{"gene":"KDM2B","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2012,"finding":"KDM2B (FBXL10) specifically recognizes non-methylated CpG island DNA via its CxxC domain and recruits Polycomb Repressive Complex 1 (PRC1), contributing to histone H2A lysine 119 ubiquitylation (H2AK119ub1) and gene repression. CGIs are occupied by low levels of KDM2B-PRC1 complex genome-wide, suggesting a sampling mechanism for polycomb-mediated silencing.","method":"ChIP-seq, genome-wide binding analysis, Co-IP, functional domain analysis in mouse ESCs","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genome-wide ChIP-seq, domain mutagenesis, replicated across multiple labs in same year","pmids":["23256043"],"is_preprint":false},{"year":2013,"finding":"Fbxl10/KDM2B interacts with Ring1B and Nspc1 to form a noncanonical PRC1 complex required for H2AK119ub1 in mouse ESCs. Both its DNA-binding capability and integration into PRC1 are required for H2AK119 ubiquitylation; Fbxl10 depletion causes a major loss of H2AK119ub1 and decreased Ring1B binding to target genes.","method":"Co-IP, genome-wide ChIP-seq, genetic loss-of-function with domain mutants in mouse ESCs","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP-seq, domain mutant rescue experiments, replicated in same year by independent lab","pmids":["23395003"],"is_preprint":false},{"year":2013,"finding":"Kdm2b maintains mESC undifferentiated state by binding CpG islands genome-wide via its CxxC-ZF domain, interacting with core PRC1 components, and recruiting PRC1 to CGIs of early lineage-specific genes to repress their expression. Oct4 and Sox2 directly regulate Kdm2b expression.","method":"Co-IP, ChIP-seq, domain deletion/mutant analysis, shRNA knockdown, gene expression profiling in mESCs","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP-seq, domain mutants), replicated core PRC1-recruitment finding across labs","pmids":["23502314"],"is_preprint":false},{"year":2008,"finding":"Jhdm1b/KDM2B is a histone H3 lysine 36 (H3K36) demethylase. Knockdown in primary MEFs inhibits cell proliferation and induces cellular senescence in a pRb- and p53-dependent manner. KDM2B targets the p15(Ink4b) locus and regulates its expression in an enzymatic activity-dependent manner; loss of p15(Ink4b) rescues proliferation defects caused by KDM2B knockdown.","method":"In vitro demethylase assay, ChIP, shRNA knockdown, genetic rescue experiments in MEFs","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay plus mutagenesis plus genetic epistasis (p15 rescue), replicated in multiple subsequent studies","pmids":["18836456"],"is_preprint":false},{"year":2007,"finding":"JHDM1B/KDM2B localizes to the nucleolus, preferentially binds the transcribed region of ribosomal DNA, and represses rRNA gene transcription. Repression depends on the JmjC domain, which demethylates trimethylated H3K4 specifically in the nucleolus. JHDM1B negatively affects cell size and proliferation in a JmjC domain-dependent manner.","method":"Subcellular fractionation/immunofluorescence (nucleolar localization), ChIP, RNAi, in vitro demethylase assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro demethylase assay, direct localization with functional consequence, ChIP at rDNA, JmjC domain dependence established","pmids":["17994099"],"is_preprint":false},{"year":2007,"finding":"Fbxl10/KDM2B forms a novel complex with Ring1B/Rnf2 that also contains BcoR, CK2alpha, Skp1, and Nspc1/Pcgf1, distinct from canonical PRC1. Identified by proteomics/mass spectrometry purification of biotinylated Ring1B.","method":"In vivo biotinylation tagging, streptavidin pulldown, mass spectrometry identification","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome, single lab, confirmed by iterative purification but not by mutagenesis/reconstitution","pmids":["17296600"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the KDM2B/SKP1/BCORL1/PCGF1 tetrameric complex was solved. The BCORL1 PUFD domain positions residues preceding the RAWUL domain of PCGF1 to create an extended interface for interaction with KDM2B unique to PRC1.1. This also reveals how KDM2B may simultaneously function in PRC1.1 and SCF ubiquitin ligase complex.","method":"In vitro complex assembly, crystal structure determination","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus in vitro reconstitution, single lab but atomic-resolution structural validation","pmids":["27568929"],"is_preprint":false},{"year":2009,"finding":"Ndy1/KDM2B represses the Ink4a/Arf locus through a JmjC domain-dependent process: it counteracts senescence-associated down-regulation of Ezh2 (PRC2), leading to global and locus-specific up-regulation of H3K27me3, which promotes Bmi1 (PRC1) binding at the Ink4a/Arf locus. KDM2B also demethylates locus-associated H3K36me2 and H3K4me3 and binds Ezh2.","method":"ChIP, Co-IP (KDM2B-Ezh2 interaction), shRNA knockdown, histone modification analysis in MEFs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, domain-dependent functional analysis, single lab","pmids":["19202064"],"is_preprint":false},{"year":2011,"finding":"KDM2B/JHDM1b functions as an H3K36 dimethyl-specific demethylase and is required for leukemic transformation. Ectopic Kdm2b transforms hematopoietic progenitors; its knockdown impairs Hoxa9/Meis1-induced leukemia. The mechanism requires active H3K36me2 demethylation to silence p15(Ink4b) in leukemic stem cells.","method":"Retroviral overexpression, shRNA knockdown, in vivo leukemia models, H3K36me2 demethylase activity assay, ChIP","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — enzymatic activity established by prior Tier 1 work; gain- and loss-of-function with defined mechanism (H3K36me2 at p15Ink4b), replicated across labs","pmids":["21310926"],"is_preprint":false},{"year":2011,"finding":"KDM2B is induced by FGF-2 via CREB phosphorylation downstream of DYRK1A. KDM2B and EZH2 co-bind the miR-101 promoter and repress it; KDM2B binding is independent of EZH2 but EZH2 binding depends on KDM2B. This NDY1/KDM2B-miR-101-EZH2 positive feedback axis mediates FGF-2 effects on cell proliferation, migration, and angiogenesis.","method":"ChIP, Co-IP, shRNA knockdown, luciferase reporter assays, signaling pathway analysis","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, epistasis experiments, single lab","pmids":["21777817"],"is_preprint":false},{"year":2011,"finding":"KDM2B silences let-7b and miR-101 through locus-specific H3K36me2 demethylation, preventing these miRNAs from targeting EZH2 mRNA; this upregulates EZH2 and promotes immortalization of MEFs. The KDM2B-let-7-EZH2 pathway also promotes proliferation of Ink4a/Arf null fibroblasts.","method":"ChIP, shRNA knockdown, miRNA overexpression/inhibition, epistasis experiments in MEFs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing H3K36me2 demethylation at miR loci, epistasis, single lab","pmids":["21757686"],"is_preprint":false},{"year":2012,"finding":"Kdm2b promotes iPSC generation by binding to and demethylating H3K36me2 at early responsive gene promoters, enhancing their activation early in reprogramming. This capacity depends on both demethylase and DNA-binding activities and is largely independent of its anti-senescence role.","method":"Retroviral overexpression, domain mutant analysis, ChIP, gene expression profiling during reprogramming","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with domain mutants, functional reprogramming assay, single lab","pmids":["22522173"],"is_preprint":false},{"year":2015,"finding":"Complete inactivation of Fbxl10 leads to dense de novo methylation specifically at promoters co-occupied by both FBXL10 and Polycomb repressive complexes, causing embryonic lethality at midgestation. FBXL10 thus protects Polycomb-bound promoters against ectopic de novo DNA methylation; deletion of PRC1/PRC2 components alone did not lead to ectopic methylation.","method":"Conditional/complete gene knockout in mice, whole-genome bisulfite sequencing, ChIP","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with genome-wide methylation profiling and genetic controls (PRC mutants), strong phenotypic readout","pmids":["25848754"],"is_preprint":false},{"year":2007,"finding":"Fbl10/KDM2B interacts with c-Jun, is present at the c-jun promoter (dependent on c-Jun recruitment), binds unmethylated CpG sequences via its CxxC zinc finger, and tethers transcriptional repressor complexes to repress c-Jun-mediated transcription. Fbl10 is downregulated by UV irradiation inversely with c-Jun induction.","method":"ChIP, Co-IP, CxxC domain DNA-binding assay, RNAi, cell-cycle and apoptosis assays","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, domain-binding experiments, single lab","pmids":["17704768"],"is_preprint":false},{"year":2013,"finding":"KDM2B drives pancreatic cancer tumorigenicity via two transcriptional mechanisms: (1) repression of developmental genes by co-binding with Polycomb group proteins at transcriptional start sites; (2) activation of metabolic genes (protein synthesis, mitochondrial function) co-bound by MYC and KDM5A. Both loss- and gain-of-function experiments linked to genome-wide ChIP-seq confirmed these programs.","method":"ChIP-seq, genome-wide gene expression, gain/loss-of-function experiments, mouse PDAC model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq, multiple orthogonal methods, in vivo model validation","pmids":["23321669"],"is_preprint":false},{"year":2018,"finding":"SS18-SSX1 oncoprotein physically interacts with PRC1.1 (containing KDM2B) and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands. Via KDM2B, SS18-SSX1 aberrantly activates polycomb-repressed developmental genes; KDM2B depletion restores repression and leads to irreversible mesenchymal differentiation.","method":"Co-IP, ChIP-seq, shRNA depletion, functional genomics in synovial sarcoma cells","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP-seq, clean depletion with defined differentiation phenotype","pmids":["29502955"],"is_preprint":false},{"year":2016,"finding":"KDM2B, via its F-box domain, assembles an SCF (CRL1/SCF^KDM2B) E3 ubiquitin ligase complex and targets c-Fos for polyubiquitylation and degradation. EGF-induced c-Fos S374 phosphorylation dissociates c-Fos from KDM2B, stabilizing c-Fos; tumor-derived KDM2B mutations impair c-Fos degradation.","method":"Co-IP, ubiquitylation assay, mutagenesis (S374), cell proliferation assays, tumor mutation analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitylation assay, mutagenesis with functional rescue, Co-IP of SCF complex","pmids":["26725323"],"is_preprint":false},{"year":2018,"finding":"KDM2B is a di- and trimethyl H3K79 demethylase in addition to its H3K36 activity. KDM2B occupies promoters of HOXA7 and MEIS1 and induces their transcriptional repression via H3K79 demethylation. KDM2B knockdown