#0]. As a quantitative rather than absolute modulator of canonical Wnt signaling, PYGO2 tunes \\u03b2-catenin output in a tissue-specific manner across kidney branching morphogenesis [#2] and functions within the nuclear \\u03b2-catenin/BCL9/BCL9-2 complex to activate targets such as c-Myc, with its requirement dependent on signaling context [#8]. At target loci, PYGO2 is transiently acetylated by CBP/p300 within its N-terminal homology domain and nuclear localization sequence, displacing it from nucleus to cytoplasm as a recycling mechanism following target gene activation [#9]. PYGO2 protein levels are controlled by Cul4-DDB1-mediated ubiquitin/proteasome degradation, which is antagonized by Akt phosphorylation at Ser48 that stabilizes the protein downstream of PI3K/Akt and Wnt signaling [#6]. In tissue contexts PYGO2 suppresses luminal/alveolar differentiation of mammary stem cells by maintaining a poised/repressed chromatin state at the Notch3 locus [#3], regulates adipogenesis through an Axin2/GSK3\\u03b2/C/EBP\\u03b2 axis [#11], and controls post-meiotic chromatin condensation during spermiogenesis independently of \\u03b2-catenin via histone H3 hyperacetylation patterning [#1]. PYGO2 functions as a driver oncogene: it promotes mammary tumor initiation [#4], prostate cancer growth and metastasis including orchestration of an immune-suppressive p53/Sp1/Kit/Ido1 network hostile to cytotoxic T lymphocytes [#10, #12], and confers chemoresistance by directly activating MDR1/ABCB1 transcription [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established whether PYGO proteins are absolute or quantitative requirements for canonical Wnt signaling in mammals, resolving their role as graded modulators rather than essential switches.\",\n      \"evidence\": \"Targeted Pygo1/Pygo2 double deletion in mice with BAT-gal Wnt reporter and kidney morphogenesis analysis\",\n      \"pmids\": [\"17425782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular basis of tissue-specific Wnt dependence\", \"No biochemical mechanism for graded coactivation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a \\u03b2-catenin-independent role for PYGO2 in chromatin remodeling, expanding its function beyond Wnt coactivation.\",\n      \"evidence\": \"Hypomorphic Pygo2 mouse model with histological and expression analysis of spermiogenesis\",\n      \"pmids\": [\"18614164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking PYGO2 to histone H3 hyperacetylation patterning not resolved\", \"Direct chromatin targets in spermatids not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the core molecular mechanism of PYGO2 as an H3K4-methyl reader that recruits H3K4 methyltransferase complexes to drive H3K4me3 at Wnt target loci.\",\n      \"evidence\": \"In vivo knockout, ChIP, direct K4-methyl H3 binding assays, and mammary regeneration assays\",\n      \"pmids\": [\"19487454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the recruited methyltransferase complex not fully resolved\", \"Distinction between global versus locus-specific effects incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed PYGO2 enforces stem cell identity by maintaining repressed chromatin at a specific differentiation locus, linking its reader function to lineage control.\",\n      \"evidence\": \"Epithelial knockout, mammary transplantation, ChIP at Notch3 locus, and Notch/Wnt pharmacological modulation\",\n      \"pmids\": [\"23684539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PYGO2 establishes a poised/repressed rather than active state at Notch3 unclear\", \"Co-repressor partners at the locus not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed PYGO2 functionally at the transformation step of Wnt-driven tumorigenesis, distinguishing it from stem cell accumulation.\",\n      \"evidence\": \"Conditional Pygo2 knockout in MMTV-Wnt1 mice with tumor onset and transplantation assays\",\n      \"pmids\": [\"23334328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets governing tumor-initiating lineage potential not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected PYGO2 to p53 acetylation downstream of \\u03b2-catenin during progenitor cell cycle entry, integrating Wnt with a tumor-suppressor pathway.\",\n      \"evidence\": \"Conditional epithelial knockout, \\u03b2-catenin gain-of-function mice, and p53 acetylation immunostaining in keratinocytes\",\n      \"pmids\": [\"24982158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect role of PYGO2 in p53 acetylation not separated\", \"Acetyltransferase responsible not identified in this context\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the post-translational control of PYGO2 abundance, defining Cul4-DDB1 degradation antagonized by Akt phosphorylation at Ser48.\",\n      \"evidence\": \"Proteasome inhibition, Cul4/DDB1 co-IP, S48 mutagenesis, and Akt kinase/ubiquitylation assays\",\n      \"pmids\": [\"26170450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate recognition subunit of the Cul4-DDB1 complex not identified\", \"Stoichiometry and dynamics of Akt-Wnt crosstalk not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended PYGO2's H3K4me3-driven survival function to glioma, supporting a generalizable chromatin mechanism in cancer.\",\n      \"evidence\": \"Lentiviral siRNA knockdown in U251 cells with proliferation, apoptosis, neurosphere, and H3K4me3 readouts\",\n      \"pmids\": [\"25869613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line, no in vivo validation\", \"Direct chromatin targets in glioma not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated context-dependence of PYGO2 in colon tumorigenesis within the \\u03b2-catenin/BCL9 complex, showing it is required downstream of \\u03b2-catenin gain but dispensable upon APC loss.