{"gene":"KDM2B","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2012,"finding":"KDM2B (FBXL10) specifically recognizes non-methylated CpG islands via its CxxC zinc-finger domain and recruits Polycomb Repressive Complex 1 (PRC1) to these sites, contributing to histone H2A lysine 119 ubiquitylation (H2AK119ub1) and gene repression genome-wide.","method":"Genome-wide ChIP-seq, co-immunoprecipitation, biochemical domain analysis, CxxC domain binding assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (ChIP-seq, Co-IP, biochemical binding assays), replicated across multiple independent labs","pmids":["23256043"],"is_preprint":false},{"year":2013,"finding":"Fbxl10/KDM2B interacts with Ring1B and Nspc1 (PCGF1), forming a noncanonical PRC1 complex (ncPRC1) required for H2AK119ub1 in mouse ESCs; Fbxl10 depletion causes loss of Ring1B binding to target genes and major loss of H2AK119ub1, and its DNA-binding capability and PRC1 integration are both required for ubiquitylation.","method":"Co-immunoprecipitation, genome-wide ChIP-seq, knockdown/rescue with domain mutants, genetic epistasis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP, genome-wide ChIP, functional domain mutagenesis rescue; replicated by independent labs","pmids":["23395003"],"is_preprint":false},{"year":2013,"finding":"Kdm2b maintains mESC pluripotency by binding CpG islands via its CxxC-ZF domain and recruiting PRC1 to repress lineage-specific genes; Oct4 and Sox2 directly regulate Kdm2b transcription, defining an Oct4-Sox2-Kdm2b-PRC1-CGI regulatory axis.","method":"ChIP, Co-IP, CxxC domain mutants, loss-of-function (knockdown), gene expression analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, Co-IP, domain mutants, KD phenotype), replicated finding","pmids":["23502314"],"is_preprint":false},{"year":2008,"finding":"KDM2B (Jhdm1b) is a histone H3 lysine 36 demethylase (H3K36me1/me2) that targets the p15(Ink4b) locus to repress its expression in an enzymatic activity-dependent manner, thereby regulating cell proliferation and cellular senescence.","method":"In vitro histone demethylase assay, ChIP, shRNA knockdown with p15Ink4b rescue epistasis, cell proliferation assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzymatic assay, ChIP, genetic epistasis rescue; replicated across multiple labs","pmids":["18836456"],"is_preprint":false},{"year":2007,"finding":"JHDM1B/KDM2B is a nucleolar protein that binds the transcribed region of ribosomal DNA and represses ribosomal RNA gene transcription through JmjC domain-dependent demethylation of H3K4me3 in the nucleolus.","method":"Subcellular fractionation/localization, ChIP on rDNA, RNAi knockdown, in vitro demethylase assay with JmjC domain mutants, cell size/proliferation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzymatic assay with domain mutants, ChIP, localization with functional consequence; highly cited foundational paper","pmids":["17994099"],"is_preprint":false},{"year":2007,"finding":"KDM2B (Fbxl10/JHDM1B) forms a novel complex with Ring1B/Rnf2 that also includes BCOR (BcoR), CK2α, Skp1, and Nspc1/PCGF1; this was identified as a distinct ncPRC1-like complex separate from canonical PRC1 and E2F6 complexes.","method":"In vivo biotinylation tagging, streptavidin pulldown, mass spectrometry proteomics, iterative complex purification","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 2 — high-throughput proteomics with iterative purification; replicated by subsequent independent studies","pmids":["17296600"],"is_preprint":false},{"year":2011,"finding":"KDM2B (NDY1) synergizes with EZH2 to repress miR-101 by co-binding its promoter; EZH2 binding to the miR-101 promoter depends on KDM2B, but KDM2B binds independently; this axis mediates FGF-2-driven cell proliferation, migration, and angiogenesis downstream of CREB/DYRK1A.","method":"ChIP, Co-IP, promoter reporter assays, shRNA knockdown, epistasis experiments, cell proliferation/migration/angiogenesis assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal ChIP, functional epistasis, multiple orthogonal assays","pmids":["21777817"],"is_preprint":false},{"year":2011,"finding":"KDM2B/JHDM1b silences p15(Ink4b) through active demethylation of H3K36me2 at the locus; ectopic KDM2B expression is sufficient to transform hematopoietic progenitors, and its depletion in leukemic stem cells impairs self-renewal in vitro and in vivo.","method":"Retroviral overexpression, shRNA knockdown, in vitro and in vivo transplantation assays, ChIP for H3K36me2","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — gain/loss-of-function with defined molecular mechanism (H3K36me2 at p15Ink4b), in vivo validation","pmids":["21310926"],"is_preprint":false},{"year":2009,"finding":"Ndy1/KDM2B represses the Ink4a/Arf locus by: (1) counteracting senescence-associated down-regulation of EZH2 via JmjC domain-dependent global H3K27me3 upregulation; (2) directly binding the Ink4a/Arf locus to demethylate H3K36me2 and H3K4me3; (3) promoting Bmi1 binding and blocking RNA Pol II recruitment.","method":"ChIP, Co-IP (Ndy1-Ezh2 interaction), demethylase assays, MEF immortalization assays, knockdown/overexpression","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — multiple ChIP experiments, Co-IP, functional mechanistic epistasis, replicated","pmids":["19202064"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the KDM2B/SKP1/BCORL1/PCGF1 tetrameric complex reveals that the BCORL1 PUFD domain positions residues preceding the PCGF1 RAWUL domain to create an extended interface for KDM2B interaction unique to PRC1.1; in vitro assembly identifies the minimal four-component PRC1.1 complex as two heterodimers (KDM2B/SKP1 and BCORL1/PCGF1).","method":"Crystal structure determination, in vitro complex assembly, biochemical pulldown assays, analytical