{"gene":"PYGO2","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2009,"finding":"Pygo2 facilitates K4 trimethylation of histone H3 (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":"Mouse genetic ablation (complete and epithelia-specific), ChIP, histone methylation assays, direct binding assays, mammary transplantation/regeneration assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in vivo KO, direct binding, ChIP, and functional rescue in a single study","pmids":["19487454"],"is_preprint":false},{"year":2008,"finding":"Pygo2 is expressed in elongating spermatids during chromatin remodeling, and its loss leads to spermiogenesis arrest accompanied by reduced expression of protamines and transition protein 2, and drastically altered histone H3 hyperacetylation, independent of β-catenin signaling.","method":"Hypomorphic mouse alleles, qRT-PCR, histological analysis of spermatids, histone H3 acetylation analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function in vivo with defined molecular phenotype (histone H3 acetylation) and β-catenin independence established","pmids":["18614164"],"is_preprint":false},{"year":2007,"finding":"Mammalian Pygo1/Pygo2 function as quantitative modulators of Wnt/β-catenin signaling rather than essential components; Pygo2 knockout causes defects in ureteric bud branching morphogenesis during kidney development, with reduced BAT-gal Wnt reporter activity in a tissue-specific manner.","method":"Targeted knockout mice (>80% coding sequence deletion including PHD domain), BAT-gal Wnt reporter, confocal analysis, microarray","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 — genetic null alleles with pathway reporter readout and epistasis analysis","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 maintaining a poised/repressed chromatin state at the Notch3 locus and is required for β-catenin binding at that locus.","method":"Epithelia-specific Pygo2 KO, transplantation assays, ChIP, Notch signaling inhibition/activation, gene expression profiling","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic epistasis (Wnt/Notch), ChIP at defined locus, and loss-of-function with specific molecular and cellular phenotype","pmids":["23684539"],"is_preprint":false},{"year":2014,"finding":"Pygo2 facilitates β-catenin-induced activation of hair follicle stem/progenitor cells; β-catenin and Pygo2 converge to induce accumulation and acetylation of p53 upon cell cycle entry of hair follicle early progenitor cells.","method":"Epithelia-specific KO mice, depilation assay, skin hyperplasia model, Western blot, immunofluorescence, cultured keratinocytes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with defined molecular event (p53 acetylation) and epistasis with β-catenin gain-of-function","pmids":["24982158"],"is_preprint":false},{"year":2015,"finding":"Pygo2 protein is degraded through the ubiquitin/proteasome pathway via the Cul4-DDB1 E3 ubiquitin ligase complex, and Akt-mediated phosphorylation at serine 48 stabilizes Pygo2 by decreasing its ubiquitylation.","method":"Proteasome inhibitor treatment, Co-IP with Cul4/DDB1, phosphorylation site mutagenesis, ubiquitylation assays, Akt inhibition/activation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical reconstitution of ubiquitylation, site-directed mutagenesis, and Co-IP with E3 ligase components","pmids":["26170450"],"is_preprint":false},{"year":2016,"finding":"Pygo2 activates MDR1 (P-glycoprotein) expression in breast cancer cells via the Wnt/β-catenin pathway, and its inhibition restores drug sensitivity and reduces breast cancer stem cell populations.","method":"Wnt pathway PCR array, Pygo2 knockdown/overexpression, MDR1 reporter assays, in vivo mouse xenograft chemoresistance model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — gain/loss-of-function with defined molecular target (MDR1) and in vivo validation, but pathway placement relies on existing Wnt/β-catenin framework","pmids":["26876203"],"is_preprint":false},{"year":2016,"finding":"Pygo2 acts as a co-activator in a nuclear complex with β-catenin/BCL9/BCL9-2 to increase Wnt target gene transcription (specifically c-Myc), and its loss reduces chemically-induced and β-catenin GOF-driven intestinal tumorigenesis but not APC LOF-driven tumors.","method":"Pygo2 KO mice, chemical carcinogenesis model, conditional intestinal Apc LOF and Ctnnb1 GOF mouse models, target gene expression analysis","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis across multiple in vivo tumor models with pathway-specific readouts","pmids":["27811361"],"is_preprint":false},{"year":2016,"finding":"Pygo2 is transiently acetylated by CBP/p300 histone acetyltransferases (but not GCN5/PCAF) at specific lysine residues in its N-terminal homology domain when bound to the activated TCF/β-catenin transcription complex; p300-mediated acetylation of lysines in the Pygo2 nuclear localization sequence displaces Pygo2 from the nucleus to the cytoplasm, suggesting a recycling mechanism post-activation.","method":"In vitro acetylation assays with CBP/p300/GCN5/PCAF, site-directed mutagenesis of lysine residues, subcellular fractionation, Co-IP with TCF/β-catenin