{"gene":"PCGF6","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2002,"finding":"MBLR (PCGF6) is a RING finger protein that directly interacts with Ring1B via its RING finger domain, acts as a transcriptional repressor in transfected cells, localizes to the nucleoplasm in interphase and diffuse cytoplasm in mitotic cells, and is specifically phosphorylated at serine 32 during mitosis, most likely by CDK7.","method":"In vitro biochemical interaction assay, immunocytochemistry, transfection-based transcriptional repressor assay, cell-cycle phosphorylation analysis","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct in vitro interaction data, localization by immunocytochemistry, and phosphorylation mapping, but single lab with limited mechanistic follow-up on functional consequences","pmids":["12167161"],"is_preprint":false},{"year":2007,"finding":"PCGF6 (Ring6a/MBLR) is a component of a native JARID1d demethylase complex in human cells; it directly interacts with the H3K4 trimethyl demethylase JARID1d and regulates its enzymatic activity toward trimethyl H3K4. Both proteins co-occupy the Engrailed 2 gene promoter and regulate its expression and H3K4 methylation levels.","method":"Native complex isolation/co-immunoprecipitation from human cells, direct interaction mapping, in vitro demethylase activity assay with PCGF6, ChIP at the Engrailed 2 locus, RNAi depletion","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — native complex purification, in vitro enzymatic assay showing PCGF6 modulates JARID1d activity, ChIP validation, multiple orthogonal methods in a high-quality study","pmids":["17320162"],"is_preprint":false},{"year":2014,"finding":"Pcgf6 knockdown in mouse ESCs decreases expression of pluripotency genes and de-represses mesodermal- and spermatogenesis-specific genes, and Pcgf6 can replace Sox2 in the generation of germline-competent iPSCs, establishing a non-redundant role in pluripotency maintenance.","method":"shRNA knockdown in mouse ESCs, gene expression analysis, hematopoietic differentiation assays, iPSC reprogramming with factor substitution","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with defined transcriptional and differentiation phenotypes, iPSC reprogramming rescue, single lab","pmids":["25187489"],"is_preprint":false},{"year":2016,"finding":"PCGF6 associates with the H3K4me3 demethylase JARID1c in dendritic cells and together they negatively regulate H3K4me3 levels; rapid downregulation of PCGF6 upon stimulation is necessary to permit full DC activation, and PCGF6 silencing enhances both spontaneous and stimulated DC activation.","method":"Co-immunoprecipitation (PCGF6–JARID1c association), ChIP (H3K4me3 levels), siRNA silencing with DC activation readouts","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP interaction, ChIP chromatin mark changes, loss-of-function phenotype, single lab","pmids":["27498878"],"is_preprint":false},{"year":2016,"finding":"In mouse ESCs, Pcgf6 acts as a positive transcriptional regulator binding predominantly to promoters with active chromatin marks; knockdown reduces expression of Oct4, Sox2, and Nanog, while overexpression prevents their downregulation and impairs differentiation. The genomic binding profile of Pcgf6 resembles trithorax group proteins rather than canonical PRC1/PRC2.","method":"ChIP-seq (binding profile), shRNA knockdown, overexpression, gene expression analysis in mouse ESCs","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP-seq plus loss- and gain-of-function experiments, single lab","pmids":["27247273"],"is_preprint":false},{"year":2017,"finding":"PCGF6 forms a non-canonical PRC1 complex (PCGF6-PRC1) with RING1A/B and E2F6-associated factors; this complex represses germ cell-related gene promoters in mouse ESCs by recruiting RING1B and mediating H2AK119 mono-ubiquitination. The MAX/MGA heterodimer recruits PCGF6 to target loci, linking sequence-specific recognition to PRC1-dependent silencing.","method":"Conditional Pcgf6 knockout in mouse ESCs, ChIP-seq (PCGF6, RING1B, H2AK119ub1), co-immunoprecipitation (PCGF6–MAX/MGA), RNA-seq, embryo phenotyping","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, ChIP-seq, reciprocal Co-IP for MAX/MGA recruitment, H2AK119ub1 readout, multiple orthogonal methods replicated across the same study","pmids":["28304275"],"is_preprint":false},{"year":2017,"finding":"CRISPR-Cas9 deletion of Pcgf6 in mouse ESCs causes severe self-renewal defects, de-repression of spermatogenesis/differentiation genes, and dramatically reduced PRC1.6 binding to target chromatin without loss of H2AK119ub1, indicating Pcgf6 is specifically required for PRC1.6 chromatin recruitment in an H2AK119ub1-independent manner.","method":"CRISPR-Cas9 knockout in mouse ESCs, ChIP (H2AK119ub1, PRC1.6 components), RNA-seq, self-renewal assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with ChIP showing loss of PRC1.6 at targets but preserved H2AK119ub1, multiple orthogonal methods, corroborates PMID:28304275","pmids":["28049731"],"is_preprint":false},{"year":2019,"finding":"PCGF6 is recruited by OCT4 to super-enhancer regions upstream of cell cycle-associated genes in mouse ESCs, and activates these genes by regulating super-enhancer–promoter chromatin interactions in 3D, as shown by