\",\n      \"evidence\": \"Pygo2 knockout mice with chemically induced colon tumors and intestinal Ctnnb1 GOF / Apc LOF models\",\n      \"pmids\": [\"27811361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis for differential requirement between Ctnnb1 GOF and Apc LOF lesions unexplained\", \"Complex assembly dynamics not structurally resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered a regulated recycling mechanism whereby CBP/p300 acetylation of PYGO2 at the active TCF/\\u03b2-catenin complex drives its nuclear export.\",\n      \"evidence\": \"Co-IP, lysine mutagenesis, subcellular fractionation, Axin2 reporter, and in vitro acetylation assays\",\n      \"pmids\": [\"27647933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Deacetylase that resets PYGO2 not identified\", \"Functional consequence of acetylation-dependent GCN5 association unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked PYGO2 to chemoresistance by activating MDR1 expression via Wnt/\\u03b2-catenin and identifying it as the top upregulated Wnt component in resistant breast cancer cells.\",\n      \"evidence\": \"Wnt PCR array screen, siRNA knockdown, MDR1 reporter assays, and xenograft model\",\n      \"pmids\": [\"26876203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PYGO2 binding at the MDR1 locus not demonstrated in this study\", \"Whether effect is solely Wnt-dependent not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Validated PYGO2 as an amplicon-encoded driver oncogene in prostate cancer required for ligand-induced Wnt transcriptional output.\",\n      \"evidence\": \"In vivo gain-of-function screen, overexpression/shRNA in PDX and mouse models, and Wnt reporter assays\",\n      \"pmids\": [\"29769196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional targets driving metastasis not yet defined here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a non-canonical PYGO2 mechanism in adipogenesis acting through an Axin2/GSK3\\u03b2/C/EBP\\u03b2/Snail axis with a metabolic phenotype.\",\n      \"evidence\": \"Adipocyte precursor-specific knockout mice, fractionation, GSK3\\u03b2 translocation, co-IP, and metabolic phenotyping\",\n      \"pmids\": [\"30279163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PYGO2 controls cytoplasmic Axin2 levels not mechanistically resolved\", \"Direct versus chromatin-mediated regulation of Axin2 unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided direct evidence that PYGO2 binds the MDR1 promoter to drive transcriptional activation and chemoresistance, strengthening the earlier breast cancer correlation.\",\n      \"evidence\": \"ChIP/promoter binding assay at MDR1, siRNA knockdown, and cisplatin sensitivity assays in gastric cancer cells\",\n      \"pmids\": [\"33854595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, limited mechanistic depth\", \"Cofactors at the MDR1 promoter not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified EFNA4 as an upstream physical partner stabilizing PYGO2 and acting through it to drive Wnt signaling in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, and PYGO2 overexpression rescue with Wnt and tumor phenotype readouts\",\n      \"pmids\": [\"36404439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which EFNA4 stabilizes PYGO2 protein unknown\", \"Single Co-IP without structural mapping of the interaction\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed PYGO2 as an orchestrator of an immune-suppressive tumor microenvironment, linking it to immunotherapy response in prostate cancer.\",\n      \"evidence\": \"Transgenic metastatic prostate cancer models with Pygo2 deletion, CTL flow cytometry, p53/Sp1/Kit/Ido1 pathway dissection, and checkpoint blockade combinations\",\n      \"pmids\": [\"36897957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PYGO2 transcriptional targets within the p53/Sp1/Kit/Ido1 network not fully mapped\", \"Whether the immune effect requires Wnt coactivation unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined BRPF1 as a direct downstream transcriptional effector of PYGO2 coordinated with H3K4me2/3 in colon cancer, offering a targeting strategy.\",\n      \"evidence\": \"Luciferase reporter, ChIP-qPCR at the BRPF1 promoter, knockdown/overexpression, and GSK5959 inhibition in tumor models\",\n      \"pmids\": [\"37423512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study\", \"Generality of PYGO2-BRPF1 axis beyond colon cancer not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PYGO2's chromatin-reading, Wnt-coactivation, and \\u03b2-catenin-independent functions are mechanistically partitioned across tissues, and the identity of the H3K4 methyltransferase complexes and co-repressors it engages at specific loci, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of PYGO2 within the \\u03b2-catenin/BCL9 complex on chromatin\", \"Determinants of context-dependent activation versus repression not defined\", \"Comprehensive genome-wide direct target map lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 8, 10, 13, 16]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [13, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8, 10]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 10, 13, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 12, 16]}\n    ],\n    \"complexes\": [\n      \"\\u03b2-catenin/BCL9/BCL9-2 coactivator complex\",\n      \"Cul4-DDB1 E3 ubiquitin ligase complex (substrate)\"\n    ],\n    \"partners\": [\n      \"CTNNB1\",\n      \"BCL9\",\n      \"BCL9-2\",\n      \"CREBBP/EP300\",\n      \"CUL4\",\n      \"DDB1\",\n      \"EFNA4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}