increases genome-wide H3K79 methylation, and KDM2B-depleted cells show displacement of SIRT1 from chromatin with concomitant increases in H3K79me and H4K16ac.","method":"In vitro demethylase assay, ChIP, genome-wide H3K79 methylation analysis, SIRT1 displacement assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro demethylase assay for H3K79 plus genome-wide and ChIP validation, single lab, novel substrate claim needs independent replication","pmids":["29763382"],"is_preprint":false},{"year":2018,"finding":"The FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) is rapidly and transiently recruited to DNA damage sites in a PARP1- and TIMELESS-dependent manner. At damage sites, FRRUC promotes H2AK119 mono-ubiquitylation, local H2A decrease, and H2A.Z incorporation, facilitating transcriptional repression, DSB signaling, and homologous recombination repair. FRRUC activity is required for proper recruitment of BMI1-RNF2 and MEL18-RNF2 complexes upon genotoxic stress.","method":"Live-cell imaging (FRAP/recruitment kinetics), ChIP, Co-IP, genetic depletion with HR assay, H2A.Z incorporation assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, direct localization to damage sites with functional consequence in DNA repair","pmids":["29985131"],"is_preprint":false},{"year":2014,"finding":"NDY1/KDM2B functions as a master regulator of PRC1 and PRC2 miRNA targets by repressing miRNAs that target polycomb complex members. Its knockdown de-represses these miRNAs, downregulating polycomb proteins. KDM2B is required for self-renewal of breast cancer stem cells (mammosphere formation, ALDH/CD44 markers), and its knockdown induces differentiation.","method":"shRNA knockdown, mammosphere assay, FACS for stem markers, miRNA profiling, rescue experiments","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional stem cell assays with miRNA epistasis, single lab","pmids":["24853546"],"is_preprint":false},{"year":2016,"finding":"FBXL10/KDM2B inhibits adipogenesis via its F-box and leucine-rich repeat domains by recruiting a noncanonical PRC1 (containing RING1B, SKP1, PCGF1, and BCOR). Knockdown of RING1B or SKP1 prevents FBXL10-mediated repression of adipogenesis. ChIP-seq shows FBXL10 recruits RING1B to loci surrounding Cdk1, Uhrf1, and Pparg genes. The JmjC demethylase domain is not required for this function.","method":"ChIP-seq, Co-IP, domain deletion analysis (F-box/LRR vs JmjC), shRNA knockdown, adipogenesis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, domain mutants, genetic rescue, single lab","pmids":["25533466"],"is_preprint":false},{"year":2019,"finding":"KDM2B promotes IL-6 production by binding the Il6 promoter and interacting with Brg1 (SWI/SNF ATPase) to facilitate chromatin accessibility, and directly recruits RNA Polymerase II to initiate Il6 transcription. This function is independent of its demethylase activity. KDM2B-deficient mice show reduced IL-6 and resistance to endotoxin shock.","method":"ChIP, Co-IP (KDM2B-Brg1), ATAC-seq/chromatin accessibility, conditional KO mice, ELISA","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, KO mouse phenotype, demethylase-independent mechanism shown, single lab","pmids":["31197256"],"is_preprint":false},{"year":2012,"finding":"Fbxl10 acts as an H3K4me3 demethylase (rather than primarily H3K36me2) based on in vitro purification and biochemical assays of its JmjC domain. Its PHD domain exhibits dual function: binding H3K4me3 and H3K36me2 AND exhibiting E3 ubiquitin ligase activity. Fbxl10 is recruited to Ccl7, Xist, Crabp2, and RipK3 promoters with reduced H3K4me3 but unchanged H3K36me2.","method":"In vitro demethylase assay with purified JmjC domain, PHD domain E3 ligase assay, ChIP, ChIP-seq","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 1 / Weak — in vitro assays but H3K4me3 demethylase assignment contradicts other studies; single lab, not replicated","pmids":["22825849"],"is_preprint":false},{"year":2021,"finding":"KDM2B demethylates the non-histone substrate serum response factor (SRF) at K165, negatively regulating muscle differentiation. The methyltransferase SET7 counteracts KDM2B by methylating SRF K165, which is required for transcriptional activation of SRF-dependent muscle genes. Both KDM2B and SET7 regulate the balance of SRF K165 methylation.","method":"Co-IP, in vitro demethylase assay on SRF substrate, ChIP, muscle differentiation assays, SET7 inhibitor experiments","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro demethylase assay on non-histone substrate, Co-IP, functional epistasis with SET7, single lab","pmids":["33564100"],"is_preprint":false},{"year":2019,"finding":"Tip60 acetylates KDM2B at lysine 758 in osteosarcoma cells. Acetylation of KDM2B decreases its capacity to bind nucleosomes and diminishes its demethylase activity toward nucleosomal (but not bulk histone) substrates, reducing its binding to p21 and PUMA promoters and enhancing its oncogenic effects.","method":"Co-IP, in vitro demethylase assay (nucleosomal substrate), acetylation mutagenesis (K758), ChIP, tumor growth assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro nucleosomal demethylase assay, acetylation mutagenesis, Co-IP, single lab","pmids":["31218831"],"is_preprint":false},{"year":2020,"finding":"KDM2B directly suppresses let-7b expression via H3K36me2 demethylation at the let-7b locus in ovarian cancer cells, thereby allowing EZH2 upregulation (let-7b targets EZH2). This KDM2B-let-7b-EZH2 axis promotes cancer cell proliferation and migration.","method":"ChIP (H3K36me2 at let-7b locus), let-7b overexpression rescue, EZH2 knockdown epistasis, xenograft model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at specific locus, epistasis experiments, single lab","pmids":["33091189"],"is_preprint":false},{"year":2017,"finding":"Kdm2b promotes Oct4-induced somatic reprogramming through recruitment of variant PRC1.1 complex to CpG islands. BMP-SMAD signaling attenuates PRC1.1 occupation and H2AK119 ubiquitination at developmental genes, enabling mesendodermal factor expression that suppresses reprogramming.","method":"ChIP-seq, Co-IP, domain mutant rescue, BMP signaling inhibition/activation experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, domain mutants, epistasis with BMP pathway, single lab","pmids":["29166607"],"is_preprint":false},{"year":2016,"finding":"KDM2B cooperates with polycomb and trithorax complexes to regulate hematopoietic lineage commitment, differentiation, cytokine signaling, and cell cycle. KDM2B maintains lymphoid leukemias but restrains RAS-driven myeloid transformation, demonstrating context-dependent opposing roles.","method":"Kdm2b conditional KO mice, RNA-seq of HSPCs, ChIP-seq in human leukemias","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model, RNA-seq, ChIP-seq, single lab","pmids":["26808549"],"is_preprint":false},{"year":2018,"finding":"EBNA3C (EBV) physically interacts with KDM2B, and this interaction is important for removal of H3K4me3 at EBNA3C target genes (COBLL1, ADAM28-ADAMDEC1 locus), contributing to transcriptional repression. Full COBLL1 repression requires both H3K4me3 removal (via KDM2B interaction) and H3K27me3 deposition (via Polycomb recruitment).","method":"Co-IP (EBNA3C-KDM2B), ChIP (H3K4me3, H3K27me3), recombinant EBV with RBPJ interaction motif mutations","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, mutant virus genetic analysis, single lab","pmids":["30135119"],"is_preprint":false},{"year":2020,"finding":"KDM2B-mediated H3K79 demethylation regulates cell cycle progression by controlling timely PCNA dissociation from chromatin during S phase. PCNA binds chromatin in an H3K79me-dependent manner; KDM2B depletion causes aberrant PCNA retention on chromatin and slowed DNA replication.","method":"KDM2B depletion in 293T cells, H3K79R mutant histone, Co-IP, peptide pulldown, ITC, ChIP, iPOND, DNA fiber assay, flow cytometry","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ITC for PCNA-H3K79me interaction, iPOND, DNA fiber assay, single lab","pmids":["33029857"],"is_preprint":false},{"year":2019,"finding":"ELKS1 stabilizes Kdm2b protein in mast cells; Kdm2b is an essential regulator of STX4 (Syntaxin 4) and Stxbp2 transcription required for mast cell degranulation. Loss of ELKS1 reduces Kdm2b stability, decreasing STX4/Stxbp2 transcription and impairing degranulation both in vivo and in vitro.","method":"Mast cell-specific ELKS1 knockout mice, Co-IP (ELKS1-Kdm2b), ChIP (Kdm2b at STX4/Stxbp2 promoters), degranulation assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse, Co-IP, ChIP, functional degranulation readout, single lab","pmids":["32937583"],"is_preprint":false},{"year":2015,"finding":"Fbxl10 directly binds regulatory regions of Nsg2 and oxidative phosphorylation genes, upregulating their expression. Fbxl10 overexpression in HSCs leads to G0/G1-to-S transition acceleration, progenitor cell expansion, and development of myeloid or B-lymphoid leukemia with complete penetrance in transgenic mice.","method":"ChIP-seq, transgenic mouse model (HSC-specific overexpression), gene expression analysis, metabolic profiling","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, transgenic mouse with defined leukemia phenotype, single lab","pmids":["25872778"],"is_preprint":false},{"year":2011,"finding":"Fbxl10 deficiency causes increased apoptosis in neuroepithelium and mesenchyme during embryonic development, associated with increased p19ARF expression, leading to neural tube defects and exencephaly. Fbxl10 thus regulates cell proliferation and death in neural progenitors via p19ARF suppression.","method":"Fbxl10 knockout mouse generation, in situ hybridization, apoptosis analysis (TUNEL), p19ARF expression analysis","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout mouse with defined neural phenotype and molecular mechanism, single lab","pmids":["21220025"],"is_preprint":false},{"year":2016,"finding":"Alternative short isoforms of KDM2B (KDM2B-SF), lacking the N-terminal demethylase domain, bind CpG island promoters of Wnt target genes (Axin2, Cyclin D1) and repress their expression. KDM2B-SF interacts with TCF7L1, a Wnt transcriptional mediator, to repress Wnt-responsive transcription. The DNA-binding domain is required for this repression; the demethylase domain is dispensable.","method":"Luciferase reporter assay (Wnt-responsive), ChIP at Axin2/CyclinD1 promoters, Co-IP (KDM2B-SF with TCF7L1), isoform overexpression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, luciferase reporter, domain mapping, single lab","pmids":["33104714"],"is_preprint":false},{"year":2023,"finding":"KDM2B, via its chromatin-association (CxxC) domain, transcriptionally silences Wnt signaling genes in hippocampal neural progenitors. Loss of the CxxC domain reduces polycomb repressive complex