complex, Axin2 reporter assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro acetyltransferase assays, mutagenesis of specific lysines, and functional localization consequence","pmids":["27647933"],"is_preprint":false},{"year":2018,"finding":"Pygo2 is a driver oncogene at the 1q21.3 amplicon; its overexpression enhances primary tumor growth and lymph node invasion in prostate cancer, and it is necessary for transcriptional activation in response to ligand-induced Wnt/β-catenin signaling.","method":"In vivo gain-of-function tumorigenesis screen, PYGO2 shRNA knockdown, patient-derived xenograft models, Wnt reporter assays, invasion assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — functional genomics screen confirmed with in vivo KD/OE, PDX models, and Wnt pathway reporter","pmids":["29769196"],"is_preprint":false},{"year":2018,"finding":"Pygo2 inhibition during adipogenesis leads to downregulation of Axin2 in the cytoplasm, releasing Axin2-bound GSK3β to translocate to the nucleus where it phosphorylates C/EBPβ and Snail, activating C/EBPα and PPARγ expression to promote adipocyte differentiation; Pygo2-deficient mice show increased adiposity and impaired glucose tolerance.","method":"Pygo2 KO adipocyte precursor-specific mice, embryonic fibroblast differentiation assays, nuclear fractionation, Western blot for GSK3β phosphorylation targets, glucose tolerance tests","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — adipocyte-specific KO mice with mechanistic pathway dissection (Axin2/GSK3β/C-EBPβ axis) and multiple in vitro and in vivo readouts","pmids":["30279163"],"is_preprint":false},{"year":2013,"finding":"Epithelia-specific ablation of Pygo2 in MMTV-Wnt1 mice significantly delays mammary tumor onset and decreases tumor-initiating capability of MMTV-Wnt1 tumor cells upon transplantation, while hyperbranching and canonical Wnt signaling output are largely unaffected, placing Pygo2 downstream of mammary stem cell accumulation in transformation.","method":"Epithelia-specific Pygo2 KO in MMTV-Wnt1 transgenic mice, mammary transplantation assays, Wnt reporter analysis, tumor onset tracking","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vivo with specific pathway readout and functional transplantation assay","pmids":["23334328"],"is_preprint":false},{"year":2023,"finding":"Pygo2 orchestrates a p53/Sp1/Kit/Ido1 signaling network to suppress cytotoxic T lymphocyte (CTL) infiltration and activation in prostate cancer, creating an immune-hostile microenvironment; Pygo2 deletion augments CTL responses and sensitizes tumors to immune checkpoint blockade.","method":"Transgenic mouse models of metastatic prostate adenocarcinoma, Pygo2 deletion, flow cytometry of tumor-infiltrating lymphocytes, genetic/pharmacological inhibition, adoptive cell transfer, ICB treatment","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple in vivo models with mechanistic pathway (p53/Sp1/Kit/Ido1) and orthogonal immunotherapy approaches","pmids":["36897957"],"is_preprint":false},{"year":2023,"finding":"Pygo2 coordinates with H3K4me2/3 modifications to activate BRPF1 transcription by binding to the BRPF1 promoter, and Pygo2-driven colon cancer progression depends on BRPF1, making BRPF1 an epigenetic vulnerability in Pygo2-high colorectal cancer.","method":"ChIP-qPCR, luciferase reporter assay, Pygo2 overexpression/knockdown, in vivo subcutaneous tumor model, BRPF1 inhibitor (GSK5959) treatment","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assays establish direct Pygo2 binding at BRPF1 promoter with in vivo validation, single lab","pmids":["37423512"],"is_preprint":false},{"year":2021,"finding":"Pygo2 directly binds the MDR1 promoter region and promotes MDR1 transcriptional activation in gastric cancer drug-resistant cells.","method":"ChIP assay at MDR1 promoter, Pygo2 knockdown in drug-resistant gastric cancer cells, MDR1 expression analysis, cisplatin sensitivity assay","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP evidence for direct promoter binding with functional drug-sensitivity readout, single lab","pmids":["33854595"],"is_preprint":false},{"year":2020,"finding":"PVT1 lncRNA upregulates Pygo2 expression by sponging miR-619-5p, and Pygo2-mediated activation of Wnt/β-catenin signaling in turn drives PVT1 expression via TCF/LEF binding elements in the PVT1 promoter, forming a feed-forward loop promoting gemcitabine resistance in pancreatic cancer.","method":"Gain/loss-of-function assays, qRT-PCR, Western blot, luciferase reporter for TBE elements in PVT1 promoter, xenograft tumor models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — luciferase reporter and miRNA sponge assays support the loop mechanism, but no direct Pygo2 ChIP at PVT1 TBE","pmids":["32727463"],"is_preprint":false},{"year":2022,"finding":"EFNA4 (Ephrin A4) interacts with PYGO2 and positively regulates PYGO2 protein expression; EFNA4 knockdown blocks Wnt/β-catenin signaling in hepatocellular carcinoma cells in a PYGO2-dependent manner.","method":"Co-IP (EFNA4-PYGO2 interaction), gene gain/loss-of-function, Western blot for Wnt pathway components","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with