co-localization with OCT4, promoter capture Hi-C, and gene expression analysis.","method":"ChIP-seq (PCGF6, OCT4), promoter capture Hi-C, gene expression analysis in ESCs","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP-seq co-occupancy with OCT4, Hi-C chromatin interaction data, single lab","pmids":["31041782"],"is_preprint":false},{"year":2020,"finding":"PCGF6 co-localizes with G9A/GLP histone methyltransferase and HDAC1/2 on promoters of germ cell-related genes in mouse ESCs; recruitment of G9A/GLP and HDAC1/2 to these promoters depends on PCGF6 binding, and their presence correlates with H3K9 methylation and reduced histone acetylation. Pcgf6-deficient mice show partial embryonic lethality and reduced fertility, with robust de-repression of germ cell-related genes in somatic tissues.","method":"Co-immunoprecipitation, ChIP (G9A, GLP, HDAC1/2, H3K9me, H3K4me3), RNA-seq, Pcgf6 knockout mice, immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP shows PCGF6-dependent recruitment of G9A/GLP and HDAC1/2 to targets, co-IP interaction, in vivo KO phenotype, multiple orthogonal methods","pmids":["32482889"],"is_preprint":false},{"year":2022,"finding":"In human PSCs, PCGF6 directly interacts with MYC and together they co-occupy a distal regulatory element of SOX2 to activate SOX2 expression; PCGF6 depletion impairs neuroectoderm differentiation and de-represses WNT/β-catenin signaling, promoting mesendoderm fate, while SOX2 overexpression rescues the neuroectoderm phenotype.","method":"Co-immunoprecipitation (PCGF6–MYC), ChIP (co-occupancy at SOX2 distal enhancer), genomic deletion of SOX2-regulatory element, PCGF6 shRNA depletion, SOX2 rescue overexpression, transcriptome analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP interaction, ChIP co-occupancy, regulatory element deletion phenocopying PCGF6 KD, rescue by SOX2 OE, multiple orthogonal methods","pmids":["35933409"],"is_preprint":false},{"year":2023,"finding":"In papillary RCC cells, PCGF6 interacts with MAX and KDM5D to form a complex; MAX recruits PCGF6 and KDM5D to the CpG island of the MAZ promoter, facilitating H3K4 histone demethylation and hypomethylation, thereby activating MAZ expression, which in turn upregulates CDK4 to drive tumor cell proliferation.","method":"Co-immunoprecipitation (PCGF6–MAX–KDM5D complex), ChIP (KDM5D, MAX at MAZ promoter), bisulfite sequencing (CpG methylation), overexpression/knockdown with proliferation assays","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for complex, ChIP for promoter binding, DNA methylation assay, single lab","pmids":["36890610"],"is_preprint":false},{"year":2024,"finding":"In mouse intestinal epithelium, PCGF6 regulates Tuft cell differentiation independently of H2AK119ub1 deposition and RING1A/B; PCGF6 chromatin occupancy extends outside Polycomb repressive domains to unique promoter and distal regulatory elements through MGA-mediated E-BOX recognition, and involves H3K9me2 deposition at target promoters. PCGF6 inactivation causes autonomous accumulation of Tuft cells not phenocopied by RING1A/B loss.","method":"Conditional Pcgf6 knockout in mouse intestinal epithelium, ChIP-seq (PCGF6, H2AK119ub1, H3K9me2), comparison with RING1A/B knockout phenotype, MGA co-occupancy analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with distinct phenotype from RING1A/B KO, ChIP-seq for chromatin marks, MGA co-occupancy, multiple orthogonal methods","pmids":["38228142"],"is_preprint":false}],"current_model":"PCGF6 is a Polycomb group RING finger protein that assembles into the non-canonical PRC1.6 complex with RING1A/B, E2F6-associated factors, and the MAX/MGA heterodimer to silence germ cell-related and lineage-specific genes via H2AK119ub1, H3K9me2 (through G9A/GLP recruitment), and histone deacetylation (via HDAC1/2); it also functions in an activation mode—partnering with MYC at enhancers to drive SOX2 and pluripotency gene expression—and modulates H3K4 methylation by associating with JARID1d/JARID1c demethylases, while being subject to cell-cycle-dependent phosphorylation at Ser32 by CDK7 during mitosis."},"narrative":{"mechanistic_narrative":"PCGF6 is a Polycomb group RING finger protein that operates as a sequence-targeted chromatin regulator, functioning predominantly to silence germ cell-related and lineage-specific genes while also acting in a context-dependent activation mode at pluripotency and cell-cycle loci [PMID:28304275, PMID:32482889, PMID:35933409]. In its repressive role, PCGF6 nucleates a non-canonical PRC1.6 complex with RING1A/B and E2F6-associated factors, with the MAX/MGA heterodimer recognizing E-BOX motifs to recruit the complex to target promoters and mediate RING1B-dependent H2AK119 mono-ubiquitination [PMID:28304275, PMID:38228142]. PCGF6 is itself the critical recruitment subunit: its loss collapses PRC1.6 binding at target chromatin without eliminating H2AK119ub1, showing that its targeting function is separable from the ubiquitin mark [PMID:28049731]. Silencing is reinforced through PCGF6-dependent recruitment of the G9A/GLP H3K9 methyltransferase and HDAC1/2, coupling H3K9me2 deposition and histone deacetylation to repression of germ cell genes [PMID:32482889]. PCGF6 also associates with the H3K4 demethylases JARID1d/KDM5D and JARID1c/KDM5C