ultracentrifugation","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with biochemical validation of assembly requirements","pmids":["27568929"],"is_preprint":false},{"year":2015,"finding":"Complete inactivation of Fbxl10 leads to dense de novo DNA methylation specifically at promoters co-occupied by FBXL10 and Polycomb repressive complexes, establishing FBXL10 as the first factor whose loss causes gain of genomic DNA methylation; this protection requires FBXL10 but not Polycomb components alone.","method":"Fbxl10 knockout mouse model, whole-genome bisulfite sequencing/methylation analysis, genetic epistasis with PRC1/PRC2 component knockouts","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — complete KO with genome-wide methylation analysis, genetic epistasis","pmids":["25848754"],"is_preprint":false},{"year":2013,"finding":"KDM2B drives pancreatic cancer through two distinct transcriptional mechanisms: (1) repression of developmental genes via co-binding with PcG proteins at transcriptional start sites; (2) activation of metabolic genes (protein synthesis, mitochondrial function) via co-binding with MYC and KDM5A.","method":"Gain/loss-of-function in cell lines and mouse models, genome-wide ChIP-seq, gene expression profiling, mouse PDAC model (KrasG12D cooperation)","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP, in vivo mouse models, gain and loss of function; multiple orthogonal approaches","pmids":["23321669"],"is_preprint":false},{"year":2012,"finding":"Kdm2b promotes iPSC generation by binding to and demethylating H3K36me2 at early responsive gene promoters, enhancing their activation at the beginning of reprogramming; this capacity depends on both demethylase and DNA-binding activities but is largely independent of its anti-senescence role.","method":"Retroviral overexpression in reprogramming, domain mutant rescue (demethylase-dead, DNA-binding mutants), ChIP for H3K36me2, gene expression during reprogramming time course","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — domain mutant epistasis, ChIP, mechanistic dissection of demethylase vs. DNA-binding requirements","pmids":["22522173"],"is_preprint":false},{"year":2018,"finding":"KDM2B is a histone H3K79 di- and trimethyl demethylase that induces transcriptional repression of HOXA7 and MEIS1 via occupancy of their promoters and H3K79 demethylation; KDM2B-knockdown increases global H3K79 methylation; KDM2B loss displaces SIRT1 from chromatin, increasing H4K16 acetylation.","method":"In vitro demethylase assay, genome-wide H3K79 methylation analysis (ChIP-seq), KDM2B knockdown stable cell lines, Co-IP for SIRT1","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro enzymatic assay plus genome-wide ChIP, single lab","pmids":["29763382"],"is_preprint":false},{"year":2018,"finding":"The FRRUC complex (FBXL10-RNF68-RNF2) is rapidly and transiently recruited to DNA damage sites in a PARP1- and TIMELESS-dependent manner, where it promotes H2AK119 mono-ubiquitylation, local H2A.Z incorporation, transcriptional repression, DSB signaling, and homologous recombination repair.","method":"Live-cell imaging at laser-induced DNA damage sites, Co-IP, ChIP, genetic knockdowns, epistasis with BMI1-RNF2 and MEL18-RNF2 complexes, HR repair assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional consequence, epistasis, multiple orthogonal methods in single rigorous study","pmids":["29985131"],"is_preprint":false},{"year":2018,"finding":"In synovial sarcoma, SS18-SSX1 oncoprotein physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B on unmethylated CpG islands; via KDM2B, SS18-SSX1 aberrantly activates developmental genes normally silenced by polycomb; KDM2B depletion restores repression and causes irreversible mesenchymal differentiation.","method":"Co-IP, ChIP-seq, functional genomics screen, loss-of-function differentiation assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, genome-wide ChIP-seq, functional genomics; rigorous mechanistic study","pmids":["29502955"],"is_preprint":false},{"year":2011,"finding":"KDM2B counteracts senescence-associated downregulation of EZH2 by silencing let-7b and miR-101 via locus-specific H3K36me2 demethylation at their genomic loci, thereby maintaining EZH2 levels and promoting cellular proliferation/immortalization.","method":"Retroviral overexpression, ChIP for H3K36me2 at miRNA loci, let-7b overexpression epistasis, KDM2B knockdown in multiple primary cell types","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP, genetic epistasis (let-7b rescue), multiple cell types, mechanistic dissection","pmids":["21757686"],"is_preprint":false},{"year":2007,"finding":"Fbl10/KDM2B interacts with c-Jun and represses c-Jun-mediated transcription; KDM2B binds unmethylated CpG sequences in the c-jun promoter via its CxxC zinc finger, tethers transcriptional repressor complexes, and requires c-Jun for its promoter recruitment; KDM2B protein is down-regulated in response to UV inversely correlating with c-Jun induction.","method":"Co-IP, ChIP, siRNA knockdown, luciferase reporter assays, UV treatment experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ChIP, reporter assays, functional knockdown; multiple orthogonal methods","pmids":["17704768"],"is_preprint":false},{"year":2016,"finding":"KDM2B, via its F-box domain, functions as a substrate recognition subunit of the SCF(KDM2B)/CRL1 E3 ubiquitin ligase complex to target c-Fos for polyubiquitylation and degradation; EGF-induced c-Fos S374 phosphorylation dissociates c-Fos from KDM2B, stabilizing c-Fos and enabling cell proliferation.","method":"Co-IP, in vitro ubiquitylation assay, phosphomimetic/non-phosphorylatable c-Fos mutants, EGF stimulation experiments, tumor-derived KDM2B mutation analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro ubiquitylation assay, domain mutants, phospho-mutant epistasis","pmids":["26725323"],"is_preprint":false},{"year":2014,"finding":"NDY1/KDM2B functions as a master regulator of PRC1 and PRC2 by silencing a set of miRNAs that target multiple polycomb complex members; NDY1 knockdown de-represses these miRNAs and down-regulates their polycomb targets, reducing cancer stem cell self-renewal and sphere formation.","method":"shRNA knockdown in multiple tumor cell lines, mammosphere assays, stem cell marker analysis (ALDH, CD44/CD24), miRNA profiling, epistasis (miRNA re-expression)","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cell lines, miRNA epistasis, CSC phenotype; single lab","pmids":["24853546"],"is_preprint":false},{"year":2011,"finding":"Fbxl10/KDM2B deficiency in mouse neural progenitor cells causes increased apoptosis, upregulation of p19ARF (an apoptosis inducer), increased neural progenitor mitosis, and neural tube closure failure leading to exencephaly.","method":"Fbxl10 knockout mouse generation, in situ hybridization, TUNEL assay, mitotic cell counting, p19ARF qRT-PCR in embryos and MEFs","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype and molecular mechanism (p19ARF), in vivo","pmids":["21220025"],"is_preprint":false},{"year":2019,"finding":"KDM2B promotes IL-6 production in macrophages independently of its demethylase activity by interacting with Brg1 (SWI/SNF ATPase subunit) to facilitate chromatin accessibility at the Il6 promoter and directly recruiting RNA Polymerase II; KDM2B-deficient mice show decreased IL-6 and resistance to endotoxin shock.","method":"Co-IP (KDM2B-Brg1 interaction), ChIP for chromatin accessibility and Pol II, KDM2B conditional KO mice, ELISA for IL-6, ATAC-seq","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ChIP, in vivo KO, demethylase-independent mechanism established by domain mutants","pmids":["31197256"],"is_preprint":false},{"year":2014,"finding":"FBXL10/KDM2B recruits a noncanonical PRC1 complex containing RING1B, SKP1, PCGF1, and BCOR to specific genomic loci (including Cdk1, Pparg1/2) to repress adipogenesis; this function requires the F-box and leucine-rich repeat domains but not the JmjC demethylase domain.","method":"ChIP-seq, Co-IP, domain deletion mutants, siRNA knockdown of RING1B/SKP1, 3T3-L1 differentiation assays","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq, domain mutant dissection, genetic epistasis with complex components","pmids":["25533466"],"is_preprint":false},{"year":2016,"finding":"KDM2B cooperates with polycomb and trithorax complexes to regulate hematopoietic stem and progenitor cell differentiation, lineage choice, cytokine signaling, and cell cycle; KDM2B has a dichotomous role—maintaining lymphoid leukemias but restraining RAS-driven myeloid transformation—depending on cellular context.","method":"Kdm2b-null mice, RNA-seq, ChIP-seq in human leukemias, HSPC transplantation assays","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with RNA-seq and genome-wide ChIP-seq, in vivo transplantation","pmids":["26808549"],"is_preprint":false},{"year":2017,"finding":"KDM2B regulates somatic reprogramming through PRC1.1 recruitment to CpG islands; BMP-SMAD signaling attenuates PRC1.1 occupancy and H2AK119 ubiquitylation at developmental gene loci, activating mesendodermal factors and suppressing reprogramming.","method":"ChIP for PRC1.1 components and H2AK119ub1, BMP4 treatment epistasis, reprogramming efficiency assays with domain mutants","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, genetic epistasis with BMP pathway; single lab","pmids":["29166607"],"is_preprint":false},{"year":2019,"finding":"KDM2B in PRC1.1 acts as a tumor suppressor in T-cell leukemogenesis by binding nonmethylated CpG island promoters via its CxxC domain and restricting excessive NOTCH1-mediated transcriptional activation via H2AK119ub1 deposition; Kdm2b-deficient mice develop NOTCH1-dependent T-ALL.","method":"Hematopoietic-specific CxxC domain deletion mice, ChIP-seq (KDM2B, BCOR, EZH2, H2AK119ub1, H3K4me3, H3K27me3), comparison with NOTCH1 target genes in human T-ALL","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 — domain-specific KO, genome-wide ChIP-seq, in vivo leukemia model","pmids":["31471323"],"is_preprint":false},{"year":2021,"finding":"KDM2B demethylates serum response factor (SRF) at K165 (non-histone target) to negatively regulate skeletal muscle differentiation; SET7 counteracts this by methylating SRF K165; SRF K165 methylation is required for transcriptional activation of SRF-dependent muscle genes and promoter occupancy.","method":"Co-IP (KDM2B-SRF interaction), in vitro demethylation assay on SRF, SET7 inhibitor treatment, ChIP for SRF at target promoters, gain/loss-of-function differentiation assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro demethylase assay on non-histone substrate, Co-IP, ChIP; single lab","pmids":["33564100"],"is_preprint":false},{"year":2018,"finding":"KDM2B mediates H2AK119 monoubiquitylation as a PRC1 component by recognizing regulatory regions of CDH1, miR200a, and CGN genes via its DNA-recognition property (not demethylase activity), inducing H2AK119ub1 and subsequent EZH2 recruitment and H3K27 methylation required for EMT-related gene repression during TGF-β-induced EMT.","method":"ChIP for H2AK119ub1 and H3K27me3, KDM2B domain mutants (DNA-binding vs. demethylase), knockdown/overexpression in lung/pancreatic cancer lines, TGF-β treatment","journal":"Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, domain mutant dissection, functional EMT phenotype; single lab","pmids":["33779563"],"is_preprint":false},{"year":2019,"finding":"ELKS1 stabilizes KDM2B protein in mast cells, and KDM2B is an essential transcriptional regulator of Syntaxin 4 (STX4) and Stxbp2 