enrichment at Wnt gene loci, de-repressing Wnt signaling, impairing neural progenitor migration/differentiation, and causing hippocampal hypoplasia and spatial memory deficits.","method":"Conditional CxxC-domain deletion mouse (Kdm2b^ΔCxxC), ChIP-seq (PRC marks), RNA-seq, behavioral testing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined molecular mechanism (reduced PRC marks at Wnt genes), ChIP-seq, behavioral phenotype, epistasis by Wnt activation recapitulating KDM2B loss","pmids":["37838801"],"is_preprint":false},{"year":2022,"finding":"Loss of the CxxC-ZF domain of KDM2B impairs PRC1 recruitment to chromatin in neural stem cells, causing de-repression of apoptosis/cell-cycle-arrest/senescence genes, loss of NSC populations, and ASD/ID-like behavioral deficits in mice. Establishes causality between KDM2B-PRC1 chromatin regulation and ASD/ID-like phenotypes.","method":"Kdm2b CxxC-domain knock-in mouse, ChIP (PRC1 occupancy), RNA-seq, behavioral phenotyping","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-specific KI mouse, ChIP showing PRC1 loss, RNA-seq, defined behavioral phenotype","pmids":["35128353"],"is_preprint":false},{"year":2025,"finding":"CxxC domain variants of KDM2B significantly reduce its DNA-binding ability without affecting protein expression, causing a distinct neurodevelopmental syndrome (developmental delay, congenital heart defects, intellectual disability) that differs clinically from haploinsufficiency. Functional assays confirm reduced DNA binding as the mechanism for CxxC-variant pathogenicity.","method":"DNA-binding assay (functional assay with CxxC mutants), protein expression assays, cohort clinical analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional DNA-binding assay with multiple CxxC variants, large cohort, single lab","pmids":["40420380"],"is_preprint":false},{"year":2021,"finding":"KDM2B promotes IL-6-mediated inflammatory responses in macrophages by interacting with Brg1 (SWI/SNF). KDM2B knockdown in macrophages reduces IL-6 but not TNF-α, IL-1, or IFN-β, and KDM2B-deficient mice resist endotoxin shock with decreased IL-6.","method":"KDM2B conditional KO mice, ChIP (KDM2B at Il6 promoter), Co-IP (KDM2B-Brg1), ELISA","journal":"Inflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic overlap with PMID 31197256 (same Brg1 interaction), confirmatory rather than novel, single lab","pmids":["31041569"],"is_preprint":false},{"year":2021,"finding":"FBXL10 stabilizes ERRα protein by reducing its poly-ubiquitylation and promoting its mono-ubiquitylation, increasing ERRα transcriptional activity and ERRα enrichment at target gene promoters. FBXL10 facilitates ERRα/PGC1β-mediated proliferation and tumorigenesis in breast cancer.","method":"Co-IP (FBXL10-ERRα), ubiquitylation assay, reporter gene assay, ChIP (ERRα at target promoters), in vitro/in vivo proliferation assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitylation assay, ChIP, functional assays, single lab","pmids":["33450359"],"is_preprint":false},{"year":2021,"finding":"FBXL10 promotes EMT in breast cancer by interacting specifically with SNAI1 (not Slug or ZEB1), enhancing SNAI1 transcriptional repression of CDH1 by facilitating the interaction between SNAI1 and HDAC1, thereby promoting SNAI1 deacetylation. Deacetylated SNAI1 more potently suppresses E-cadherin transcription.","method":"Co-IP (FBXL10-SNAI1, SNAI1-HDAC1), reporter assay (CDH1 promoter), in vitro/in vivo migration/invasion assays, mouse lung metastasis model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, reporter assays, in vivo model, single lab","pmids":["34718323"],"is_preprint":false},{"year":2023,"finding":"KDM2B, functioning in the context of ncPRC1.1, regulates amino acid metabolism including SGOC, glutamate, and GSH pathways by enhancing chromatin accessibility and expression of MYC and ATF4. KDM2B co-occupies promoters of transcriptionally active metabolic genes together with MYC and ATF4, and regulates the expression and transcriptional activity of MYC.","method":"ChIP-seq, ATAC-seq, RNA-seq, TMT proteomics, global metabolomics, shRNA knockdown in TNBC cells","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics strategy, ChIP-seq, ATAC-seq, single lab","pmids":["37935302"],"is_preprint":false},{"year":2023,"finding":"DHX9 (DNA/RNA helicase) collaborates with KDM2B to regulate YAP1 expression in Ewing sarcoma. DHX9 enhances H3K9 chromatin demethylation by KDM2B and favors RNA Polymerase II recruitment to the YAP1 promoter. EWS-FLI1 binding to the YAP1 promoter antagonizes this activation.","method":"Co-IP (DHX9-KDM2B), ChIP (H3K9me, RNA Pol II), RNA-seq, shRNA depletion","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP, ChIP, single lab; H3K9 demethylase activity not directly demonstrated for KDM2B in prior work","pmids":["38017132"],"is_preprint":false},{"year":2020,"finding":"KDM2B overexpression activates FAK signaling and PI3K (p85 subunit upregulation) in prostate and colon cancer cells, promoting cell migration. KDM2B depletion reduces FAK activity and p85-PI3K without altering FAK gene expression/protein levels. KDM2B-driven migration is abolished by PI3K inhibitor LY294002.","method":"Western blot (FAK/PI3K activity), shRNA knockdown, wound-healing migration assay, LY294002 inhibition","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — biochemical assays, no direct mechanistic link between KDM2B and FAK established, single lab","pmids":["32175798"],"is_preprint":false},{"year":2019,"finding":"KDM2B is required for KDM2B-mediated transcriptional repression of NOTCH1 target genes in T-cell leukemia via PRC1.1. Kdm2b-deficient mice (lacking the CxxC domain) develop NOTCH1-dependent T-ALL, similar to Bcor-deficient mice, indicating PRC1.1 restricts excessive NOTCH1-mediated gene activation as a tumor suppressor.","method":"CxxC-domain specific KO mice, ChIP-seq (KDM2B, BCOR, EZH2, H2AK119ub1, H3K4me3, H3K27me3), RNA-seq, T-ALL mouse model","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional domain-specific KO, ChIP-seq with multiple histone marks, in vivo leukemia model with defined pathway (NOTCH1 antagonism)","pmids":["31471323"],"is_preprint":false},{"year":2020,"finding":"KDM2B regulates KDM2B-mediated H2AK119 monoubiquitination as a component of PRC1 to repress CDH1, miR200a, and CGN during TGF-β-induced EMT. KDM2B recruits EZH2 and induces H3K27 methylation at these loci. The DNA-recognition property (CxxC domain) but not demethylase activity is required for this function.","method":"ChIP (H2AK119ub1, EZH2 recruitment), KDM2B domain mutants, shRNA knockdown, morphological EMT assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, domain mutants separating DNA-binding from demethylase, functional EMT assays, single lab","pmids":["33779563"],"is_preprint":false},{"year":2021,"finding":"KDM2B directly binds the promoter region of MOB1 and suppresses its promoter activity, transcriptionally inhibiting MOB1 expression to regulate the Hippo pathway and promote PDAC proliferation/migration/invasion.","method":"ChIP (KDM2B at MOB1 promoter), luciferase reporter assay (MOB1 promoter), shRNA knockdown, rescue experiments","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, luciferase reporter, functional assays, single lab","pmids":["31941533"],"is_preprint":false}],"current_model":"KDM2B is a multi-domain chromatin regulator that: (1) demethylates histone H3K36me1/2 (and possibly H3K4me3 and H3K79me2/3) via its JmjC domain; (2) specifically recognizes unmethylated CpG island DNA via its CxxC zinc-finger domain and recruits a noncanonical PRC1 complex (PRC1.1, containing RING1B/RNF2, PCGF1, BCOR/BCORL1, and SKP1) to catalyze H2AK119 monoubiquitylation and gene repression; (3) acts as an F-box subunit of an SCF E3 ubiquitin ligase to target substrates including c-Fos for proteolysis; (4) represses rRNA gene transcription in the nucleolus by demethylating H3K4me3 at rDNA; (5) protects Polycomb-occupied CpG island promoters from aberrant de novo DNA methylation; (6) co-operates with EZH2/PRC2 and silences tumor-suppressor miRNAs (let-7, miR-101) to sustain EZH2 expression; and (7) is recruited to DNA damage sites via PARP1/TIMELESS to promote H2A.Z loading and homologous recombination repair."},"narrative":{"mechanistic_narrative":"KDM2B (FBXL10/JHDM1b) is a multi-domain chromatin regulator that links sequence-specific recognition of CpG island DNA to Polycomb-mediated gene silencing, and that also possesses Jumonji-domain histone demethylase and F-box-dependent ubiquitin-ligase activities [PMID:23256043, PMID:18836456, PMID:26725323]. Its defining activity is recognition of non-methylated CpG islands through the CxxC zinc-finger domain, which recruits a noncanonical PRC1 complex (PRC1.1 containing RING1B/RNF2, PCGF1/NSPC1, BCOR/BCORL1, SKP1) to catalyze H2AK119 monoubiquitylation and repress target genes genome-wide [PMID:23256043, PMID:23395003, PMID:23502314, PMID:17296600]; the BCORL1 PUFD–PCGF1 RAWUL interface defines an architecture unique to PRC1.1 and explains how KDM2B engages both PRC1.1 and an SCF ubiquitin ligase [PMID:27568929]. Both DNA binding and PRC1 integration are required for H2AK119ub1, and KDM2B loss collapses RING1B chromatin occupancy [PMID:23395003]. Through this PRC1.1 axis KDM2B maintains the undifferentiated ESC state, drives somatic reprogramming, protects Polycomb-bound promoters from aberrant de novo DNA methylation, and restrains lineage- and signaling-specific gene programs including NOTCH1 and Wnt targets [PMID:23502314, PMID:25848754, PMID:29166607, PMID:31471323, PMID:37838801]. Independently, the JmjC domain demethylates H3K36me1/2 — silencing the p15(Ink4b) and Ink4a/Arf loci to control senescence, proliferation, and leukemic transformation — and removes H3K4me3 at rDNA to repress rRNA transcription in the nucleolus [PMID:18836456, PMID:17994099, PMID:21310926, PMID:19202064]; reported additional substrates include H3K79me2/3 and the non-histone protein SRF [PMID:29763382, PMID:33564100]. As an F-box subunit, KDM2B assembles an SCF E3 ligase that polyubiquitylates c-Fos for degradation [PMID:26725323]. KDM2B sustains EZH2 expression by demethylating H3K36me2 at tumor-suppressor miRNA loci (let-7, miR-101) [PMID:21757686, PMID:33091189], and is recruited to DNA damage sites via PARP1/TIMELESS to promote H2A.Z loading and homologous recombination [PMID:29985131]. Loss or CxxC-domain variants of KDM2B cause neurodevelopmental syndromes via failed PRC1 recruitment and Wnt de-repression [PMID:37838801, PMID:35128353, PMID:40420380].","teleology":[{"year":2007,"claim":"Established the first functional activities of KDM2B: nucleolar repression of rRNA transcription via JmjC-dependent H3K4me3 demethylation, and tethering of repressor complexes to unmethylated CpG DNA via the CxxC zinc finger, framing