to regulate H3K4 trimethylation at target promoters [PMID:17320162, PMID:27498878]. Beyond this canonical repressive axis, PCGF6 can act as a positive regulator: it binds active-chromatin promoters resembling trithorax-group targets, is recruited by OCT4 to super-enhancers controlling cell-cycle genes, and partners with MYC at a SOX2 distal enhancer to activate SOX2 and direct neuroectoderm differentiation [PMID:27247273, PMID:31041782, PMID:35933409]. Genetically, PCGF6 is required for ESC self-renewal and pluripotency-gene expression, and Pcgf6-deficient mice show partial embryonic lethality, reduced fertility, and ectopic germ-cell gene de-repression in somatic tissues [PMID:25187489, PMID:32482889]. PCGF6 is phosphorylated at serine 32 during mitosis, most likely by CDK7 [PMID:12167161].","teleology":[{"year":2002,"claim":"Established PCGF6 (MBLR) as a RING finger transcriptional repressor that physically engages the PRC1 catalytic subunit Ring1B, the first link tying it to Polycomb machinery.","evidence":"In vitro interaction assay, immunocytochemistry, and transfection repressor assay with mitotic phosphorylation mapping","pmids":["12167161"],"confidence":"Medium","gaps":["Functional consequence of Ser32 phosphorylation on activity or recruitment not established","No genomic target identification","Repression shown only on transfected reporters"]},{"year":2007,"claim":"Showed PCGF6 is a subunit of a native JARID1d H3K4 demethylase complex and modulates its enzymatic activity, connecting PCGF6 to active control of H3K4 methylation at defined loci.","evidence":"Native complex purification, in vitro demethylase activity assay, ChIP at Engrailed 2, and RNAi in human cells","pmids":["17320162"],"confidence":"High","gaps":["Relationship between this demethylase complex and PRC1.6 unresolved","Genome-wide co-occupancy not mapped","Mechanism by which PCGF6 alters JARID1d catalysis unknown"]},{"year":2014,"claim":"Demonstrated a non-redundant requirement for Pcgf6 in pluripotency maintenance, including the ability to substitute for Sox2 in reprogramming, framing PCGF6 as a positive regulator of the pluripotency network.","evidence":"shRNA knockdown in mouse ESCs, expression and differentiation assays, and iPSC reprogramming with factor substitution","pmids":["25187489"],"confidence":"Medium","gaps":["Molecular basis of Sox2 substitution not defined","Direct vs indirect effects on pluripotency genes not distinguished","Single-lab loss-of-function"]},{"year":2016,"claim":"Two studies reframed PCGF6 as a positive regulator binding active-chromatin promoters and as a JARID1c partner controlling H3K4me3, revealing context-dependent activity outside canonical Polycomb repression.","evidence":"ChIP-seq, knockdown/overexpression in ESCs, and co-IP with ChIP plus DC activation readouts","pmids":["27247273","27498878"],"confidence":"Medium","gaps":["How activating and repressive modes are switched at different loci unknown","Direct catalytic versus scaffolding role at active promoters unclear","Both single-lab studies"]},{"year":2017,"claim":"Defined the PCGF6-PRC1.6 complex and established that MAX/MGA recruits PCGF6 to germ cell gene promoters for RING1B-dependent H2AK119ub1, while CRISPR deletion showed PCGF6 is required for PRC1.6 chromatin recruitment independently of the ubiquitin mark.","evidence":"Conditional and CRISPR knockout in mouse ESCs, ChIP-seq for PCGF6/RING1B/H2AK119ub1, co-IP with MAX/MGA, and RNA-seq","pmids":["28304275","28049731"],"confidence":"High","gaps":["Structural basis of PCGF6-mediated recruitment not resolved","Why H2AK119ub1 persists without PRC1.6 occupancy unexplained","Whether recruitment requires MAX/MGA at all targets not exhaustively tested"]},{"year":2019,"claim":"Identified an activation function in which OCT4 recruits PCGF6 to super-enhancers to organize enhancer-promoter contacts and drive cell-cycle gene expression, extending PCGF6 roles into 3D genome regulation.","evidence":"ChIP-seq for PCGF6 and OCT4, promoter capture Hi-C, and gene expression analysis in ESCs","pmids":["31041782"],"confidence":"Medium","gaps":["Mechanism by which PCGF6 shapes chromatin loops unknown","Whether PRC1.6 components participate at these enhancers untested","Single-lab"]},{"year":2020,"claim":"Showed PCGF6 recruits G9A/GLP and HDAC1/2 to germ cell gene promoters, coupling H3K9 methylation and histone deacetylation to silencing, and linked PCGF6 loss to embryonic lethality and fertility defects in vivo.","evidence":"Co-IP, ChIP for G9A/GLP/HDAC1/2 and histone marks, RNA-seq, and Pcgf6 knockout mice with immunohistochemistry","pmids":["32482889"],"confidence":"High","gaps":["Order and interdependence of H2AK119ub1, H3K9me2, and deacetylation not resolved","Direct vs indirect recruitment of G9A/GLP not distinguished","Tissue specificity of germ-gene de-repression not fully mapped"]},{"year":2022,"claim":"Established a direct PCGF6-MYC interaction that activates SOX2 from a distal enhancer to specify neuroectoderm fate in human PSCs, with regulatory-element deletion and SOX2 rescue confirming causality.","evidence":"Co-IP, ChIP co-occupancy, genomic enhancer deletion, shRNA depletion, and SOX2 rescue in human PSCs","pmids":["35933409"],"confidence":"High","gaps":["How the same protein