expression required for mast cell degranulation.","method":"Mast cell-specific Elks1 conditional KO mice, Co-IP (ELKS1-KDM2B interaction), ChIP for KDM2B at Stx4/Stxbp2 promoters, degranulation assays in vitro and in vivo","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO in vivo, Co-IP, ChIP, functional degranulation assay; single lab","pmids":["32937583"],"is_preprint":false},{"year":2020,"finding":"KDM2B-mediated H3K79 demethylation facilitates PCNA dissociation from chromatin during S phase by abolishing H3K79me-dependent PCNA chromatin binding; KDM2B depletion causes aberrant PCNA retention on chromatin and impairs DNA replication efficiency.","method":"PCNA-H3K79me peptide pulldown, isothermal titration calorimetry (ITC), ChIP, iPOND, DNA fiber assay, flow cytometry, KDM2B-depleted cells and H3K79R histone mutants","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 1-2 — ITC quantitative binding, in vitro pulldown, multiple functional assays; single lab","pmids":["33029857"],"is_preprint":false},{"year":2019,"finding":"Tip60 acetyltransferase acetylates KDM2B at lysine 758, which decreases KDM2B's ability to bind nucleosomes and reduces its demethylase activity toward nucleosomal (but not bulk) histone substrates, diminishing KDM2B occupancy at p21 and puma promoters and promoting tumor growth.","method":"Co-IP, in vitro acetylation/demethylase assays with nucleosome vs. bulk histone substrates, K758 acetylation mutants, ChIP for KDM2B binding, tumor xenograft models","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro acetylation and demethylase assays, site-specific mutants, ChIP; single lab","pmids":["31218831"],"is_preprint":false},{"year":2021,"finding":"FBXL10/KDM2B stabilizes ERRα protein by reducing its polyubiquitylation and promoting its mono-ubiquitylation, thereby increasing ERRα transcriptional activity and promoter occupancy at ERRα target genes to facilitate breast cancer cell proliferation.","method":"Co-IP (mass spectrometry identification then validated), ubiquitylation assays (poly vs. mono-Ub), reporter gene assay, ChIP for ERRα, in vitro and in vivo proliferation/tumor assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitylation assays, ChIP, in vivo tumor model; single lab","pmids":["33450359"],"is_preprint":false},{"year":2021,"finding":"FBXL10/KDM2B promotes EMT and breast cancer metastasis by interacting with SNAI1 and facilitating SNAI1-HDAC1 interaction, resulting in SNAI1 deacetylation and enhanced transcriptional repression of CDH1/E-cadherin.","method":"Co-IP (FBXL10-SNAI1-HDAC1 ternary complex), reporter assays for CDH1 transcription, E-cadherin protein level measurements, lung metastasis mouse model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — ternary complex Co-IP, reporter assay, in vivo metastasis model; single lab","pmids":["34718323"],"is_preprint":false},{"year":2020,"finding":"Alternative short isoforms of KDM2B (KDM2B-SF), lacking the N-terminal demethylase domain but retaining CxxC and other domains, negatively regulate canonical Wnt signaling by binding Axin2 and cyclin D1 promoters and interacting with TCF7L1, repressing Wnt target gene transcription in a DNA-binding domain-dependent manner.","method":"Luciferase reporter assays (Wnt-responsive element), ChIP, Co-IP with TCF7L1, domain deletion mutant analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP, ChIP, reporter assays, domain mutants; single lab","pmids":["33104714"],"is_preprint":false},{"year":2023,"finding":"KDM2B controls hippocampal morphogenesis and neurogenesis by transcriptionally silencing Wnt signaling genes in neural progenitors through CxxC domain-dependent chromatin association and recruitment of Polycomb repressive complexes; loss of CxxC domain (Kdm2b∆CxxC mice) causes de-repression of Wnt genes, impaired neural progenitor migration/differentiation, and spatial memory deficits.","method":"Conditional CxxC domain deletion mice, ChIP for PRC marks, RNA-seq, behavioral testing (spatial memory, fear conditioning), lineage tracing, Wnt pathway activation rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — domain-specific KO in vivo, genome-wide ChIP, RNA-seq, genetic rescue; mechanistically rigorous","pmids":["37838801"],"is_preprint":false},{"year":2022,"finding":"Loss of KDM2B CxxC-ZF domain impairs PRC1 recruitment to chromatin in neural stem cells (NSCs), causing de-repression of apoptosis and cell-cycle arrest genes, NSC senescence, loss of NSC populations in mouse brain, and ASD/ID-like behavioral and memory deficits.","method":"CxxC domain mutant knock-in mice, ChIP for PRC1/H2AK119ub1, RNA-seq, NSC culture assays, behavioral phenotyping","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — domain-specific KI mouse, genome-wide ChIP, functional NSC assays, in vivo behavioral phenotype","pmids":["35128353"],"is_preprint":false},{"year":2018,"finding":"EBNA3C (EBV nuclear antigen) interacts with KDM2B, and this interaction is required for H3K4me3 removal at EBNA3C target gene promoters (COBLL1, ADAM28-ADAMDEC1 locus) and for full EBNA3C-mediated transcriptional repression in lymphoblastoid cells.","method":"Co-IP (EBNA3C-KDM2B), ChIP for H3K4me3 at target loci, recombinant EBV with EBNA3C RBPJ-motif mutants, gene expression analysis","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ChIP, recombinant virus genetic analysis; single lab","pmids":["30135119"],"is_preprint":false},{"year":2019,"finding":"KDM2B represses Choline Kinase α (CKα) expression by binding to its promoter (Box2) during neuroblast proliferation, maintaining the undifferentiated state; KDM2B knockdown enhances CKα expression and induces neuronal differentiation even without retinoic acid.","method":"ChIP (KDM2B at Chka promoter), siRNA knockdown, gain-of-function, retinoic acid