it as a chromatin-targeted repressor.","evidence":"Nucleolar localization with rDNA ChIP and in vitro demethylase assay; Co-IP/ChIP at the c-jun promoter with CxxC DNA-binding assay; MS purification of a Ring1B complex containing KDM2B","pmids":["17994099","17704768","17296600"],"confidence":"Medium","gaps":["H3K4me3 substrate assignment later contested by H3K36 demethylase findings","noncanonical Ring1B complex composition defined biochemically but not reconstituted"]},{"year":2008,"claim":"Defined KDM2B's core enzymatic identity as an H3K36 demethylase and connected it to senescence control, showing it represses p15(Ink4b) in an activity-dependent manner.","evidence":"In vitro demethylase assay, ChIP, shRNA knockdown with genetic p15 rescue in MEFs","pmids":["18836456"],"confidence":"High","gaps":["mechanism linking H3K36 demethylation to recruitment of repressive machinery not resolved","does not address CpG-island/PRC1 function"]},{"year":2009,"claim":"Linked KDM2B to the broader Polycomb network, showing it counteracts senescence-associated EZH2 loss and promotes H3K27me3 and BMI1 binding at Ink4a/Arf, positioning it upstream of PRC2/PRC1 output.","evidence":"ChIP, KDM2B–EZH2 Co-IP, shRNA knockdown and histone-modification analysis in MEFs","pmids":["19202064"],"confidence":"Medium","gaps":["direct vs indirect basis of EZH2 cooperation unresolved","single lab"]},{"year":2011,"claim":"Showed KDM2B sustains EZH2 by silencing EZH2-targeting tumor-suppressor miRNAs through locus-specific H3K36me2 demethylation, and established its requirement for leukemic transformation.","evidence":"ChIP, shRNA, miRNA gain/loss epistasis in MEFs; retroviral transformation and in vivo leukemia models with H3K36me2 demethylase assay; FGF2–DYRK1A–CREB induction with reporter assays","pmids":["21757686","21310926","21777817"],"confidence":"Medium","gaps":["feedback-loop kinetics in primary tissue not addressed","miRNA-locus demethylation shown by ChIP but not directly causally separated from PRC1 effects"]},{"year":2012,"claim":"Resolved the central CpG-island-targeting model: KDM2B binds unmethylated CGIs genome-wide via CxxC and recruits PRC1 to deposit H2AK119ub1, providing a sampling mechanism for Polycomb silencing, and enables iPSC reprogramming.","evidence":"Genome-wide ChIP-seq, Co-IP, domain mutagenesis in mouse ESCs; reprogramming assays with demethylase/DNA-binding mutants","pmids":["23256043","22522173","22825849"],"confidence":"High","gaps":["conflicting in vitro substrate assignment (H3K4me3 vs H3K36me2) in one study","how low-occupancy sampling is converted to stable repression unclear"]},{"year":2013,"claim":"Defined the noncanonical PRC1.1 requirement, showing both DNA binding and PRC1 integration are needed for H2AK119ub1 and RING1B recruitment, and that this axis maintains the ESC undifferentiated state and drives cancer gene programs.","evidence":"Co-IP, genome-wide ChIP-seq, domain-mutant rescue in mESCs; ChIP-seq and gain/loss-of-function in PDAC model","pmids":["23395003","23502314","23321669"],"confidence":"High","gaps":["dual repressive (Polycomb) and activating (MYC/KDM5A) programs mechanistically distinct but switch undefined","stoichiometry of KDM2B within PRC1.1 in vivo unresolved"]},{"year":2015,"claim":"Demonstrated a protective genomic function: KDM2B shields Polycomb-occupied CpG-island promoters from de novo DNA methylation, with loss causing midgestation lethality not phenocopied by PRC mutants.","evidence":"Complete and conditional mouse knockout with whole-genome bisulfite sequencing and ChIP; HSC overexpression transgenic leukemia model","pmids":["25848754","25872778"],"confidence":"High","gaps":["molecular basis for excluding DNMTs from CGIs not defined","relationship between methylation protection and H2AK119ub1 deposition unresolved"]},{"year":2016,"claim":"Established KDM2B's second catalytic identity as an F-box SCF E3 ligase subunit targeting c-Fos, and solved the structure explaining how it bridges PRC1.1 and SCF, while extending PRC1.1 recruitment to non-stem contexts.","evidence":"Crystal structure of KDM2B/SKP1/BCORL1/PCGF1; in vitro ubiquitylation assay and S374 mutagenesis for c-Fos; ChIP-seq/domain analysis in adipogenesis; KO mouse hematopoietic studies","pmids":["27568929","26725323","25533466","26808549"],"confidence":"High","gaps":["full substrate repertoire of SCF^KDM2B beyond c-Fos unknown","regulation of switching between PRC1.1 and SCF assembly in cells undefined"]},{"year":2018,"claim":"Connected KDM2B to genome maintenance and expanded its substrate scope, showing PARP1/TIMELESS-dependent recruitment to DNA damage sites for H2A.Z loading and HR, and reporting H3K79 demethylase activity.","evidence":"Live-cell recruitment imaging, ChIP, HR assays for FRRUC; in vitro H3K79 demethylase assay with genome-wide validation; Co-IP/ChIP for EBNA3C interaction","pmids":["29985131","29763382","29502955","30135119"],"confidence":"High","gaps":["H3K79 demethylase activity is a novel substrate claim needing independent replication","how FRRUC composition relates to PRC1.1 at undamaged chromatin unclear"]},{"year":2020,"claim":"Extended KDM2B mechanisms to S-phase control and demethylase-independent gene regulation, showing H3K79 demethylation governs PCNA dissociation and that DNA-binding (not catalysis) drives EMT and Wnt repression.","evidence":"iPOND, ITC, DNA fiber assays in 293T cells; ChIP/domain mutants for EMT and TGF-β; isoform Co-IP with TCF7L1","pmids":["33029857","33779563","33104714","33091189"],"confidence":"Medium","gaps":["replication-timing role depends on contested H3K79 activity","demethylase-independent functions mechanistically attributed to PRC1 recruitment but not fully separated"]},{"year":2021,"claim":"Identified non-histone and stabilization-based functions, including SRF K165 demethylation balanced by SET7, ERRα and SNAI1 stabilization, and Brg1-dependent IL-6 induction.","evidence":"In vitro demethylase assay on SRF, Co-IP, ChIP, ubiquitylation assays, KO mouse phenotypes","pmids":["33564100","33450359","34718323","31197256"],"confidence":"Medium","gaps":["non-histone substrate generality unknown","how a single protein partitions among demethylase, ligase, and scaffold roles in a given cell undefined"]},{"year":2023,"claim":"Established causal links between the CxxC-PRC1 axis and neurodevelopmental disease, and tied KDM2B/PRC1.1 to metabolic gene regulation via MYC/ATF4.","evidence":"CxxC-domain conditional KO/knock-in mice with ChIP-seq, RNA-seq, and behavioral phenotyping; multi-omics in TNBC cells; CxxC-variant DNA-binding functional assays in patient cohort","pmids":["37838801","35128353","37935302","40420380"],"confidence":"High","gaps":["distinction between CxxC-variant syndrome and haploinsufficiency mechanism still being defined","tissue-specific selection of KDM2B target programs not resolved"]},{"year":null,"claim":"How KDM2B selects among its mutually exclusive activities — JmjC demethylation, PRC1.1 scaffolding, and SCF-type ubiquitin ligation — at specific loci and in specific cell types, and which reported histone substrates (H3K4me3, H3K79, H3K9) are bona fide in vivo, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["no unified model partitioning catalytic vs scaffold functions","conflicting substrate assignments across labs","regulation of PRC1.1-vs-SCF assembly switching unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,4,8,17,23]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[3,4,8]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,2,13,36]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[16,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,14,43,34]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,18]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,2,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,4,14,43]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,26,34,35]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,14,36]}],"complexes":["PRC1.1 (noncanonical PRC1)","SCF^KDM2B (CRL1) E3 ubiquitin ligase","FRRUC (FBXL10-RNF68-RNF2)"],"partners":["RING1B/RNF2","PCGF1/NSPC1","BCOR/BCORL1","SKP1","EZH2","BRG1","TIMELESS","PARP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NHM5","full_name":"Lysine-specific demethylase 2B","aliases":["CXXC-type zinc finger protein 2","F-box and leucine-rich repeat protein 10","F-box protein FBL10","F-box/LRR-repeat protein 10","JmjC domain-containing histone demethylation protein 1B","Jumonji domain-containing EMSY-interactor methyltransferase motif protein","Protein JEMMA","Protein-containing CXXC domain 2","[Histone-H3]-lysine-36 demethylase 1B"],"length_aa":1336,"mass_kda":152.6,"function":"Histone demethylase that demethylates 'Lys-4' and 'Lys-36' of histone H3, thereby playing a central role in histone code (PubMed:16362057, PubMed:17994099, PubMed:26237645). Preferentially demethylates trimethylated H3 'Lys-4' and dimethylated H3 'Lys-36' residue while it has weak or no activity for mono- and tri-methylated H3 'Lys-36' (PubMed:16362057, PubMed:17994099, PubMed:26237645). Preferentially binds the transcribed region of ribosomal RNA and represses the transcription of ribosomal RNA genes which inhibits cell growth and proliferation (PubMed:16362057, PubMed:17994099). May also serve as a substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex (Probable)","subcellular_location":"Nucleus, nucleolus; Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q8NHM5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM2B","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KDM2B","total_profiled":1310},"omim":[{"mim_id":"621474","title":"NEURODEVELOPMENTAL DISORDER WITH CONGENITAL CARDIAC DEFECTS AND VARIABLE RENAL AND OCULAR ABNORMALITIES; NEDCRO","url":"https://www.omim.org/entry/621474"},{"mim_id":"621294","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 3; ZBTB3","url":"https://www.omim.org/entry/621294"},{"mim_id":"619000","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH SEIZURES AND LANGUAGE DELAY; IDDSELD","url":"https://www.omim.org/entry/619000"},{"mim_id":"609078","title":"LYSINE DEMETHYLASE 2B; KDM2B","url":"https://www.omim.org/entry/609078"},{"mim_id":"181500","title":"SCHIZOPHRENIA; SCZD","url":"https://www.omim.org/entry/181500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KDM2B"},"hgnc":{"alias_symbol":["PCCX2","CXXC2","Fbl10","JHDM1B"],"prev_symbol":["FBXL10"]},"alphafold":{"accession":"Q8NHM5","domains":[{"cath_id":"2.60.120.650","chopping":"78-352","consensus_level":"high","plddt":94.4883,"start":78,"end":352},{"cath_id":"1.20.58.1360","chopping":"359-389_507-570","consensus_level":"medium","plddt":92.9321,"start":359,"end":570},{"cath_id":"-","chopping":"611-649","consensus_level":"medium","plddt":87.1721,"start":611,"end":649},{"cath_id":"3.30.40.10","chopping":"657-728","consensus_level":"medium","plddt":81.7364,"start":657,"end":728},{"cath_id":"3.80.10.10","chopping":"1188-1199_1210-1336","consensus_level":"medium","plddt":90.7824,"start":1188,"end":1336}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHM5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHM5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHM5-F1-predicted_aligned_error_v6.png","plddt_mean":67.