toggles between MYC-driven activation and MAX/MGA-driven repression unclear","Whether PRC1.6 catalytic components are excluded at the SOX2 enhancer untested"]},{"year":2023,"claim":"Extended the MAX-recruited, KDM5D-associated activating mechanism to cancer, showing PCGF6-MAX-KDM5D activates MAZ via H3K4 demethylation and CpG hypomethylation to drive papillary RCC proliferation.","evidence":"Co-IP, ChIP at MAZ promoter, bisulfite sequencing, and proliferation assays in RCC cells","pmids":["36890610"],"confidence":"Medium","gaps":["How a repression-associated complex produces activation here mechanistically unresolved","Link between H3K4 demethylation and DNA hypomethylation not defined","Single-lab"]},{"year":2024,"claim":"Demonstrated a PRC1-independent PCGF6 function in Tuft cell differentiation, with MGA-mediated E-BOX targeting extending occupancy beyond Polycomb domains and H3K9me2 deposition, dissociating PCGF6 phenotypes from RING1A/B and H2AK119ub1.","evidence":"Conditional knockout in mouse intestinal epithelium, ChIP-seq for PCGF6/H2AK119ub1/H3K9me2, and comparison with RING1A/B knockout","pmids":["38228142"],"confidence":"High","gaps":["Effector that enacts H2AK119ub1-independent repression incompletely defined","How MGA targeting differs between Polycomb and non-Polycomb sites unclear"]},{"year":null,"claim":"How PCGF6 is switched between PRC1.6-dependent repression and MYC/OCT4-driven enhancer activation at distinct loci, and the molecular determinants partitioning its H2AK119ub1-dependent versus -independent functions, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PCGF6 within PRC1.6 or its activating complexes","Determinants selecting repressive vs activating partners unknown","Role of Ser32 phosphorylation in mode-switching uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,5,9]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,8,5]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5,6,8,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,7,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,9,11]}],"complexes":["PRC1.6","JARID1d/KDM5D demethylase complex"],"partners":["RING1B","MAX","MGA","MYC","OCT4","KDM5D","KDM5C","G9A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BYE7","full_name":"Polycomb group RING finger protein 6","aliases":["Mel18 and Bmi1-like RING finger","RING finger protein 134"],"length_aa":350,"mass_kda":39.0,"function":"Transcriptional repressor (PubMed:12167161). May modulate the levels of histone H3K4Me3 by activating KDM5D histone demethylase (PubMed:17320162). Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:12167161). Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity (PubMed:26151332)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BYE7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PCGF6","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PCGF6","total_profiled":1310},"omim":[{"mim_id":"607816","title":"POLYCOMB GROUP RING FINGER PROTEIN 6; PCGF6","url":"https://www.omim.org/entry/607816"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PCGF6"},"hgnc":{"alias_symbol":["MBLR"],"prev_symbol":["RNF134"]},"alphafold":{"accession":"Q9BYE7","domains":[{"cath_id":"3.30.40.10","chopping":"126-217","consensus_level":"high","plddt":93.2661,"start":126,"end":217},{"cath_id":"3.10.20.90","chopping":"253-345","consensus_level":"high","plddt":87.0174,"start":253,"end":345}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYE7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYE7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYE7-F1-predicted_aligned_error_v6.png","plddt_mean":72.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PCGF6","jax_strain_url":"https://www.jax.org/strain/search?query=PCGF6"},"sequence":{"accession":"Q9BYE7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BYE7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BYE7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYE7"}},"corpus_meta":[{"pmid":"17320162","id":"PMC_17320162","title":"Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein.","date":"2007","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17320162","citation_count":209,"is_preprint":false},{"pmid":"28304275","id":"PMC_28304275","title":"PCGF6-PRC1 suppresses premature differentiation of mouse embryonic stem cells by regulating germ cell-related genes.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28304275","citation_count":118,"is_preprint":false},{"pmid":"28049731","id":"PMC_28049731","title":"Essential Role for Polycomb Group Protein Pcgf6 in Embryonic Stem Cell Maintenance and a Noncanonical Polycomb Repressive Complex 1 (PRC1) Integrity.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28049731","citation_count":48,"is_preprint":false},{"pmid":"12167161","id":"PMC_12167161","title":"MBLR, a new RING finger protein resembling mammalian Polycomb gene products, is regulated by cell cycle-dependent phosphorylation.","date":"2002","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/12167161","citation_count":40,"is_preprint":false},{"pmid":"25187489","id":"PMC_25187489","title":"Pcgf6, a polycomb group protein, regulates mesodermal lineage differentiation in murine ESCs and functions in iPS reprogramming.","date":"2014","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/25187489","citation_count":34,"is_preprint":false},{"pmid":"27498878","id":"PMC_27498878","title":"The Transcriptional Repressor Polycomb Group Factor 6, PCGF6, Negatively Regulates Dendritic Cell Activation and Promotes Quiescence.