differentiation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, gain/loss-of-function with defined promoter binding; single lab","pmids":["30629659"],"is_preprint":false},{"year":2023,"finding":"KDM2B, functioning in the ncPRC1.1 context, regulates amino acid metabolism (SGOC, glutamate, GSH pathways) by enhancing chromatin accessibility and expression of MYC and ATF4, with KDM2B co-occupying promoters of metabolic genes together with MYC and ATF4.","method":"Multi-omics (RNA-seq, quantitative TMT proteomics, metabolomics, ATAC-seq, ChIP-seq), shRNA knockdown in TNBC cell lines","journal":"Metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omics with ChIP-seq; single lab but comprehensive approach","pmids":["37935302"],"is_preprint":false},{"year":2016,"finding":"FBXL10 maintains silencing of DUSP6 (a phosphatase for ERK1/2) via recruitment of Polycomb group proteins and deposition of repressive histone modifications at the DUSP6 promoter, thereby maintaining ERK1/2 phosphorylation and promoting DLBCL cell proliferation.","method":"ChIP for PcG marks at DUSP6 promoter, RNA-seq, DUSP6 knockdown rescue of FBXL10-depleted cells, xenograft tumor model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, RNA-seq, genetic rescue epistasis, in vivo model; single lab","pmids":["29352142"],"is_preprint":false},{"year":2020,"finding":"KDM2B directly binds the MOB1 promoter and suppresses its transcriptional activity, thereby regulating the Hippo pathway; KDM2B promotes PDAC proliferation, migration, and invasion via MOB1 suppression.","method":"ChIP for KDM2B at MOB1 promoter, promoter luciferase assay, gain/loss-of-function with MOB1 epistasis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase reporter with genetic epistasis; single lab","pmids":["31941533"],"is_preprint":false},{"year":2019,"finding":"LncKdm2b (Kancr), divergently transcribed from a bidirectional promoter of Kdm2b, positively regulates Kdm2b transcription in cis by associating with hnRNPAB to facilitate a permissive chromatin environment at the Kdm2b promoter; LncKdm2b and Kdm2b are both required for proper differentiation and migration of cortical projection neurons.","method":"In vivo lineage tracing, phenotypic analysis, RNA-protein interaction (hnRNPAB pulldown), chromatin accessibility assays, CRISPRi knockdown","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo lineage tracing, RNA-protein interaction, chromatin assay; single lab","pmids":["31317506"],"is_preprint":false},{"year":2023,"finding":"DHX9 helicase enhances H3K9 chromatin demethylation by KDM2B at the YAP1 promoter and facilitates RNA Polymerase II recruitment, promoting YAP1 expression in Ewing sarcoma; DHX9 and KDM2B form a functional complex, and this axis is counteracted by EWS-FLI1 binding to the YAP1 promoter.","method":"Co-IP (DHX9-KDM2B), ChIP for H3K9me and Pol II at YAP1 promoter, transcriptome profiling, functional transformation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ChIP, transcriptome; single lab","pmids":["38017132"],"is_preprint":false},{"year":2021,"finding":"KDM2B inactivation via CRISPR-Cas9 genome-wide screen suppresses multiple heparan sulfate (HS) sulfotransferases and upregulates SULF1 sulfatase, altering HS structure and protein binding; KDM2B-deficient cell growth defects are rescued by SULF1 inactivation, establishing KDM2B as a master regulator of extracellular matrix gene expression.","method":"Genome-wide CRISPR-Cas9 screen, RNA-seq, HS sulfotransferase activity assays, SULF1 genetic epistasis","journal":"Nature chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide CRISPR screen with genetic epistasis and functional HS assays; single lab","pmids":["33846619"],"is_preprint":false},{"year":2025,"finding":"KDM2B CxxC domain missense variants significantly reduce its DNA-binding ability (measured functionally in vitro) while allowing protein expression; this DNA-binding impairment is the molecular mechanism distinguishing CxxC variants from haploinsufficiency variants, associated with a distinct neurodevelopmental syndrome phenotype.","method":"Functional DNA-binding assays with mutant KDM2B proteins, protein expression assays in vitro, clinical cohort correlation with episignature analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional in vitro DNA-binding assays with patient variants; clinical correlation supports mechanism","pmids":["40420380"],"is_preprint":false}],"current_model":"KDM2B is a multifunctional chromatin regulator that: (1) specifically recognizes unmethylated CpG islands via its CxxC zinc-finger domain to recruit a noncanonical PRC1.1 complex (containing RING1B, PCGF1, BCOR/BCORL1, and SKP1) that catalyzes H2AK119 monoubiquitylation and gene repression of developmental and lineage-specific genes; (2) acts as an H3K36me1/me2 demethylase (and also H3K79me2/3 demethylase) to regulate transcription at specific loci including p15Ink4b, Ink4a/Arf, and ribosomal RNA genes; (3) functions as an F-box subunit of SCF-E3 ubiquitin ligase to target substrates like c-Fos for proteasomal degradation; (4) is recruited to DNA damage sites via PARP1/TIMELESS to promote H2AK119ub1-dependent H2A.Z loading and homologous recombination repair; and (5) serves as a non-histone demethylase targeting SRF K165 to regulate muscle differentiation, collectively placing KDM2B at the intersection of Polycomb-mediated silencing, H3K36/K79/K4 demethylation, ubiquitin ligase activity, and DNA damage response."