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM2B","jax_strain_url":"https://www.jax.org/strain/search?query=KDM2B"},"sequence":{"accession":"Q8NHM5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NHM5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NHM5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHM5"}},"corpus_meta":[{"pmid":"23256043","id":"PMC_23256043","title":"KDM2B 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via its CxxC domain and recruits Polycomb Repressive Complex 1 (PRC1), contributing to histone H2A lysine 119 ubiquitylation (H2AK119ub1) and gene repression. CGIs are occupied by low levels of KDM2B-PRC1 complex genome-wide, suggesting a sampling mechanism for polycomb-mediated silencing.\",\n      \"method\": \"ChIP-seq, genome-wide binding analysis, Co-IP, functional domain analysis in mouse ESCs\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genome-wide ChIP-seq, domain mutagenesis, replicated across multiple labs in same year\",\n      \"pmids\": [\"23256043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fbxl10/KDM2B interacts with Ring1B and Nspc1 to form a noncanonical PRC1 complex required for H2AK119ub1 in mouse ESCs. Both its DNA-binding capability and integration into PRC1 are required for H2AK119 ubiquitylation; Fbxl10 depletion causes a major loss of H2AK119ub1 and decreased Ring1B binding to target genes.\",\n      \"method\": \"Co-IP, genome-wide ChIP-seq, genetic loss-of-function with domain mutants in mouse ESCs\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP-seq, domain mutant rescue experiments, replicated in same year by independent lab\",\n      \"pmids\": [\"23395003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Kdm2b maintains mESC undifferentiated state by binding CpG islands genome-wide via its CxxC-ZF domain, interacting with core PRC1 components, and recruiting PRC1 to CGIs of early lineage-specific genes to repress their expression. Oct4 and Sox2 directly regulate Kdm2b expression.\",\n      \"method\": \"Co-IP, ChIP-seq, domain deletion/mutant analysis, shRNA knockdown, gene expression profiling in mESCs\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP-seq, domain mutants), replicated core PRC1-recruitment finding across labs\",\n      \"pmids\": [\"23502314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Jhdm1b/KDM2B is a histone H3 lysine 36 (H3K36) demethylase. Knockdown in primary MEFs inhibits cell proliferation and induces cellular senescence in a pRb- and p53-dependent manner. KDM2B targets the p15(Ink4b) locus and regulates its expression in an enzymatic activity-dependent manner; loss of p15(Ink4b) rescues proliferation defects caused by KDM2B knockdown.\",\n      \"method\": \"In vitro demethylase assay, ChIP, shRNA knockdown, genetic rescue experiments in MEFs\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay plus mutagenesis plus genetic epistasis (p15 rescue), replicated in multiple subsequent studies\",\n      \"pmids\": [\"18836456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JHDM1B/KDM2B localizes to the nucleolus, preferentially binds the transcribed region of ribosomal DNA, and represses rRNA gene transcription. Repression depends on the JmjC domain, which demethylates trimethylated H3K4 specifically in the nucleolus. JHDM1B negatively affects cell size and proliferation in a JmjC domain-dependent manner.\",\n      \"method\": \"Subcellular fractionation/immunofluorescence (nucleolar localization), ChIP, RNAi, in vitro demethylase assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro demethylase assay, direct localization with functional consequence, ChIP at rDNA, JmjC domain dependence established\",\n      \"pmids\": [\"17994099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fbxl10/KDM2B forms a novel complex with Ring1B/Rnf2 that also contains BcoR, CK2alpha, Skp1, and Nspc1/Pcgf1, distinct from canonical PRC1. Identified by proteomics/mass spectrometry purification of biotinylated Ring1B.\",\n      \"method\": \"In vivo biotinylation tagging, streptavidin pulldown, mass spectrometry identification\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome, single lab, confirmed by iterative purification but not by mutagenesis/reconstitution\",\n      \"pmids\": [\"17296600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the KDM2B/SKP1/BCORL1/PCGF1 tetrameric complex was solved. The BCORL1 PUFD domain positions residues preceding the RAWUL domain of PCGF1 to create an extended interface for interaction with KDM2B unique to PRC1.1. This also reveals how KDM2B may simultaneously function in PRC1.1 and SCF ubiquitin ligase complex.\",\n      \"method\": \"In vitro complex assembly, crystal structure determination\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus in vitro reconstitution, single lab but atomic-resolution structural validation\",\n      \"pmids\": [\"27568929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ndy1/KDM2B represses the Ink4a/Arf locus through a JmjC domain-dependent process: it counteracts senescence-associated down-regulation of Ezh2 (PRC2), leading to global and locus-specific up-regulation of H3K27me3, which promotes Bmi1 (PRC1) binding at the Ink4a/Arf locus. KDM2B also demethylates locus-associated H3K36me2 and H3K4me3 and binds Ezh2.\",\n      \"method\": \"ChIP, Co-IP (KDM2B-Ezh2 interaction), shRNA knockdown, histone modification analysis in MEFs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, domain-dependent functional analysis, single lab\",\n      \"pmids\": [\"19202064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM2B/JHDM1b functions as an H3K36 dimethyl-specific demethylase and is required for leukemic transformation. Ectopic Kdm2b transforms hematopoietic progenitors; its knockdown impairs Hoxa9/Meis1-induced leukemia. The mechanism requires active H3K36me2 demethylation to silence p15(Ink4b) in leukemic stem cells.\",\n      \"method\": \"Retroviral overexpression, shRNA knockdown, in vivo leukemia models, H3K36me2 demethylase activity assay, ChIP\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — enzymatic activity established by prior Tier 1 work; gain- and loss-of-function with defined mechanism (H3K36me2 at p15Ink4b), replicated across labs\",\n      \"pmids\": [\"21310926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM2B is induced by FGF-2 via CREB phosphorylation downstream of DYRK1A. KDM2B and EZH2 co-bind the miR-101 promoter and repress it; KDM2B binding is independent of EZH2 but EZH2 binding depends on KDM2B. This NDY1/KDM2B-miR-101-EZH2 positive feedback axis mediates FGF-2 effects on cell proliferation, migration, and angiogenesis.\",\n      \"method\": \"ChIP, Co-IP, shRNA knockdown, luciferase reporter assays, signaling pathway analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, epistasis experiments, single lab\",\n      \"pmids\": [\"21777817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM2B silences let-7b and miR-101 through locus-specific H3K36me2 demethylation, preventing these miRNAs from targeting EZH2 mRNA; this upregulates EZH2 and promotes immortalization of MEFs. The KDM2B-let-7-EZH2 pathway also promotes proliferation of Ink4a/Arf null fibroblasts.\",\n      \"method\": \"ChIP, shRNA knockdown, miRNA overexpression/inhibition, epistasis experiments in MEFs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing H3K36me2 demethylation at miR loci, epistasis, single lab\",\n      \"pmids\": [\"21757686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Kdm2b promotes iPSC generation by binding to and demethylating H3K36me2 at early responsive gene promoters, enhancing their activation early in reprogramming. This capacity depends on both demethylase and DNA-binding activities and is largely independent of its anti-senescence role.\",\n      \"method\": \"Retroviral overexpression, domain mutant analysis, ChIP, gene expression profiling during reprogramming\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with domain mutants, functional reprogramming assay, single lab\",\n      \"pmids\": [\"22522173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Complete inactivation of Fbxl10 leads to dense de novo methylation specifically at promoters co-occupied by both FBXL10 and Polycomb repressive complexes, causing embryonic lethality at midgestation. FBXL10 thus protects Polycomb-bound promoters against ectopic de novo DNA methylation; deletion of PRC1/PRC2 components alone did not lead to ectopic methylation.\",\n      \"method\": \"Conditional/complete gene knockout in mice, whole-genome bisulfite sequencing, ChIP\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with genome-wide methylation profiling and genetic controls (PRC mutants), strong phenotypic readout\",\n      \"pmids\": [\"25848754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fbl10/KDM2B interacts with c-Jun, is present at the c-jun promoter (dependent on c-Jun recruitment), binds unmethylated CpG sequences via its CxxC zinc finger, and tethers transcriptional repressor complexes to repress c-Jun-mediated transcription. Fbl10 is downregulated by UV irradiation inversely with c-Jun induction.\",\n      \"method\": \"ChIP, Co-IP, CxxC domain DNA-binding assay, RNAi, cell-cycle and apoptosis assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, domain-binding experiments, single lab\",\n      \"pmids\": [\"17704768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM2B drives pancreatic cancer tumorigenicity via two transcriptional mechanisms: (1) repression of developmental genes by co-binding with Polycomb group proteins at transcriptional start sites; (2) activation of metabolic genes (protein synthesis, mitochondrial function) co-bound by MYC and KDM5A. Both loss- and gain-of-function experiments linked to genome-wide ChIP-seq confirmed these programs.\",\n      \"method\": \"ChIP-seq, genome-wide gene expression, gain/loss-of-function experiments, mouse PDAC model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq, multiple orthogonal methods, in vivo model validation\",\n      \"pmids\": [\"23321669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SS18-SSX1 oncoprotein physically interacts with PRC1.1 (containing KDM2B) and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands. Via KDM2B, SS18-SSX1 aberrantly activates polycomb-repressed developmental genes; KDM2B depletion restores repression and leads to irreversible mesenchymal differentiation.