partial mechanistic follow-up, single lab","pmids":["36404439"],"is_preprint":false}],"current_model":"PYGO2 is a PHD finger-containing chromatin effector and context-dependent Wnt/β-catenin coactivator that binds H3K4me2/3 marks and recruits histone H3 K4 methyltransferase complexes to facilitate H3K4me3 and target gene activation; it is stabilized by Akt-mediated phosphorylation at Ser48 (opposing Cul4-DDB1 E3 ubiquitin ligase-mediated degradation) and transiently acetylated by CBP/p300 at its NLS to recycle it from the nucleus; in addition to its Wnt co-activator role it suppresses Notch3 expression in mammary stem/basal cells, promotes spermatid chromatin remodeling (histone H3 hyperacetylation) independently of β-catenin, regulates adipogenesis through the Axin2/GSK3β/C/EBPβ axis, and shapes the tumor immune microenvironment via a p53/Sp1/Kit/Ido1 network that suppresses cytotoxic T cell infiltration."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing that mammalian Pygo2 is a quantitative modulator rather than an essential on/off switch of Wnt/β-catenin signaling resolved whether the obligate requirement seen in Drosophila is conserved, revealing tissue-specific sensitivity in kidney branching morphogenesis.","evidence":"Pygo2 null mice with BAT-gal Wnt reporter and confocal/microarray analysis","pmids":["17425782"],"confidence":"High","gaps":["Molecular mechanism by which Pygo2 modulates Wnt output not defined","Redundancy with Pygo1 not fully dissected","No direct chromatin-level mechanism identified"]},{"year":2008,"claim":"Demonstrating that Pygo2 is required for histone H3 hyperacetylation and protamine/transition protein expression in spermatids established a β-catenin-independent chromatin-remodeling function, fundamentally expanding the gene's functional repertoire beyond Wnt signaling.","evidence":"Hypomorphic mouse alleles with spermatid histological and histone acetylation analysis","pmids":["18614164"],"confidence":"High","gaps":["Identity of the acetyltransferase recruited by Pygo2 in spermatids unknown","Whether the PHD domain mediates this function not tested","No structural basis for β-catenin-independent chromatin binding"]},{"year":2009,"claim":"Identifying Pygo2 as an H3K4me reader that recruits H3K4 methyltransferase complexes provided the first direct biochemical mechanism linking Pygo2's PHD finger to epigenetic mark propagation and mammary progenitor expansion.","evidence":"ChIP, direct histone binding assays, epithelia-specific and complete KO mice, mammary transplantation","pmids":["19487454"],"confidence":"High","gaps":["Specific methyltransferase complex identity not determined","Whether H3K4me reading and Wnt co-activation are separable activities unclear","No structural resolution of PHD–H3K4me interaction in mammalian Pygo2"]},{"year":2013,"claim":"Showing that Pygo2 suppresses Notch3 transcription in mammary stem cells and delays Wnt1-driven tumor onset established it as a chromatin-state gatekeeper at the Wnt–Notch signaling interface, explaining how it controls cell-fate decisions beyond simple Wnt target activation.","evidence":"Epithelia-specific KO in normal and MMTV-Wnt1 mice, ChIP at Notch3, transplantation, Notch pathway manipulation","pmids":["23684539","23334328"],"confidence":"High","gaps":["Mechanism by which Pygo2 maintains poised/repressed state at Notch3 not fully resolved","Whether Pygo2-Notch3 axis operates outside mammary tissue untested"]},{"year":2014,"claim":"Linking Pygo2 and β-catenin to p53 accumulation and acetylation during hair follicle progenitor cell cycle entry revealed a convergence between Wnt signaling and the p53 pathway, identifying a new downstream effector axis.","evidence":"Epithelia-specific KO mice, depilation and skin hyperplasia models, cultured keratinocytes","pmids":["24982158"],"confidence":"High","gaps":["Whether Pygo2 acts on p53 directly or through intermediate chromatin targets unknown","Functional consequence of p53 acetylation in this context not determined"]},{"year":2015,"claim":"Identifying Cul4-DDB1 as the E3 ligase for Pygo2 degradation and Akt-mediated Ser48 phosphorylation as a stabilizing signal defined the post-translational control circuit governing Pygo2 protein levels.","evidence":"Co-IP with Cul4/DDB1, ubiquitylation assays, Ser48 mutagenesis, proteasome inhibitor treatment","pmids":["26170450"],"confidence":"High","gaps":["DDB1-associated substrate receptor (DCAF) not identified","In vivo validation of the Akt-Pygo2 stability axis not shown","Interplay between phosphorylation and acetylation-based recycling unknown"]},{"year":2016,"claim":"Demonstrating CBP/p300-mediated acetylation of Pygo2's NLS lysines and consequent nuclear export established a post-activation recycling mechanism and revealed how Pygo2 is cleared from active TCF/β-catenin complexes, while parallel work defined the BCL9/β-catenin/Pygo2 complex as a coactivator of c-Myc in intestinal tumorigenesis.","evidence":"In vitro acetyltransferase assays, NLS lysine mutagenesis, subcellular fractionation; Pygo2 KO in chemical carcinogenesis and Ctnnb1 GOF/Apc LOF mouse models","pmids":["27647933","27811361","26876203"],"confidence":"High","gaps":["Deacetylase