},"narrative":{"teleology":[{"year":2007,"claim":"Identification of KDM2B's core biochemical activities and interaction partners established it as both a histone demethylase and a PRC1-associated chromatin regulator, resolving what molecular functions this JmjC-domain protein performs.","evidence":"Proteomic identification of Ring1B/PCGF1/BCOR/SKP1 complex via biotin tagging and mass spectrometry; nucleolar localization and JmjC-dependent H3K4me3 demethylation at rDNA; CxxC-dependent binding to unmethylated CpG at the c-jun promoter with transcriptional repression","pmids":["17296600","17994099","17704768"],"confidence":"High","gaps":["Catalytic specificity toward different histone marks not yet systematically compared","Whether demethylase and PRC1 functions act at the same or distinct loci was unclear","No structural basis for complex assembly"]},{"year":2008,"claim":"Establishing KDM2B as an H3K36me2 demethylase at the p15Ink4b locus linked its enzymatic activity to a defined cell proliferation/senescence regulatory pathway.","evidence":"In vitro histone demethylase assay, ChIP at p15Ink4b, shRNA knockdown with epistasis rescue","pmids":["18836456"],"confidence":"High","gaps":["Whether H3K36me2 demethylation is sufficient or requires concurrent PRC1 activity at this locus","Substrate specificity in vivo beyond Ink4b not addressed"]},{"year":2009,"claim":"Demonstrating that KDM2B represses the Ink4a/Arf locus through a multi-layered mechanism—direct H3K36me2/H3K4me3 demethylation, indirect EZH2 stabilization, and Bmi1 recruitment—revealed how a single factor coordinates PRC1, PRC2, and demethylase activities to bypass senescence.","evidence":"ChIP for multiple histone marks, Co-IP for Ndy1-Ezh2, MEF immortalization with gain/loss-of-function","pmids":["19202064"],"confidence":"High","gaps":["Relative contribution of each mechanism to senescence bypass not quantified","Whether EZH2 stabilization is direct or via miRNA-mediated mechanism not resolved"]},{"year":2011,"claim":"Clarifying the miRNA-mediated axis through which KDM2B maintains EZH2 levels (by silencing let-7b and miR-101 via H3K36me2 demethylation) and demonstrating KDM2B-EZH2 co-occupancy at miR-101 connected KDM2B's demethylase function to a broader Polycomb maintenance circuit.","evidence":"ChIP at miRNA loci, epistasis with let-7b overexpression, Co-IP and ChIP for KDM2B-EZH2 co-binding at miR-101 promoter, functional proliferation/migration assays","pmids":["21757686","21777817"],"confidence":"High","gaps":["Whether EZH2 regulation is the primary or accessory function of KDM2B in proliferating cells","Generality of this miRNA axis beyond the cell types tested"]},{"year":2011,"claim":"In vivo knockout revealed that KDM2B is required for neural tube closure through regulation of p19ARF, establishing its physiological necessity in development beyond cultured cells.","evidence":"Fbxl10 knockout mouse, TUNEL and mitotic assays in neural progenitors, p19ARF qRT-PCR","pmids":["21220025"],"confidence":"Medium","gaps":["Whether the neural tube phenotype reflects demethylase or PRC1 function not resolved","Contribution of other Ink4a/Arf locus products not fully dissected"]},{"year":2012,"claim":"Genome-wide demonstration that KDM2B's CxxC domain targets it to unmethylated CpG islands to recruit PRC1 and deposit H2AK119ub1 genome-wide resolved the long-standing question of how PRC1 finds its targets independently of PRC2.","evidence":"Genome-wide ChIP-seq for KDM2B and PRC1 components, CxxC domain binding assays, Co-IP","pmids":["23256043"],"confidence":"High","gaps":["How CpG island targeting is modulated at different loci not addressed","Contribution of other CxxC-containing proteins to the same pathway"]},{"year":2012,"claim":"KDM2B's role in somatic cell reprogramming was shown to depend on H3K36me2 demethylation at early-responsive gene promoters rather than its anti-senescence activity, functionally separating its demethylase and Ink4a/Arf regulatory roles.","evidence":"Retroviral overexpression in reprogramming, demethylase-dead and DNA-binding mutant rescue, ChIP for H3K36me2 during reprogramming time course","pmids":["22522173"],"confidence":"High","gaps":["Whether PRC1 recruitment also contributes to reprogramming efficiency","Generality beyond mouse reprogramming system"]},{"year":2013,"claim":"Defining the PRC1.1 complex composition and demonstrating its requirement for H2AK119ub1 in ESCs, combined with the finding that Oct4/Sox2 regulate Kdm2b transcription, placed KDM2B at the center of a core pluripotency-Polycomb regulatory circuit.","evidence":"Reciprocal Co-IP, genome-wide ChIP-seq in mESCs, knockdown/rescue with domain mutants","pmids":["23395003","23502314"],"confidence":"High","gaps":["Redundancy with other ncPRC1 complexes in ESCs not fully resolved","How Kdm2b expression is regulated beyond Oct4/Sox2"]},{"year":2013,"claim":"Discovery of KDM2B's dual transcriptional role—repressing developmental genes with Polycomb while activating metabolic genes with MYC/KDM5A—in pancreatic cancer established it as a bifunctional chromatin regulator rather than a dedicated repressor.","evidence":"Genome-wide ChIP-seq, gene expression profiling, gain/loss-of-function in mouse PDAC model","pmids":["23321669"],"confidence":"High","gaps":["Structural basis for switching between repressive and activating complexes unknown","Whether MYC interaction is direct or chromatin-proximity-mediated"]},{"year":2015,"claim":"Complete Fbxl10 inactivation caused de novo DNA methylation specifically at Polycomb/FBXL10-co-occupied promoters, establishing KDM2B as the first factor whose loss causes gain of DNA methylation and revealing an unexpected link between CpG island PRC1 recruitment and DNA methylation protection.","evidence":"Fbxl10 knockout mouse, whole-genome bisulfite sequencing, genetic epistasis with PRC1/PRC2 knockouts","pmids":["25848754"],"confidence":"High","gaps":["Mechanism by which KDM2B/PRC1 prevents DNMT access not elucidated","Whether this is a direct or indirect effect of H2AK119ub1 loss"]},{"year":2016,"claim":"Crystal structure of the KDM2B/SKP1/BCORL1/PCGF1 tetramer