\",\n      \"method\": \"Co-IP, ChIP-seq, shRNA depletion, functional genomics in synovial sarcoma cells\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP-seq, clean depletion with defined differentiation phenotype\",\n      \"pmids\": [\"29502955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM2B, via its F-box domain, assembles an SCF (CRL1/SCF^KDM2B) E3 ubiquitin ligase complex and targets c-Fos for polyubiquitylation and degradation. EGF-induced c-Fos S374 phosphorylation dissociates c-Fos from KDM2B, stabilizing c-Fos; tumor-derived KDM2B mutations impair c-Fos degradation.\",\n      \"method\": \"Co-IP, ubiquitylation assay, mutagenesis (S374), cell proliferation assays, tumor mutation analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitylation assay, mutagenesis with functional rescue, Co-IP of SCF complex\",\n      \"pmids\": [\"26725323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM2B is a di- and trimethyl H3K79 demethylase in addition to its H3K36 activity. KDM2B occupies promoters of HOXA7 and MEIS1 and induces their transcriptional repression via H3K79 demethylation. KDM2B knockdown increases genome-wide H3K79 methylation, and KDM2B-depleted cells show displacement of SIRT1 from chromatin with concomitant increases in H3K79me and H4K16ac.\",\n      \"method\": \"In vitro demethylase assay, ChIP, genome-wide H3K79 methylation analysis, SIRT1 displacement assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro demethylase assay for H3K79 plus genome-wide and ChIP validation, single lab, novel substrate claim needs independent replication\",\n      \"pmids\": [\"29763382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) is rapidly and transiently recruited to DNA damage sites in a PARP1- and TIMELESS-dependent manner. At damage sites, FRRUC promotes H2AK119 mono-ubiquitylation, local H2A decrease, and H2A.Z incorporation, facilitating transcriptional repression, DSB signaling, and homologous recombination repair. FRRUC activity is required for proper recruitment of BMI1-RNF2 and MEL18-RNF2 complexes upon genotoxic stress.\",\n      \"method\": \"Live-cell imaging (FRAP/recruitment kinetics), ChIP, Co-IP, genetic depletion with HR assay, H2A.Z incorporation assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, direct localization to damage sites with functional consequence in DNA repair\",\n      \"pmids\": [\"29985131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NDY1/KDM2B functions as a master regulator of PRC1 and PRC2 miRNA targets by repressing miRNAs that target polycomb complex members. Its knockdown de-represses these miRNAs, downregulating polycomb proteins. KDM2B is required for self-renewal of breast cancer stem cells (mammosphere formation, ALDH/CD44 markers), and its knockdown induces differentiation.\",\n      \"method\": \"shRNA knockdown, mammosphere assay, FACS for stem markers, miRNA profiling, rescue experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional stem cell assays with miRNA epistasis, single lab\",\n      \"pmids\": [\"24853546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FBXL10/KDM2B inhibits adipogenesis via its F-box and leucine-rich repeat domains by recruiting a noncanonical PRC1 (containing RING1B, SKP1, PCGF1, and BCOR). Knockdown of RING1B or SKP1 prevents FBXL10-mediated repression of adipogenesis. ChIP-seq shows FBXL10 recruits RING1B to loci surrounding Cdk1, Uhrf1, and Pparg genes. The JmjC demethylase domain is not required for this function.\",\n      \"method\": \"ChIP-seq, Co-IP, domain deletion analysis (F-box/LRR vs JmjC), shRNA knockdown, adipogenesis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, domain mutants, genetic rescue, single lab\",\n      \"pmids\": [\"25533466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM2B promotes IL-6 production by binding the Il6 promoter and interacting with Brg1 (SWI/SNF ATPase) to facilitate chromatin accessibility, and directly recruits RNA Polymerase II to initiate Il6 transcription. This function is independent of its demethylase activity. KDM2B-deficient mice show reduced IL-6 and resistance to endotoxin shock.\",\n      \"method\": \"ChIP, Co-IP (KDM2B-Brg1), ATAC-seq/chromatin accessibility, conditional KO mice, ELISA\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, KO mouse phenotype, demethylase-independent mechanism shown, single lab\",\n      \"pmids\": [\"31197256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Fbxl10 acts as an H3K4me3 demethylase (rather than primarily H3K36me2) based on in vitro purification and biochemical assays of its JmjC domain. Its PHD domain exhibits dual function: binding H3K4me3 and H3K36me2 AND exhibiting E3 ubiquitin ligase activity. Fbxl10 is recruited to Ccl7, Xist, Crabp2, and RipK3 promoters with reduced H3K4me3 but unchanged H3K36me2.\",\n      \"method\": \"In vitro demethylase assay with purified JmjC domain, PHD domain E3 ligase assay, ChIP, ChIP-seq\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro assays but H3K4me3 demethylase assignment contradicts other studies; single lab, not replicated\",\n      \"pmids\": [\"22825849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM2B demethylates the non-histone substrate serum response factor (SRF) at K165, negatively regulating muscle differentiation. The methyltransferase SET7 counteracts KDM2B by methylating SRF K165, which is required for transcriptional activation of SRF-dependent muscle genes. Both KDM2B and SET7 regulate the balance of SRF K165 methylation.\",\n      \"method\": \"Co-IP, in vitro demethylase assay on SRF substrate, ChIP, muscle differentiation assays, SET7 inhibitor experiments\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro demethylase assay on non-histone substrate, Co-IP, functional epistasis with SET7, single lab\",\n      \"pmids\": [\"33564100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tip60 acetylates KDM2B at lysine 758 in osteosarcoma cells. Acetylation of KDM2B decreases its capacity to bind nucleosomes and diminishes its demethylase activity toward nucleosomal (but not bulk histone) substrates, reducing its binding to p21 and PUMA promoters and enhancing its oncogenic effects.\",\n      \"method\": \"Co-IP, in vitro demethylase assay (nucleosomal substrate), acetylation mutagenesis (K758), ChIP, tumor growth assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro nucleosomal demethylase assay, acetylation mutagenesis, Co-IP, single lab\",\n      \"pmids\": [\"31218831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM2B directly suppresses let-7b expression via H3K36me2 demethylation at the let-7b locus in ovarian cancer cells, thereby allowing EZH2 upregulation (let-7b targets EZH2). This KDM2B-let-7b-EZH2 axis promotes cancer cell proliferation and migration.\",\n      \"method\": \"ChIP (H3K36me2 at let-7b locus), let-7b overexpression rescue, EZH2 knockdown epistasis, xenograft model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at specific locus, epistasis experiments, single lab\",\n      \"pmids\": [\"33091189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Kdm2b promotes Oct4-induced somatic reprogramming through recruitment of variant PRC1.1 complex to CpG islands. BMP-SMAD signaling attenuates PRC1.1 occupation and H2AK119 ubiquitination at developmental genes, enabling mesendodermal factor expression that suppresses reprogramming.\",\n      \"method\": \"ChIP-seq, Co-IP, domain mutant rescue, BMP signaling inhibition/activation experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, domain mutants, epistasis with BMP pathway, single lab\",\n      \"pmids\": [\"29166607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM2B cooperates with polycomb and trithorax complexes to regulate hematopoietic lineage commitment, differentiation, cytokine signaling, and cell cycle. KDM2B maintains lymphoid leukemias but restrains RAS-driven myeloid transformation, demonstrating context-dependent opposing roles.\",\n      \"method\": \"Kdm2b conditional KO mice, RNA-seq of HSPCs, ChIP-seq in human leukemias\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model, RNA-seq, ChIP-seq, single lab\",\n      \"pmids\": [\"26808549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EBNA3C (EBV) physically interacts with KDM2B, and this interaction is important for removal of H3K4me3 at EBNA3C target genes (COBLL1, ADAM28-ADAMDEC1 locus), contributing to transcriptional repression. Full COBLL1 repression requires both H3K4me3 removal (via KDM2B interaction) and H3K27me3 deposition (via Polycomb recruitment).\",\n      \"method\": \"Co-IP (EBNA3C-KDM2B), ChIP (H3K4me3, H3K27me3), recombinant EBV with RBPJ interaction motif mutations\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, mutant virus genetic analysis, single lab\",\n      \"pmids\": [\"30135119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM2B-mediated H3K79 demethylation regulates cell cycle progression by controlling timely PCNA dissociation from chromatin during S phase. PCNA binds chromatin in an H3K79me-dependent manner; KDM2B depletion causes aberrant PCNA retention on chromatin and slowed DNA replication.\",\n      \"method\": \"KDM2B depletion in 293T cells, H3K79R mutant histone, Co-IP, peptide pulldown, ITC, ChIP, iPOND, DNA fiber assay, flow cytometry\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ITC for PCNA-H3K79me interaction, iPOND, DNA fiber assay, single lab\",\n      \"pmids\": [\"33029857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ELKS1 stabilizes Kdm2b protein in mast cells; Kdm2b is an essential regulator of STX4 (Syntaxin 4) and Stxbp2 transcription required for mast cell degranulation. Loss of ELKS1 reduces Kdm2b stability, decreasing STX4/Stxbp2 transcription and impairing degranulation both in vivo and in vitro.\",\n      \"method\": \"Mast cell-specific ELKS1 knockout mice, Co-IP (ELKS1-Kdm2b), ChIP (Kdm2b at STX4/Stxbp2 promoters), degranulation assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse, Co-IP, ChIP, functional degranulation readout, single lab\",\n      \"pmids\": [\"32937583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fbxl10 directly binds regulatory regions of Nsg2 and oxidative phosphorylation genes, upregulating their expression. Fbxl10 overexpression in HSCs leads to G0/G1-to-S transition acceleration, progenitor cell expansion, and development of myeloid or B-lymphoid leukemia with complete penetrance in transgenic mice.