responsible for reversing NLS acetylation not identified","Whether nuclear export requires exportin machinery or passive diffusion unknown","Reason Pygo2 loss does not affect Apc LOF tumors mechanistically unexplained"]},{"year":2018,"claim":"Defining Pygo2 as a driver oncogene at the 1q21.3 amplicon in prostate cancer and uncovering a Wnt-independent role in adipogenesis via the Axin2/GSK3β/C/EBPβ axis broadened PYGO2's functional scope to metabolic regulation and cancer genomics.","evidence":"In vivo tumorigenesis screens with PDX models; adipocyte-specific KO mice with nuclear fractionation and glucose tolerance tests","pmids":["29769196","30279163"],"confidence":"High","gaps":["Whether the Axin2/GSK3β pathway is a direct transcriptional target of Pygo2 or secondary to Wnt modulation not resolved","Structural basis for Pygo2 oncogenic gain-of-function at 1q21.3 undetermined"]},{"year":2023,"claim":"Revealing that Pygo2 drives immune evasion through a p53/Sp1/Kit/Ido1 network suppressing CTL infiltration, and identifying BRPF1 as a direct transcriptional target in colorectal cancer, opened new therapeutic vulnerabilities.","evidence":"Transgenic metastatic prostate cancer models with Pygo2 deletion, flow cytometry, adoptive transfer, ICB treatment; ChIP-qPCR at BRPF1 promoter, BRPF1 inhibitor in vivo","pmids":["36897957","37423512"],"confidence":"High","gaps":["Whether the Kit/Ido1 axis is a direct Pygo2 chromatin target or downstream of p53 not fully resolved","BRPF1 dependency in non-colorectal Pygo2-high cancers not tested","No pharmacological Pygo2 inhibitor validated"]},{"year":null,"claim":"Key open questions remain: the identity of the specific H3K4 methyltransferase complex recruited by Pygo2, the structural basis of its PHD–H3K4me interaction in mammals, how its phosphorylation and acetylation codes are integrated to control its activity and localization, and whether its immune-modulatory and chromatin-remodeling roles converge mechanistically.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of mammalian Pygo2 PHD–histone interaction","Integration of Akt phosphorylation and CBP/p300 acetylation signals not addressed","Pharmacological inhibition of Pygo2 not achieved"]}],"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":[0,3,7,8,13,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,7,9,10]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,3,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,7,8,13,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]}],"complexes":["β-catenin/BCL9/BCL9-2/TCF transcription complex"],"partners":["CTNNB1","BCL9","BCL9L","DDB1","CUL4A","CREBBP","EP300"],"other_free_text":[]},"mechanistic_narrative":"PYGO2 is a PHD finger-containing chromatin effector that reads H3K4me2/3 marks and recruits histone H3 K4 methyltransferase complexes to promote H3K4 trimethylation at target loci, functioning as a context-dependent coactivator of the Wnt/β-catenin–TCF transcriptional complex through association with BCL9/BCL9-2 [PMID:19487454, PMID:27811361]. Beyond canonical Wnt signaling, PYGO2 has β-catenin-independent roles in spermatid chromatin remodeling—where it drives histone H3 hyperacetylation required for protamine expression [PMID:18614164]—and suppresses Notch3 transcription in mammary stem/basal cells to restrain luminal differentiation [PMID:23684539]. PYGO2 protein stability is controlled by Akt-mediated Ser48 phosphorylation opposing Cul4-DDB1 E3 ligase-dependent ubiquitylation, and CBP/p300-mediated acetylation of its nuclear localization signal drives nuclear-to-cytoplasmic recycling after transcriptional activation [PMID:26170450, PMID:27647933]. In the tumor microenvironment PYGO2 orchestrates a p53/Sp1/Kit/Ido1 network that suppresses cytotoxic T-cell infiltration, and its deletion sensitizes prostate tumors to immune checkpoint blockade [PMID:36897957]."},"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":316,"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":105,"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":"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":"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":26,"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":9,"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":9,"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":8,"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":"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":"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":"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":"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":"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":"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":"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":"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":"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":"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":"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":"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},{"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22369,"output_tokens":4268,"usd":0.065563},"stage2":{"model":"claude-opus-4-6","input_tokens":7821,"output_tokens":3071,"usd":0.17382},"total_usd":0.239383,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"Pygo2 