revealed the architectural basis for PRC1.1 assembly, showing that BCORL1 creates a unique extended interface for KDM2B recruitment distinct from other PRC1 variants.","evidence":"Crystal structure determination, in vitro complex assembly, analytical ultracentrifugation","pmids":["27568929"],"confidence":"High","gaps":["No structure of full PRC1.1 with RING1B or DNA/nucleosome substrate","How the F-box/LRR region integrates with SCF versus PRC1 architecturally"]},{"year":2016,"claim":"Identification of KDM2B as an SCF E3 ubiquitin ligase F-box subunit that targets c-Fos for degradation established a non-chromatin enzymatic function and revealed a phosphorylation-dependent switch controlling substrate release.","evidence":"In vitro ubiquitylation assay, Co-IP, phosphomimetic c-Fos mutants, EGF stimulation","pmids":["26725323"],"confidence":"High","gaps":["Full substrate repertoire of SCF(KDM2B) unknown","How cells balance KDM2B between PRC1.1 and SCF complexes"]},{"year":2016,"claim":"Comprehensive analysis of Kdm2b-null hematopoietic stem cells revealed context-dependent roles—maintaining lymphoid leukemias but restraining RAS-driven myeloid transformation—demonstrating that KDM2B's function is not uniformly oncogenic or tumor-suppressive.","evidence":"Kdm2b-null mice, RNA-seq, ChIP-seq in human leukemias, HSPC transplantation","pmids":["26808549"],"confidence":"High","gaps":["Molecular basis for cell-type-specific oncogenic versus tumor-suppressive switching not defined","Role of specific KDM2B domains in each context not dissected"]},{"year":2018,"claim":"Discovery that the FRRUC complex (FBXL10-RNF68-RNF2) is recruited to DNA damage sites via PARP1/TIMELESS to catalyze H2AK119ub1 and promote H2A.Z loading and homologous recombination extended KDM2B's function beyond transcriptional regulation into the DNA damage response.","evidence":"Live-cell imaging at laser-induced damage sites, Co-IP, ChIP, epistasis with canonical PRC1, HR repair assays","pmids":["29985131"],"confidence":"High","gaps":["Structural basis for PARP1/TIMELESS-mediated recruitment unknown","Whether FRRUC and PRC1.1 are the same or distinct complexes at damage sites","Relative contribution versus canonical PRC1 in DDR"]},{"year":2018,"claim":"Demonstrating KDM2B demethylase activity toward H3K79me2/me3 expanded its substrate repertoire beyond H3K36/K4 and identified HOXA7/MEIS1 repression as a functional consequence, with implications for leukemia gene regulation.","evidence":"In vitro demethylase assay on H3K79 substrates, genome-wide H3K79me ChIP-seq, SIRT1 displacement analysis","pmids":["29763382"],"confidence":"Medium","gaps":["H3K79 demethylase activity not independently confirmed by a second lab","Relative catalytic efficiency toward H3K79 versus H3K36 not quantified"]},{"year":2019,"claim":"KDM2B was shown to activate IL-6 transcription independently of its demethylase activity by recruiting Brg1 (SWI/SNF) and RNA Polymerase II, revealing a scaffolding/transcriptional activation mode distinct from its canonical repressive functions.","evidence":"Co-IP for KDM2B-Brg1, ChIP for Pol II, ATAC-seq, conditional KO mice with endotoxin challenge","pmids":["31197256"],"confidence":"High","gaps":["Whether SWI/SNF cooperation is widespread or locus-specific","Structural basis for demethylase-independent activation unclear"]},{"year":2019,"claim":"Establishing KDM2B CxxC domain deletion as sufficient to cause NOTCH1-dependent T-ALL in mice demonstrated that PRC1.1-mediated silencing at CpG islands restrains oncogenic signaling and identified a tumor suppressor function.","evidence":"Hematopoietic-specific CxxC domain deletion, genome-wide ChIP-seq for PRC marks, comparison with NOTCH1 targets in human T-ALL","pmids":["31471323"],"confidence":"High","gaps":["Whether pharmacological restoration of PRC1.1 could treat T-ALL","Mechanism by which PRC1.1 specifically restrains NOTCH1 targets not fully defined"]},{"year":2020,"claim":"KDM2B-mediated H3K79 demethylation was linked to PCNA chromatin dissociation during S phase, connecting KDM2B enzymatic activity to DNA replication control beyond transcriptional regulation.","evidence":"PCNA-H3K79me peptide pulldown, ITC binding measurements, iPOND, DNA fiber assay, histone mutant epistasis","pmids":["33029857"],"confidence":"Medium","gaps":["H3K79 demethylase activity of KDM2B still awaits independent replication","In vivo replication phenotype not assessed in animal models"]},{"year":2021,"claim":"Identification of SRF K165 as a non-histone demethylation target of KDM2B established that its enzymatic activity extends to transcription factor regulation, modulating skeletal muscle differentiation.","evidence":"In vitro demethylation assay on SRF, Co-IP, ChIP for SRF at muscle gene promoters, differentiation assays","pmids":["33564100"],"confidence":"Medium","gaps":["Full non-histone substrate repertoire unexplored","In vivo muscle phenotype in Kdm2b-deficient animals not reported"]},{"year":2022,"claim":"CxxC domain-specific knock-in mice showed that impaired PRC1 recruitment in neural stem cells causes senescence, NSC loss, and ASD/ID-like behavioral deficits, directly linking KDM2B-PRC1.1 to neurodevelopmental phenotypes.","evidence":"CxxC domain mutant knock-in mice, ChIP for PRC1/H2AK119ub1, RNA-seq, NSC assays, behavioral phenotyping","pmids":["35128353"],"confidence":"High","gaps":["Whether phenotype is entirely PRC1-dependent or involves demethylase-independent scaffolding","Human genetic validation not yet available at this time point"]},{"year":2023,"claim":"In vivo CxxC deletion demonstrated KDM2B controls hippocampal neurogenesis by silencing Wnt signaling genes through Polycomb recruitment, causing spatial memory deficits when lost, and multi-omics in cancer cells revealed KDM2B/PRC1.1 regulates