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27498878","citation_count":32,"is_preprint":false},{"pmid":"32482889","id":"PMC_32482889","title":"The polycomb group protein PCGF6 mediates germline gene silencing by recruiting histone-modifying proteins to target gene promoters.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32482889","citation_count":26,"is_preprint":false},{"pmid":"27247273","id":"PMC_27247273","title":"Polycomb Group Protein Pcgf6 Acts as a Master Regulator to Maintain Embryonic Stem Cell Identity.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27247273","citation_count":25,"is_preprint":false},{"pmid":"35933409","id":"PMC_35933409","title":"PCGF6 controls neuroectoderm specification of human pluripotent stem cells by activating SOX2 expression.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35933409","citation_count":15,"is_preprint":false},{"pmid":"31041782","id":"PMC_31041782","title":"PCGF6 regulates stem cell pluripotency as a transcription activator via super-enhancer dependent chromatin interactions.","date":"2019","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/31041782","citation_count":9,"is_preprint":false},{"pmid":"36890610","id":"PMC_36890610","title":"PCGF6/MAX/KDM5D facilitates MAZ/CDK4 axis expression and pRCC progression by hypomethylation of the DNA promoter.","date":"2023","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/36890610","citation_count":5,"is_preprint":false},{"pmid":"38228142","id":"PMC_38228142","title":"PCGF6 controls murine Tuft cell differentiation via H3K9me2 modification independently of Polycomb repression.","date":"2024","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/38228142","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7687,"output_tokens":3483,"usd":0.037653,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10975,"output_tokens":4277,"usd":0.0809,"stage2_stop_reason":"end_turn"},"total_usd":0.118553,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"MBLR (PCGF6) is a RING finger protein that directly interacts with Ring1B via its RING finger domain, acts as a transcriptional repressor in transfected cells, localizes to the nucleoplasm in interphase and diffuse cytoplasm in mitotic cells, and is specifically phosphorylated at serine 32 during mitosis, most likely by CDK7.\",\n      \"method\": \"In vitro biochemical interaction assay, immunocytochemistry, transfection-based transcriptional repressor assay, cell-cycle phosphorylation analysis\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct in vitro interaction data, localization by immunocytochemistry, and phosphorylation mapping, but single lab with limited mechanistic follow-up on functional consequences\",\n      \"pmids\": [\"12167161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PCGF6 (Ring6a/MBLR) is a component of a native JARID1d demethylase complex in human cells; it directly interacts with the H3K4 trimethyl demethylase JARID1d and regulates its enzymatic activity toward trimethyl H3K4. Both proteins co-occupy the Engrailed 2 gene promoter and regulate its expression and H3K4 methylation levels.\",\n      \"method\": \"Native complex isolation/co-immunoprecipitation from human cells, direct interaction mapping, in vitro demethylase activity assay with PCGF6, ChIP at the Engrailed 2 locus, RNAi depletion\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — native complex purification, in vitro enzymatic assay showing PCGF6 modulates JARID1d activity, ChIP validation, multiple orthogonal methods in a high-quality study\",\n      \"pmids\": [\"17320162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Pcgf6 knockdown in mouse ESCs decreases expression of pluripotency genes and de-represses mesodermal- and spermatogenesis-specific genes, and Pcgf6 can replace Sox2 in the generation of germline-competent iPSCs, establishing a non-redundant role in pluripotency maintenance.\",\n      \"method\": \"shRNA knockdown in mouse ESCs, gene expression analysis, hematopoietic differentiation assays, iPSC reprogramming with factor substitution\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with defined transcriptional and differentiation phenotypes, iPSC reprogramming rescue, single lab\",\n      \"pmids\": [\"25187489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PCGF6 associates with the H3K4me3 demethylase JARID1c in dendritic cells and together they negatively regulate H3K4me3 levels; rapid downregulation of PCGF6 upon stimulation is necessary to permit full DC activation, and PCGF6 silencing enhances both spontaneous and stimulated DC activation.\",\n      \"method\": \"Co-immunoprecipitation (PCGF6–JARID1c association), ChIP (H3K4me3 levels), siRNA silencing with DC activation readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP interaction, ChIP chromatin mark changes, loss-of-function phenotype, single lab\",\n      \"pmids\": [\"27498878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In mouse ESCs, Pcgf6 acts as a positive transcriptional regulator binding predominantly to promoters with active chromatin marks; knockdown reduces expression of Oct4, Sox2, and Nanog, while overexpression prevents their downregulation and impairs differentiation. The genomic binding profile of Pcgf6 resembles trithorax group proteins rather than canonical PRC1/PRC2.