facilitates K4 trimethylation of histone H3 (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\": \"Mouse genetic ablation (complete and epithelia-specific), ChIP, histone methylation assays, direct binding assays, mammary transplantation/regeneration assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vivo KO, direct binding, ChIP, and functional rescue in a single study\",\n      \"pmids\": [\"19487454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pygo2 is expressed in elongating spermatids during chromatin remodeling, and its loss leads to spermiogenesis arrest accompanied by reduced expression of protamines and transition protein 2, and drastically altered histone H3 hyperacetylation, independent of β-catenin signaling.\",\n      \"method\": \"Hypomorphic mouse alleles, qRT-PCR, histological analysis of spermatids, histone H3 acetylation analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function in vivo with defined molecular phenotype (histone H3 acetylation) and β-catenin independence established\",\n      \"pmids\": [\"18614164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mammalian Pygo1/Pygo2 function as quantitative modulators of Wnt/β-catenin signaling rather than essential components; Pygo2 knockout causes defects in ureteric bud branching morphogenesis during kidney development, with reduced BAT-gal Wnt reporter activity in a tissue-specific manner.\",\n      \"method\": \"Targeted knockout mice (>80% coding sequence deletion including PHD domain), BAT-gal Wnt reporter, confocal analysis, microarray\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic null alleles with pathway reporter readout and epistasis analysis\",\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 maintaining a poised/repressed chromatin state at the Notch3 locus and is required for β-catenin binding at that locus.\",\n      \"method\": \"Epithelia-specific Pygo2 KO, transplantation assays, ChIP, Notch signaling inhibition/activation, gene expression profiling\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic epistasis (Wnt/Notch), ChIP at defined locus, and loss-of-function with specific molecular and cellular phenotype\",\n      \"pmids\": [\"23684539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Pygo2 facilitates β-catenin-induced activation of hair follicle stem/progenitor cells; β-catenin and Pygo2 converge to induce accumulation and acetylation of p53 upon cell cycle entry of hair follicle early progenitor cells.\",\n      \"method\": \"Epithelia-specific KO mice, depilation assay, skin hyperplasia model, Western blot, immunofluorescence, cultured keratinocytes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with defined molecular event (p53 acetylation) and epistasis with β-catenin gain-of-function\",\n      \"pmids\": [\"24982158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pygo2 protein is degraded through the ubiquitin/proteasome pathway via the Cul4-DDB1 E3 ubiquitin ligase complex, and Akt-mediated phosphorylation at serine 48 stabilizes Pygo2 by decreasing its ubiquitylation.\",\n      \"method\": \"Proteasome inhibitor treatment, Co-IP with Cul4/DDB1, phosphorylation site mutagenesis, ubiquitylation assays, Akt inhibition/activation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical reconstitution of ubiquitylation, site-directed mutagenesis, and Co-IP with E3 ligase components\",\n      \"pmids\": [\"26170450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pygo2 activates MDR1 (P-glycoprotein) expression in breast cancer cells via the Wnt/β-catenin pathway, and its inhibition restores drug sensitivity and reduces breast cancer stem cell populations.\",\n      \"method\": \"Wnt pathway PCR array, Pygo2 knockdown/overexpression, MDR1 reporter assays, in vivo mouse xenograft chemoresistance model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss-of-function with defined molecular target (MDR1) and in vivo validation, but pathway placement relies on existing Wnt/β-catenin framework\",\n      \"pmids\": [\"26876203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pygo2 acts as a co-activator in a nuclear complex with β-catenin/BCL9/BCL9-2 to increase Wnt target gene transcription (specifically c-Myc), and its loss reduces chemically-induced and β-catenin GOF-driven intestinal tumorigenesis but not APC LOF-driven tumors.\",\n      \"method\": \"Pygo2 KO mice, chemical carcinogenesis model, conditional intestinal Apc LOF and Ctnnb1 GOF mouse models, target gene expression analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis across multiple in vivo tumor models with pathway-specific readouts\",\n      \"pmids\": [\"27811361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pygo2 is transiently acetylated by CBP/p300 histone acetyltransferases (but not GCN5/PCAF) at specific lysine residues in its N-terminal homology domain when bound to the activated TCF/β-catenin transcription complex; p300-mediated acetylation of lysines in the Pygo2 nuclear localization sequence displaces Pygo2 from the nucleus to the cytoplasm, suggesting a recycling mechanism post-activation.