\",\n      \"method\": \"ChIP-seq, transgenic mouse model (HSC-specific overexpression), gene expression analysis, metabolic profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, transgenic mouse with defined leukemia phenotype, single lab\",\n      \"pmids\": [\"25872778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fbxl10 deficiency causes increased apoptosis in neuroepithelium and mesenchyme during embryonic development, associated with increased p19ARF expression, leading to neural tube defects and exencephaly. Fbxl10 thus regulates cell proliferation and death in neural progenitors via p19ARF suppression.\",\n      \"method\": \"Fbxl10 knockout mouse generation, in situ hybridization, apoptosis analysis (TUNEL), p19ARF expression analysis\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout mouse with defined neural phenotype and molecular mechanism, single lab\",\n      \"pmids\": [\"21220025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Alternative short isoforms of KDM2B (KDM2B-SF), lacking the N-terminal demethylase domain, bind CpG island promoters of Wnt target genes (Axin2, Cyclin D1) and repress their expression. KDM2B-SF interacts with TCF7L1, a Wnt transcriptional mediator, to repress Wnt-responsive transcription. The DNA-binding domain is required for this repression; the demethylase domain is dispensable.\",\n      \"method\": \"Luciferase reporter assay (Wnt-responsive), ChIP at Axin2/CyclinD1 promoters, Co-IP (KDM2B-SF with TCF7L1), isoform overexpression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, luciferase reporter, domain mapping, single lab\",\n      \"pmids\": [\"33104714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM2B, via its chromatin-association (CxxC) domain, transcriptionally silences Wnt signaling genes in hippocampal neural progenitors. Loss of the CxxC domain reduces polycomb repressive complex enrichment at Wnt gene loci, de-repressing Wnt signaling, impairing neural progenitor migration/differentiation, and causing hippocampal hypoplasia and spatial memory deficits.\",\n      \"method\": \"Conditional CxxC-domain deletion mouse (Kdm2b^ΔCxxC), ChIP-seq (PRC marks), RNA-seq, behavioral testing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined molecular mechanism (reduced PRC marks at Wnt genes), ChIP-seq, behavioral phenotype, epistasis by Wnt activation recapitulating KDM2B loss\",\n      \"pmids\": [\"37838801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of the CxxC-ZF domain of KDM2B impairs PRC1 recruitment to chromatin in neural stem cells, causing de-repression of apoptosis/cell-cycle-arrest/senescence genes, loss of NSC populations, and ASD/ID-like behavioral deficits in mice. Establishes causality between KDM2B-PRC1 chromatin regulation and ASD/ID-like phenotypes.\",\n      \"method\": \"Kdm2b CxxC-domain knock-in mouse, ChIP (PRC1 occupancy), RNA-seq, behavioral phenotyping\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-specific KI mouse, ChIP showing PRC1 loss, RNA-seq, defined behavioral phenotype\",\n      \"pmids\": [\"35128353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CxxC domain variants of KDM2B significantly reduce its DNA-binding ability without affecting protein expression, causing a distinct neurodevelopmental syndrome (developmental delay, congenital heart defects, intellectual disability) that differs clinically from haploinsufficiency. Functional assays confirm reduced DNA binding as the mechanism for CxxC-variant pathogenicity.\",\n      \"method\": \"DNA-binding assay (functional assay with CxxC mutants), protein expression assays, cohort clinical analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional DNA-binding assay with multiple CxxC variants, large cohort, single lab\",\n      \"pmids\": [\"40420380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM2B promotes IL-6-mediated inflammatory responses in macrophages by interacting with Brg1 (SWI/SNF). KDM2B knockdown in macrophages reduces IL-6 but not TNF-α, IL-1, or IFN-β, and KDM2B-deficient mice resist endotoxin shock with decreased IL-6.\",\n      \"method\": \"KDM2B conditional KO mice, ChIP (KDM2B at Il6 promoter), Co-IP (KDM2B-Brg1), ELISA\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic overlap with PMID 31197256 (same Brg1 interaction), confirmatory rather than novel, single lab\",\n      \"pmids\": [\"31041569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXL10 stabilizes ERRα protein by reducing its poly-ubiquitylation and promoting its mono-ubiquitylation, increasing ERRα transcriptional activity and ERRα enrichment at target gene promoters. FBXL10 facilitates ERRα/PGC1β-mediated proliferation and tumorigenesis in breast cancer.\",\n      \"method\": \"Co-IP (FBXL10-ERRα), ubiquitylation assay, reporter gene assay, ChIP (ERRα at target promoters), in vitro/in vivo proliferation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitylation assay, ChIP, functional assays, single lab\",\n      \"pmids\": [\"33450359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXL10 promotes EMT in breast cancer by interacting specifically with SNAI1 (not Slug or ZEB1), enhancing SNAI1 transcriptional repression of CDH1 by facilitating the interaction between SNAI1 and HDAC1, thereby promoting SNAI1 deacetylation. Deacetylated SNAI1 more potently suppresses E-cadherin transcription.\",\n      \"method\": \"Co-IP (FBXL10-SNAI1, SNAI1-HDAC1), reporter assay (CDH1 promoter), in vitro/in vivo migration/invasion assays, mouse lung metastasis model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, reporter assays, in vivo model, single lab\",\n      \"pmids\": [\"34718323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM2B, functioning in the context of ncPRC1.1, regulates amino acid metabolism including SGOC, glutamate, and GSH pathways by enhancing chromatin accessibility and expression of MYC and ATF4. KDM2B co-occupies promoters of transcriptionally active metabolic genes together with MYC and ATF4, and regulates the expression and transcriptional activity of MYC.\",\n      \"method\": \"ChIP-seq, ATAC-seq, RNA-seq, TMT proteomics, global metabolomics, shRNA knockdown in TNBC cells\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics strategy, ChIP-seq, ATAC-seq, single lab\",\n      \"pmids\": [\"37935302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DHX9 (DNA/RNA helicase) collaborates with KDM2B to regulate YAP1 expression in Ewing sarcoma. DHX9 enhances H3K9 chromatin demethylation by KDM2B and favors RNA Polymerase II recruitment to the YAP1 promoter. EWS-FLI1 binding to the YAP1 promoter antagonizes this activation.\",\n      \"method\": \"Co-IP (DHX9-KDM2B), ChIP (H3K9me, RNA Pol II), RNA-seq, shRNA depletion\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP, ChIP, single lab; H3K9 demethylase activity not directly demonstrated for KDM2B in prior work\",\n      \"pmids\": [\"38017132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM2B overexpression activates FAK signaling and PI3K (p85 subunit upregulation) in prostate and colon cancer cells, promoting cell migration. KDM2B depletion reduces FAK activity and p85-PI3K without altering FAK gene expression/protein levels. KDM2B-driven migration is abolished by PI3K inhibitor LY294002.\",\n      \"method\": \"Western blot (FAK/PI3K activity), shRNA knockdown, wound-healing migration assay, LY294002 inhibition\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — biochemical assays, no direct mechanistic link between KDM2B and FAK established, single lab\",\n      \"pmids\": [\"32175798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM2B is required for KDM2B-mediated transcriptional repression of NOTCH1 target genes in T-cell leukemia via PRC1.1. Kdm2b-deficient mice (lacking the CxxC domain) develop NOTCH1-dependent T-ALL, similar to Bcor-deficient mice, indicating PRC1.1 restricts excessive NOTCH1-mediated gene activation as a tumor suppressor.\",\n      \"method\": \"CxxC-domain specific KO mice, ChIP-seq (KDM2B, BCOR, EZH2, H2AK119ub1, H3K4me3, H3K27me3), RNA-seq, T-ALL mouse model\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional domain-specific KO, ChIP-seq with multiple histone marks, in vivo leukemia model with defined pathway (NOTCH1 antagonism)\",\n      \"pmids\": [\"31471323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM2B regulates KDM2B-mediated H2AK119 monoubiquitination as a component of PRC1 to repress CDH1, miR200a, and CGN during TGF-β-induced EMT. KDM2B recruits EZH2 and induces H3K27 methylation at these loci. The DNA-recognition property (CxxC domain) but not demethylase activity is required for this function.\",\n      \"method\": \"ChIP (H2AK119ub1, EZH2 recruitment), KDM2B domain mutants, shRNA knockdown, morphological EMT assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, domain mutants separating DNA-binding from demethylase, functional EMT assays, single lab\",\n      \"pmids\": [\"33779563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM2B directly binds the promoter region of MOB1 and suppresses its promoter activity, transcriptionally inhibiting MOB1 expression to regulate the Hippo pathway and promote PDAC proliferation/migration/invasion.\",\n      \"method\": \"ChIP (KDM2B at MOB1 promoter), luciferase reporter assay (MOB1 promoter), shRNA knockdown, rescue experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, luciferase reporter, functional assays, single lab\",\n      \"pmids\": [\"31941533\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM2B is a multi-domain chromatin regulator that: (1) demethylates histone H3K36me1/2 (and possibly H3K4me3 and H3K79me2/3) via its JmjC domain; (2) specifically recognizes unmethylated CpG island DNA via its CxxC zinc-finger domain and recruits a noncanonical PRC1 complex (PRC1.1, containing RING1B/RNF2, PCGF1, BCOR/BCORL1, and SKP1) to catalyze H2AK119 monoubiquitylation and gene repression; (3) acts as an F-box subunit of an SCF E3 ubiquitin ligase to target substrates including c-Fos for proteolysis; (4) represses rRNA gene transcription in the nucleolus by demethylating H3K4me3 at rDNA; (5) protects Polycomb-occupied CpG island promoters from aberrant de novo DNA methylation; (6) co-operates with EZH2/PRC2 and silences tumor-suppressor miRNAs (let-7, miR-101) to sustain EZH2 expression; and (7) is recruited to DNA damage sites via PARP1/TIMELESS to promote H2A.Z loading and homologous recombination repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM2B (FBXL10/JHDM1b) is a multi-domain chromatin regulator that links sequence-specific recognition of CpG island DNA to Polycomb-mediated gene silencing, and that also possesses Jumonji-domain histone demethylase and F-box-dependent ubiquitin-ligase activities [#0, #3, #16]. Its defining activity is recognition of non-methylated CpG islands through the CxxC zinc-finger domain, which recruits a noncanonical PRC1 complex (PRC1.1 containing RING1B/RNF2, PCGF1/NSPC1, BCOR/BCORL1, SKP1) to catalyze H2AK119 monoubiquitylation and repress target genes genome-wide [#0, #1, #2, #5]; the BCORL1 PUFD–PCGF1 RAWUL