\",\n      \"method\": \"ChIP-seq (binding profile), shRNA knockdown, overexpression, gene expression analysis in mouse ESCs\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP-seq plus loss- and gain-of-function experiments, single lab\",\n      \"pmids\": [\"27247273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PCGF6 forms a non-canonical PRC1 complex (PCGF6-PRC1) with RING1A/B and E2F6-associated factors; this complex represses germ cell-related gene promoters in mouse ESCs by recruiting RING1B and mediating H2AK119 mono-ubiquitination. The MAX/MGA heterodimer recruits PCGF6 to target loci, linking sequence-specific recognition to PRC1-dependent silencing.\",\n      \"method\": \"Conditional Pcgf6 knockout in mouse ESCs, ChIP-seq (PCGF6, RING1B, H2AK119ub1), co-immunoprecipitation (PCGF6–MAX/MGA), RNA-seq, embryo phenotyping\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, ChIP-seq, reciprocal Co-IP for MAX/MGA recruitment, H2AK119ub1 readout, multiple orthogonal methods replicated across the same study\",\n      \"pmids\": [\"28304275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRISPR-Cas9 deletion of Pcgf6 in mouse ESCs causes severe self-renewal defects, de-repression of spermatogenesis/differentiation genes, and dramatically reduced PRC1.6 binding to target chromatin without loss of H2AK119ub1, indicating Pcgf6 is specifically required for PRC1.6 chromatin recruitment in an H2AK119ub1-independent manner.\",\n      \"method\": \"CRISPR-Cas9 knockout in mouse ESCs, ChIP (H2AK119ub1, PRC1.6 components), RNA-seq, self-renewal assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with ChIP showing loss of PRC1.6 at targets but preserved H2AK119ub1, multiple orthogonal methods, corroborates PMID:28304275\",\n      \"pmids\": [\"28049731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PCGF6 is recruited by OCT4 to super-enhancer regions upstream of cell cycle-associated genes in mouse ESCs, and activates these genes by regulating super-enhancer–promoter chromatin interactions in 3D, as shown by co-localization with OCT4, promoter capture Hi-C, and gene expression analysis.\",\n      \"method\": \"ChIP-seq (PCGF6, OCT4), promoter capture Hi-C, gene expression analysis in ESCs\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP-seq co-occupancy with OCT4, Hi-C chromatin interaction data, single lab\",\n      \"pmids\": [\"31041782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PCGF6 co-localizes with G9A/GLP histone methyltransferase and HDAC1/2 on promoters of germ cell-related genes in mouse ESCs; recruitment of G9A/GLP and HDAC1/2 to these promoters depends on PCGF6 binding, and their presence correlates with H3K9 methylation and reduced histone acetylation. Pcgf6-deficient mice show partial embryonic lethality and reduced fertility, with robust de-repression of germ cell-related genes in somatic tissues.\",\n      \"method\": \"Co-immunoprecipitation, ChIP (G9A, GLP, HDAC1/2, H3K9me, H3K4me3), RNA-seq, Pcgf6 knockout mice, immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP shows PCGF6-dependent recruitment of G9A/GLP and HDAC1/2 to targets, co-IP interaction, in vivo KO phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"32482889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In human PSCs, PCGF6 directly interacts with MYC and together they co-occupy a distal regulatory element of SOX2 to activate SOX2 expression; PCGF6 depletion impairs neuroectoderm differentiation and de-represses WNT/β-catenin signaling, promoting mesendoderm fate, while SOX2 overexpression rescues the neuroectoderm phenotype.\",\n      \"method\": \"Co-immunoprecipitation (PCGF6–MYC), ChIP (co-occupancy at SOX2 distal enhancer), genomic deletion of SOX2-regulatory element, PCGF6 shRNA depletion, SOX2 rescue overexpression, transcriptome analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP interaction, ChIP co-occupancy, regulatory element deletion phenocopying PCGF6 KD, rescue by SOX2 OE, multiple orthogonal methods\",\n      \"pmids\": [\"35933409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In papillary RCC cells, PCGF6 interacts with MAX and KDM5D to form a complex; MAX recruits PCGF6 and KDM5D to the CpG island of the MAZ promoter, facilitating H3K4 histone demethylation and hypomethylation, thereby activating MAZ expression, which in turn upregulates CDK4 to drive tumor cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation (PCGF6–MAX–KDM5D complex), ChIP (KDM5D, MAX at MAZ promoter), bisulfite sequencing (CpG methylation), overexpression/knockdown with proliferation assays\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for complex, ChIP for promoter binding, DNA methylation assay, single lab\",\n      \"pmids\": [\"36890610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In mouse intestinal epithelium, PCGF6 regulates Tuft cell differentiation independently of H2AK119ub1 deposition and RING1A/B; PCGF6 chromatin occupancy extends outside Polycomb repressive domains to unique promoter and distal regulatory elements through MGA-mediated E-BOX recognition, and involves H3K9me2 deposition at target promoters. PCGF6 inactivation causes autonomous accumulation of Tuft cells not phenocopied by RING1A/B loss.