\",\n      \"method\": \"In vitro acetylation assays with CBP/p300/GCN5/PCAF, site-directed mutagenesis of lysine residues, subcellular fractionation, Co-IP with TCF/β-catenin complex, Axin2 reporter assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro acetyltransferase assays, mutagenesis of specific lysines, and functional localization consequence\",\n      \"pmids\": [\"27647933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Pygo2 is a driver oncogene at the 1q21.3 amplicon; its overexpression enhances primary tumor growth and lymph node invasion in prostate cancer, and it is necessary for transcriptional activation in response to ligand-induced Wnt/β-catenin signaling.\",\n      \"method\": \"In vivo gain-of-function tumorigenesis screen, PYGO2 shRNA knockdown, patient-derived xenograft models, Wnt reporter assays, invasion assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional genomics screen confirmed with in vivo KD/OE, PDX models, and Wnt pathway reporter\",\n      \"pmids\": [\"29769196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Pygo2 inhibition during adipogenesis leads to downregulation of Axin2 in the cytoplasm, releasing Axin2-bound GSK3β to translocate to the nucleus where it phosphorylates C/EBPβ and Snail, activating C/EBPα and PPARγ expression to promote adipocyte differentiation; Pygo2-deficient mice show increased adiposity and impaired glucose tolerance.\",\n      \"method\": \"Pygo2 KO adipocyte precursor-specific mice, embryonic fibroblast differentiation assays, nuclear fractionation, Western blot for GSK3β phosphorylation targets, glucose tolerance tests\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — adipocyte-specific KO mice with mechanistic pathway dissection (Axin2/GSK3β/C-EBPβ axis) and multiple in vitro and in vivo readouts\",\n      \"pmids\": [\"30279163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Epithelia-specific ablation of Pygo2 in MMTV-Wnt1 mice significantly delays mammary tumor onset and decreases tumor-initiating capability of MMTV-Wnt1 tumor cells upon transplantation, while hyperbranching and canonical Wnt signaling output are largely unaffected, placing Pygo2 downstream of mammary stem cell accumulation in transformation.\",\n      \"method\": \"Epithelia-specific Pygo2 KO in MMTV-Wnt1 transgenic mice, mammary transplantation assays, Wnt reporter analysis, tumor onset tracking\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with specific pathway readout and functional transplantation assay\",\n      \"pmids\": [\"23334328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pygo2 orchestrates a p53/Sp1/Kit/Ido1 signaling network to suppress cytotoxic T lymphocyte (CTL) infiltration and activation in prostate cancer, creating an immune-hostile microenvironment; Pygo2 deletion augments CTL responses and sensitizes tumors to immune checkpoint blockade.\",\n      \"method\": \"Transgenic mouse models of metastatic prostate adenocarcinoma, Pygo2 deletion, flow cytometry of tumor-infiltrating lymphocytes, genetic/pharmacological inhibition, adoptive cell transfer, ICB treatment\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo models with mechanistic pathway (p53/Sp1/Kit/Ido1) and orthogonal immunotherapy approaches\",\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, and Pygo2-driven colon cancer progression depends on BRPF1, making BRPF1 an epigenetic vulnerability in Pygo2-high colorectal cancer.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, Pygo2 overexpression/knockdown, in vivo subcutaneous tumor model, BRPF1 inhibitor (GSK5959) treatment\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assays establish direct Pygo2 binding at BRPF1 promoter with in vivo validation, single lab\",\n      \"pmids\": [\"37423512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pygo2 directly binds the MDR1 promoter region and promotes MDR1 transcriptional activation in gastric cancer drug-resistant cells.\",\n      \"method\": \"ChIP assay at MDR1 promoter, Pygo2 knockdown in drug-resistant gastric cancer cells, MDR1 expression analysis, cisplatin sensitivity assay\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP evidence for direct promoter binding with functional drug-sensitivity readout, single lab\",\n      \"pmids\": [\"33854595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PVT1 lncRNA upregulates Pygo2 expression by sponging miR-619-5p, and Pygo2-mediated activation of Wnt/β-catenin signaling in turn drives PVT1 expression via TCF/LEF binding elements in the PVT1 promoter, forming a feed-forward loop promoting gemcitabine resistance in pancreatic cancer.\",\n      \"method\": \"Gain/loss-of-function assays, qRT-PCR, Western blot, luciferase reporter for TBE elements in PVT1 promoter, xenograft tumor models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — luciferase reporter and miRNA sponge assays support the loop mechanism, but no direct Pygo2 ChIP at PVT1 TBE\",\n      \"pmids\": [\"32727463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EFNA4 (Ephrin A4) interacts with PYGO2 and positively regulates PYGO2 protein expression; EFNA4 knockdown blocks Wnt/β-catenin signaling in hepatocellular carcinoma cells in a PYGO2-dependent manner.