interface defines an architecture unique to PRC1.1 and explains how KDM2B engages both PRC1.1 and an SCF ubiquitin ligase [#6]. Both DNA binding and PRC1 integration are required for H2AK119ub1, and KDM2B loss collapses RING1B chromatin occupancy [#1]. Through this PRC1.1 axis KDM2B maintains the undifferentiated ESC state, drives somatic reprogramming, protects Polycomb-bound promoters from aberrant de novo DNA methylation, and restrains lineage- and signaling-specific gene programs including NOTCH1 and Wnt targets [#2, #12, #26, #43, #34]. Independently, the JmjC domain demethylates H3K36me1/2 — silencing the p15(Ink4b) and Ink4a/Arf loci to control senescence, proliferation, and leukemic transformation — and removes H3K4me3 at rDNA to repress rRNA transcription in the nucleolus [#3, #4, #8, #7]; reported additional substrates include H3K79me2/3 and the non-histone protein SRF [#17, #23]. As an F-box subunit, KDM2B assembles an SCF E3 ligase that polyubiquitylates c-Fos for degradation [#16]. KDM2B sustains EZH2 expression by demethylating H3K36me2 at tumor-suppressor miRNA loci (let-7, miR-101) [#10, #25], and is recruited to DNA damage sites via PARP1/TIMELESS to promote H2A.Z loading and homologous recombination [#18]. Loss or CxxC-domain variants of KDM2B cause neurodevelopmental syndromes via failed PRC1 recruitment and Wnt de-repression [#34, #35, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the first functional activities of KDM2B: nucleolar repression of rRNA transcription via JmjC-dependent H3K4me3 demethylation, and tethering of repressor complexes to unmethylated CpG DNA via the CxxC zinc finger, framing it as a chromatin-targeted repressor.\",\n      \"evidence\": \"Nucleolar localization with rDNA ChIP and in vitro demethylase assay; Co-IP/ChIP at the c-jun promoter with CxxC DNA-binding assay; MS purification of a Ring1B complex containing KDM2B\",\n      \"pmids\": [\"17994099\", \"17704768\", \"17296600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"H3K4me3 substrate assignment later contested by H3K36 demethylase findings\", \"noncanonical Ring1B complex composition defined biochemically but not reconstituted\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined KDM2B's core enzymatic identity as an H3K36 demethylase and connected it to senescence control, showing it represses p15(Ink4b) in an activity-dependent manner.\",\n      \"evidence\": \"In vitro demethylase assay, ChIP, shRNA knockdown with genetic p15 rescue in MEFs\",\n      \"pmids\": [\"18836456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism linking H3K36 demethylation to recruitment of repressive machinery not resolved\", \"does not address CpG-island/PRC1 function\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked KDM2B to the broader Polycomb network, showing it counteracts senescence-associated EZH2 loss and promotes H3K27me3 and BMI1 binding at Ink4a/Arf, positioning it upstream of PRC2/PRC1 output.\",\n      \"evidence\": \"ChIP, KDM2B–EZH2 Co-IP, shRNA knockdown and histone-modification analysis in MEFs\",\n      \"pmids\": [\"19202064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct vs indirect basis of EZH2 cooperation unresolved\", \"single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed KDM2B sustains EZH2 by silencing EZH2-targeting tumor-suppressor miRNAs through locus-specific H3K36me2 demethylation, and established its requirement for leukemic transformation.\",\n      \"evidence\": \"ChIP, shRNA, miRNA gain/loss epistasis in MEFs; retroviral transformation and in vivo leukemia models with H3K36me2 demethylase assay; FGF2–DYRK1A–CREB induction with reporter assays\",\n      \"pmids\": [\"21757686\", \"21310926\", \"21777817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"feedback-loop kinetics in primary tissue not addressed\", \"miRNA-locus demethylation shown by ChIP but not directly causally separated from PRC1 effects\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the central CpG-island-targeting model: KDM2B binds unmethylated CGIs genome-wide via CxxC and recruits PRC1 to deposit H2AK119ub1, providing a sampling mechanism for Polycomb silencing, and enables iPSC reprogramming.\",\n      \"evidence\": \"Genome-wide ChIP-seq, Co-IP, domain mutagenesis in mouse ESCs; reprogramming assays with demethylase/DNA-binding mutants\",\n      \"pmids\": [\"23256043\", \"22522173\", \"22825849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"conflicting in vitro substrate assignment (H3K4me3 vs H3K36me2) in one study\", \"how low-occupancy sampling is converted to stable repression unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the noncanonical PRC1.1 requirement, showing both DNA binding and PRC1 integration are needed for H2AK119ub1 and RING1B recruitment, and that this axis maintains the ESC undifferentiated state and drives cancer gene programs.\",\n      \"evidence\": \"Co-IP, genome-wide ChIP-seq, domain-mutant rescue in mESCs; ChIP-seq and gain/loss-of-function in PDAC model\",\n      \"pmids\": [\"23395003\", \"23502314\", \"23321669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"dual repressive (Polycomb) and activating (MYC/KDM5A) programs mechanistically distinct but switch undefined\", \"stoichiometry of KDM2B within PRC1.1 in vivo unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated a protective genomic function: KDM2B shields Polycomb-occupied CpG-island promoters from de novo DNA methylation, with loss causing midgestation lethality not phenocopied by PRC mutants.\",\n      \"evidence\": \"Complete and conditional mouse knockout with whole-genome bisulfite sequencing and ChIP; HSC overexpression transgenic leukemia model\",\n      \"pmids\": [\"25848754\", \"25872778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular basis for excluding DNMTs from CGIs not defined\", \"relationship between methylation protection and H2AK119ub1 deposition unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established KDM2B's second catalytic identity as an F-box SCF E3 ligase subunit targeting c-Fos, and solved the structure explaining how it bridges PRC1.1 and SCF, while extending PRC1.1 recruitment to non-stem contexts.\",\n      \"evidence\": \"Crystal structure of KDM2B/SKP1/BCORL1/PCGF1; in vitro ubiquitylation assay and S374 mutagenesis for c-Fos; ChIP-seq/domain analysis in adipogenesis; KO mouse hematopoietic studies\",\n      \"pmids\": [\"27568929\", \"26725323\", \"25533466\", \"26808549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"full substrate repertoire of SCF^KDM2B beyond c-Fos unknown\", \"regulation of switching between PRC1.1 and SCF assembly in cells undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected KDM2B to genome maintenance and expanded its substrate scope, showing PARP1/TIMELESS-dependent recruitment to DNA damage sites for H2A.Z loading and HR, and reporting H3K79 demethylase activity.\",\n      \"evidence\": \"Live-cell recruitment imaging, ChIP, HR assays for FRRUC; in vitro H3K79 demethylase assay with genome-wide validation; Co-IP/ChIP for EBNA3C interaction\",\n      \"pmids\": [\"29985131\", \"29763382\", \"29502955\", \"30135119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"H3K79 demethylase activity is a novel substrate claim needing independent replication\", \"how FRRUC composition relates to PRC1.1 at undamaged chromatin unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended KDM2B mechanisms to S-phase control and demethylase-independent gene regulation, showing H3K79 demethylation governs PCNA dissociation and that DNA-binding (not catalysis) drives EMT and Wnt repression.\",\n      \"evidence\": \"iPOND, ITC, DNA fiber assays in 293T cells; ChIP/domain mutants for EMT and TGF-β; isoform Co-IP with TCF7L1\",\n      \"pmids\": [\"33029857\", \"33779563\", \"33104714\", \"33091189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"replication-timing role depends on contested H3K79 activity\", \"demethylase-independent functions mechanistically attributed to PRC1 recruitment but not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified non-histone and stabilization-based functions, including SRF K165 demethylation balanced by SET7, ERRα and SNAI1 stabilization, and Brg1-dependent IL-6 induction.\",\n      \"evidence\": \"In vitro demethylase assay on SRF, Co-IP, ChIP, ubiquitylation assays, KO mouse phenotypes\",\n      \"pmids\": [\"33564100\", \"33450359\", \"34718323\", \"31197256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"non-histone substrate generality unknown\", \"how a single protein partitions among demethylase, ligase, and scaffold roles in a given cell undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established causal links between the CxxC-PRC1 axis and neurodevelopmental disease, and tied KDM2B/PRC1.1 to metabolic gene regulation via MYC/ATF4.\",\n      \"evidence\": \"CxxC-domain conditional KO/knock-in mice with ChIP-seq, RNA-seq, and behavioral phenotyping; multi-omics in TNBC cells; CxxC-variant DNA-binding functional assays in patient cohort\",\n      \"pmids\": [\"37838801\", \"35128353\", \"37935302\", \"40420380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"distinction between CxxC-variant syndrome and haploinsufficiency mechanism still being defined\", \"tissue-specific selection of KDM2B target programs not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KDM2B selects among its mutually exclusive activities — JmjC demethylation, PRC1.1 scaffolding, and SCF-type ubiquitin ligation — at specific loci and in specific cell types, and which reported histone substrates (H3K4me3, H3K79, H3K9) are bona fide in vivo, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no unified model partitioning catalytic vs scaffold functions\", \"conflicting substrate assignments across labs\", \"regulation of PRC1.1-vs-SCF assembly switching unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 4, 8, 17, 23]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [3, 4, 8]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 13, 36]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [16, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 14, 43, 34]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 2, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 4, 14, 43]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 26, 34, 35]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 14, 36]}\n    ],\n    \"complexes\": [\n      \"PRC1.1 (noncanonical PRC1)\",\n      \"SCF^KDM2B (CRL1) E3 ubiquitin ligase\",\n      \"FRRUC (FBXL10-RNF68-RNF2)\"\n    ],\n    \"partners\": [\n      \"RING1B/RNF2\",\n      \"PCGF1/NSPC1\",\n      \"BCOR/BCORL1\",\n      \"SKP1\",\n      \"EZH2\",\n      \"BRG1\",\n      \"TIMELESS\",\n      \"PARP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}