\",\n      \"method\": \"Conditional Pcgf6 knockout in mouse intestinal epithelium, ChIP-seq (PCGF6, H2AK119ub1, H3K9me2), comparison with RING1A/B knockout phenotype, MGA co-occupancy analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with distinct phenotype from RING1A/B KO, ChIP-seq for chromatin marks, MGA co-occupancy, multiple orthogonal methods\",\n      \"pmids\": [\"38228142\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PCGF6 is a Polycomb group RING finger protein that assembles into the non-canonical PRC1.6 complex with RING1A/B, E2F6-associated factors, and the MAX/MGA heterodimer to silence germ cell-related and lineage-specific genes via H2AK119ub1, H3K9me2 (through G9A/GLP recruitment), and histone deacetylation (via HDAC1/2); it also functions in an activation mode—partnering with MYC at enhancers to drive SOX2 and pluripotency gene expression—and modulates H3K4 methylation by associating with JARID1d/JARID1c demethylases, while being subject to cell-cycle-dependent phosphorylation at Ser32 by CDK7 during mitosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PCGF6 is a Polycomb group RING finger protein that operates as a sequence-targeted chromatin regulator, functioning predominantly to silence germ cell-related and lineage-specific genes while also acting in a context-dependent activation mode at pluripotency and cell-cycle loci [#5, #8, #9]. In its repressive role, PCGF6 nucleates a non-canonical PRC1.6 complex with RING1A/B and E2F6-associated factors, with the MAX/MGA heterodimer recognizing E-BOX motifs to recruit the complex to target promoters and mediate RING1B-dependent H2AK119 mono-ubiquitination [#5, #11]. PCGF6 is itself the critical recruitment subunit: its loss collapses PRC1.6 binding at target chromatin without eliminating H2AK119ub1, showing that its targeting function is separable from the ubiquitin mark [#6]. Silencing is reinforced through PCGF6-dependent recruitment of the G9A/GLP H3K9 methyltransferase and HDAC1/2, coupling H3K9me2 deposition and histone deacetylation to repression of germ cell genes [#8]. PCGF6 also associates with the H3K4 demethylases JARID1d/KDM5D and JARID1c/KDM5C to regulate H3K4 trimethylation at target promoters [#1, #3]. Beyond this canonical repressive axis, PCGF6 can act as a positive regulator: it binds active-chromatin promoters resembling trithorax-group targets, is recruited by OCT4 to super-enhancers controlling cell-cycle genes, and partners with MYC at a SOX2 distal enhancer to activate SOX2 and direct neuroectoderm differentiation [#4, #7, #9]. Genetically, PCGF6 is required for ESC self-renewal and pluripotency-gene expression, and Pcgf6-deficient mice show partial embryonic lethality, reduced fertility, and ectopic germ-cell gene de-repression in somatic tissues [#2, #8]. PCGF6 is phosphorylated at serine 32 during mitosis, most likely by CDK7 [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established PCGF6 (MBLR) as a RING finger transcriptional repressor that physically engages the PRC1 catalytic subunit Ring1B, the first link tying it to Polycomb machinery.\",\n      \"evidence\": \"In vitro interaction assay, immunocytochemistry, and transfection repressor assay with mitotic phosphorylation mapping\",\n      \"pmids\": [\"12167161\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of Ser32 phosphorylation on activity or recruitment not established\", \"No genomic target identification\", \"Repression shown only on transfected reporters\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed PCGF6 is a subunit of a native JARID1d H3K4 demethylase complex and modulates its enzymatic activity, connecting PCGF6 to active control of H3K4 methylation at defined loci.\",\n      \"evidence\": \"Native complex purification, in vitro demethylase activity assay, ChIP at Engrailed 2, and RNAi in human cells\",\n      \"pmids\": [\"17320162\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Relationship between this demethylase complex and PRC1.6 unresolved\", \"Genome-wide co-occupancy not mapped\", \"Mechanism by which PCGF6 alters JARID1d catalysis unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated a non-redundant requirement for Pcgf6 in pluripotency maintenance, including the ability to substitute for Sox2 in reprogramming, framing PCGF6 as a positive regulator of the pluripotency network.\",\n      \"evidence\": \"shRNA knockdown in mouse ESCs, expression and differentiation assays, and iPSC reprogramming with factor substitution\",\n      \"pmids\": [\"25187489\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular basis of Sox2 substitution not defined\", \"Direct vs indirect effects on pluripotency genes not distinguished\", \"Single-lab loss-of-function\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Two studies reframed PCGF6 as a positive regulator binding active-chromatin promoters and as a JARID1c partner controlling H3K4me3, revealing context-dependent activity outside canonical Polycomb repression.