\",\n      \"method\": \"Co-IP (EFNA4-PYGO2 interaction), gene gain/loss-of-function, Western blot for Wnt pathway components\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with partial mechanistic follow-up, single lab\",\n      \"pmids\": [\"36404439\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PYGO2 is a PHD finger-containing chromatin effector and context-dependent Wnt/β-catenin coactivator that binds H3K4me2/3 marks and recruits histone H3 K4 methyltransferase complexes to facilitate H3K4me3 and target gene activation; it is stabilized by Akt-mediated phosphorylation at Ser48 (opposing Cul4-DDB1 E3 ubiquitin ligase-mediated degradation) and transiently acetylated by CBP/p300 at its NLS to recycle it from the nucleus; in addition to its Wnt co-activator role it suppresses Notch3 expression in mammary stem/basal cells, promotes spermatid chromatin remodeling (histone H3 hyperacetylation) independently of β-catenin, regulates adipogenesis through the Axin2/GSK3β/C/EBPβ axis, and shapes the tumor immune microenvironment via a p53/Sp1/Kit/Ido1 network that suppresses cytotoxic T cell infiltration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PYGO2 is a PHD finger-containing chromatin effector that reads H3K4me2/3 marks and recruits histone H3 K4 methyltransferase complexes to promote H3K4 trimethylation at target loci, functioning as a context-dependent coactivator of the Wnt/β-catenin–TCF transcriptional complex through association with BCL9/BCL9-2 [PMID:19487454, PMID:27811361]. Beyond canonical Wnt signaling, PYGO2 has β-catenin-independent roles in spermatid chromatin remodeling—where it drives histone H3 hyperacetylation required for protamine expression [PMID:18614164]—and suppresses Notch3 transcription in mammary stem/basal cells to restrain luminal differentiation [PMID:23684539]. PYGO2 protein stability is controlled by Akt-mediated Ser48 phosphorylation opposing Cul4-DDB1 E3 ligase-dependent ubiquitylation, and CBP/p300-mediated acetylation of its nuclear localization signal drives nuclear-to-cytoplasmic recycling after transcriptional activation [PMID:26170450, PMID:27647933]. In the tumor microenvironment PYGO2 orchestrates a p53/Sp1/Kit/Ido1 network that suppresses cytotoxic T-cell infiltration, and its deletion sensitizes prostate tumors to immune checkpoint blockade [PMID:36897957].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that mammalian Pygo2 is a quantitative modulator rather than an essential on/off switch of Wnt/β-catenin signaling resolved whether the obligate requirement seen in Drosophila is conserved, revealing tissue-specific sensitivity in kidney branching morphogenesis.\",\n      \"evidence\": \"Pygo2 null mice with BAT-gal Wnt reporter and confocal/microarray analysis\",\n      \"pmids\": [\"17425782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which Pygo2 modulates Wnt output not defined\",\n        \"Redundancy with Pygo1 not fully dissected\",\n        \"No direct chromatin-level mechanism identified\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that Pygo2 is required for histone H3 hyperacetylation and protamine/transition protein expression in spermatids established a β-catenin-independent chromatin-remodeling function, fundamentally expanding the gene's functional repertoire beyond Wnt signaling.\",\n      \"evidence\": \"Hypomorphic mouse alleles with spermatid histological and histone acetylation analysis\",\n      \"pmids\": [\"18614164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the acetyltransferase recruited by Pygo2 in spermatids unknown\",\n        \"Whether the PHD domain mediates this function not tested\",\n        \"No structural basis for β-catenin-independent chromatin binding\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying Pygo2 as an H3K4me reader that recruits H3K4 methyltransferase complexes provided the first direct biochemical mechanism linking Pygo2's PHD finger to epigenetic mark propagation and mammary progenitor expansion.\",\n      \"evidence\": \"ChIP, direct histone binding assays, epithelia-specific and complete KO mice, mammary transplantation\",\n      \"pmids\": [\"19487454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific methyltransferase complex identity not determined\",\n        \"Whether H3K4me reading and Wnt co-activation are separable activities unclear\",\n        \"No structural resolution of PHD–H3K4me interaction in mammalian Pygo2\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that Pygo2 suppresses Notch3 transcription in mammary stem cells and delays Wnt1-driven tumor onset established it as a chromatin-state gatekeeper at the Wnt–Notch signaling interface, explaining how it controls cell-fate decisions beyond simple Wnt target activation.\",\n      \"evidence\": \"Epithelia-specific KO in normal and MMTV-Wnt1 mice, ChIP at Notch3, transplantation, Notch pathway manipulation\",\n      \"pmids\": [\"23684539\", \"23334328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which Pygo2 maintains poised/repressed state at Notch3 not fully resolved\",\n        \"Whether Pygo2-Notch3 axis operates outside mammary tissue untested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linking Pygo2 and β-catenin to p53 accumulation and acetylation during hair follicle progenitor cell cycle entry revealed a convergence between Wnt signaling and the p53 pathway, identifying a new downstream effector axis.\",\n      \"evidence\": \"Epithelia-specific KO mice, depilation and skin hyperplasia models, cultured keratinocytes\",\n      \"pmids\": [\"24982158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Pygo2 acts on p53 directly or through intermediate chromatin targets unknown\",\n        \"Functional consequence of p53 acetylation in this context not determined\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying Cul4-DDB1 as the E3 ligase for Pygo2 degradation and Akt-mediated Ser48 phosphorylation as a stabilizing signal defined the post-translational control circuit governing Pygo2 protein levels.\",\n      \"evidence\": \"Co-IP with Cul4/DDB1, ubiquitylation assays, Ser48 mutagenesis, proteasome inhibitor treatment\",\n      \"pmids\": [\"26170450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"DDB1-associated substrate receptor (DCAF) not identified\",\n        \"In vivo validation of the Akt-Pygo2 stability axis not shown\",\n        \"Interplay between phosphorylation and acetylation-based recycling unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating CBP/p300-mediated acetylation of Pygo2's NLS lysines and consequent nuclear export established a post-activation recycling mechanism and revealed how Pygo2 is cleared from active TCF/β-catenin complexes, while parallel work defined the BCL9/β-catenin/Pygo2 complex as a coactivator of c-Myc in intestinal tumorigenesis.\",\n      \"evidence\": \"In vitro acetyltransferase assays, NLS lysine mutagenesis, subcellular fractionation; Pygo2 KO in chemical carcinogenesis and Ctnnb1 GOF/Apc LOF mouse models\",\n      \"pmids\": [\"27647933\", \"27811361\", \"26876203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Deacetylase responsible for reversing NLS acetylation not identified\",\n        \"Whether nuclear export requires exportin machinery or passive diffusion unknown\",\n        \"Reason Pygo2 loss does not affect Apc LOF tumors mechanistically unexplained\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining Pygo2 as a driver oncogene at the 1q21.3 amplicon in prostate cancer and uncovering a Wnt-independent role in adipogenesis via the Axin2/GSK3β/C/EBPβ axis broadened PYGO2's functional scope to metabolic regulation and cancer genomics.\",\n      \"evidence\": \"In vivo tumorigenesis screens with PDX models; adipocyte-specific KO mice with nuclear fractionation and glucose tolerance tests\",\n      \"pmids\": [\"29769196\", \"30279163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the Axin2/GSK3β pathway is a direct transcriptional target of Pygo2 or secondary to Wnt modulation not resolved\",\n        \"Structural basis for Pygo2 oncogenic gain-of-function at 1q21.3 undetermined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealing that Pygo2 drives immune evasion through a p53/Sp1/Kit/Ido1 network suppressing CTL infiltration, and identifying BRPF1 as a direct transcriptional target in colorectal cancer, opened new therapeutic vulnerabilities.\",\n      \"evidence\": \"Transgenic metastatic prostate cancer models with Pygo2 deletion, flow cytometry, adoptive transfer, ICB treatment; ChIP-qPCR at BRPF1 promoter, BRPF1 inhibitor in vivo\",\n      \"pmids\": [\"36897957\", \"37423512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the Kit/Ido1 axis is a direct Pygo2 chromatin target or downstream of p53 not fully resolved\",\n        \"BRPF1 dependency in non-colorectal Pygo2-high cancers not tested\",\n        \"No pharmacological Pygo2 inhibitor validated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions remain: the identity of the specific H3K4 methyltransferase complex recruited by Pygo2, the structural basis of its PHD–H3K4me interaction in mammals, how its phosphorylation and acetylation codes are integrated to control its activity and localization, and whether its immune-modulatory and chromatin-remodeling roles converge mechanistically.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of mammalian Pygo2 PHD–histone interaction\",\n        \"Integration of Akt phosphorylation and CBP/p300 acetylation signals not addressed\",\n        \"Pharmacological inhibition of Pygo2 not achieved\"\n      ]\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, 3, 7, 8, 13, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 7, 9, 10]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 3, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 7, 8, 13, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"β-catenin/BCL9/BCL9-2/TCF transcription complex\"\n    ],\n    \"partners\": [\n      \"CTNNB1\",\n      \"BCL9\",\n      \"BCL9L\",\n      \"DDB1\",\n      \"CUL4A\",\n      \"CREBBP\",\n      \"EP300\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}