\",\n      \"evidence\": \"ChIP-seq, knockdown/overexpression in ESCs, and co-IP with ChIP plus DC activation readouts\",\n      \"pmids\": [\"27247273\", \"27498878\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How activating and repressive modes are switched at different loci unknown\", \"Direct catalytic versus scaffolding role at active promoters unclear\", \"Both single-lab studies\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the PCGF6-PRC1.6 complex and established that MAX/MGA recruits PCGF6 to germ cell gene promoters for RING1B-dependent H2AK119ub1, while CRISPR deletion showed PCGF6 is required for PRC1.6 chromatin recruitment independently of the ubiquitin mark.\",\n      \"evidence\": \"Conditional and CRISPR knockout in mouse ESCs, ChIP-seq for PCGF6/RING1B/H2AK119ub1, co-IP with MAX/MGA, and RNA-seq\",\n      \"pmids\": [\"28304275\", \"28049731\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of PCGF6-mediated recruitment not resolved\", \"Why H2AK119ub1 persists without PRC1.6 occupancy unexplained\", \"Whether recruitment requires MAX/MGA at all targets not exhaustively tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified an activation function in which OCT4 recruits PCGF6 to super-enhancers to organize enhancer-promoter contacts and drive cell-cycle gene expression, extending PCGF6 roles into 3D genome regulation.\",\n      \"evidence\": \"ChIP-seq for PCGF6 and OCT4, promoter capture Hi-C, and gene expression analysis in ESCs\",\n      \"pmids\": [\"31041782\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which PCGF6 shapes chromatin loops unknown\", \"Whether PRC1.6 components participate at these enhancers untested\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed PCGF6 recruits G9A/GLP and HDAC1/2 to germ cell gene promoters, coupling H3K9 methylation and histone deacetylation to silencing, and linked PCGF6 loss to embryonic lethality and fertility defects in vivo.\",\n      \"evidence\": \"Co-IP, ChIP for G9A/GLP/HDAC1/2 and histone marks, RNA-seq, and Pcgf6 knockout mice with immunohistochemistry\",\n      \"pmids\": [\"32482889\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Order and interdependence of H2AK119ub1, H3K9me2, and deacetylation not resolved\", \"Direct vs indirect recruitment of G9A/GLP not distinguished\", \"Tissue specificity of germ-gene de-repression not fully mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a direct PCGF6-MYC interaction that activates SOX2 from a distal enhancer to specify neuroectoderm fate in human PSCs, with regulatory-element deletion and SOX2 rescue confirming causality.\",\n      \"evidence\": \"Co-IP, ChIP co-occupancy, genomic enhancer deletion, shRNA depletion, and SOX2 rescue in human PSCs\",\n      \"pmids\": [\"35933409\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How the same protein toggles between MYC-driven activation and MAX/MGA-driven repression unclear\", \"Whether PRC1.6 catalytic components are excluded at the SOX2 enhancer untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the MAX-recruited, KDM5D-associated activating mechanism to cancer, showing PCGF6-MAX-KDM5D activates MAZ via H3K4 demethylation and CpG hypomethylation to drive papillary RCC proliferation.\",\n      \"evidence\": \"Co-IP, ChIP at MAZ promoter, bisulfite sequencing, and proliferation assays in RCC cells\",\n      \"pmids\": [\"36890610\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How a repression-associated complex produces activation here mechanistically unresolved\", \"Link between H3K4 demethylation and DNA hypomethylation not defined\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a PRC1-independent PCGF6 function in Tuft cell differentiation, with MGA-mediated E-BOX targeting extending occupancy beyond Polycomb domains and H3K9me2 deposition, dissociating PCGF6 phenotypes from RING1A/B and H2AK119ub1.\",\n      \"evidence\": \"Conditional knockout in mouse intestinal epithelium, ChIP-seq for PCGF6/H2AK119ub1/H3K9me2, and comparison with RING1A/B knockout\",\n      \"pmids\": [\"38228142\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Effector that enacts H2AK119ub1-independent repression incompletely defined\", \"How MGA targeting differs between Polycomb and non-Polycomb sites unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PCGF6 is switched between PRC1.6-dependent repression and MYC/OCT4-driven enhancer activation at distinct loci, and the molecular determinants partitioning its H2AK119ub1-dependent versus -independent functions, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of PCGF6 within PRC1.6 or its activating complexes\", \"Determinants selecting repressive vs activating partners unknown\", \"Role of Ser32 phosphorylation in mode-switching uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 5, 9]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 8, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 6, 8, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 7, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 9, 11]}\n    ],\n    \"complexes\": [\"PRC1.6\", \"JARID1d/KDM5D demethylase complex\"],\n    \"partners\": [\"RING1B\", \"MAX\", \"MGA\", \"MYC\", \"OCT4\", \"KDM5D\", \"KDM5C\", \"G9A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}