amino acid metabolism via MYC/ATF4 co-occupancy.","evidence":"Conditional CxxC deletion mice with behavioral testing and Wnt rescue; multi-omics (RNA-seq, proteomics, metabolomics, ATAC-seq, ChIP-seq) in TNBC cells","pmids":["37838801","37935302"],"confidence":"High","gaps":["Whether Wnt de-repression is the sole driver of hippocampal defects","Generality of metabolic regulation across cancer types"]},{"year":2025,"claim":"Functional characterization of patient-derived KDM2B CxxC missense variants confirmed that reduced DNA-binding ability is the molecular mechanism underlying a neurodevelopmental syndrome, providing the genotype-to-mechanism link for human disease.","evidence":"In vitro DNA-binding assays with mutant proteins, protein expression assays, episignature analysis in clinical cohort","pmids":["40420380"],"confidence":"Medium","gaps":["Whether CxxC variants affect PRC1.1 recruitment genome-wide in patient cells not yet shown","Therapeutic approaches not explored","Independent replication of episignature needed"]},{"year":null,"claim":"Key unresolved questions include: how KDM2B partitions between PRC1.1, SCF, and FRRUC complexes in a single cell; the full non-histone substrate repertoire; the structural basis for switching between repressive and activating transcriptional roles; and whether the H3K79 demethylase activity represents a major or minor catalytic function in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full PRC1.1 on chromatin","Partitioning between PRC1.1 and SCF complexes not measured","H3K79 demethylase activity not independently replicated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,4,8,13,26]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,2,17,44]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,4,8,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,11,21,33]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,31]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,14]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1,14]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,2,3,4,8,10,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,6,11,17,21]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[20,34,35]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[18,31]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[25,33,34]}],"complexes":["PRC1.1 (ncPRC1)","SCF(KDM2B)/CRL1","FRRUC (FBXL10-RNF68-RNF2)"],"partners":["RING1B","PCGF1","BCOR","BCORL1","SKP1","EZH2","BRG1","SIRT1"],"other_free_text":[]},"mechanistic_narrative":"KDM2B is a multifunctional chromatin regulator that operates at the intersection of Polycomb-mediated gene silencing, histone demethylation, and ubiquitin ligase signaling to control cell fate decisions including pluripotency, differentiation, senescence, and DNA damage repair. Through its CxxC zinc-finger domain, KDM2B recognizes unmethylated CpG islands and recruits a noncanonical PRC1.1 complex (RING1B, PCGF1, BCOR/BCORL1, SKP1) that catalyzes H2AK119 monoubiquitylation to silence developmental and lineage-specific genes, a function essential for embryonic stem cell self-renewal, neural progenitor maintenance, hematopoietic differentiation, and protection of CpG island promoters from aberrant DNA methylation [PMID:23256043, PMID:23395003, PMID:23502314, PMID:25848754, PMID:35128353]. Its JmjC domain demethylates H3K36me1/me2, H3K4me3, and H3K79me2/me3 at specific loci—including Ink4a/Arf, p15Ink4b, ribosomal RNA genes, and HOXA7—to regulate proliferation, senescence bypass, and transcriptional repression, while also acting as a non-histone demethylase targeting SRF K165 to modulate muscle differentiation [PMID:18836456, PMID:17994099, PMID:29763382, PMID:33564100]. KDM2B additionally functions as an F-box subunit of an SCF E3 ubiquitin ligase that targets c-Fos for proteasomal degradation, is recruited to DNA double-strand breaks via PARP1/TIMELESS to promote H2AK119ub1-dependent homologous recombination repair, and its CxxC domain variants cause a neurodevelopmental syndrome [PMID:26725323, PMID:29985131, PMID:40420380]."},"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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proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/39358887","citation_count":4,"is_preprint":false},{"pmid":"40420380","id":"PMC_40420380","title":"KDM2B variants in the CxxC domain impair its DNA-binding ability and cause a distinct neurodevelopmental syndrome.","date":"2025","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40420380","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51767,"output_tokens":10891,"usd":0.159333},"stage2":{"model":"claude-opus-4-6","input_tokens":14883,"output_tokens":5709,"usd":0.32571},"total_usd":0.485043,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM2B (FBXL10) specifically recognizes non-methylated CpG islands via its CxxC zinc-finger domain and recruits Polycomb Repressive Complex 1 (PRC1) to these sites, contributing to histone H2A lysine 119 ubiquitylation (H2AK119ub1) and gene repression genome-wide.\",\n      \"method\": \"Genome-wide ChIP-seq, co-immunoprecipitation, biochemical domain analysis, CxxC domain binding assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (ChIP-seq, Co-IP, biochemical binding assays), replicated across multiple independent labs\",\n      \"pmids\": [\"23256043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fbxl10/KDM2B interacts with Ring1B and Nspc1 (PCGF1), forming a noncanonical PRC1 complex (ncPRC1) required for H2AK119ub1 in mouse ESCs; Fbxl10 depletion causes loss of Ring1B binding to target genes and major loss of H2AK119ub1, and its DNA-binding capability and PRC1 integration are both required for ubiquitylation.\",\n      \"method\": \"Co-immunoprecipitation, genome-wide ChIP-seq, knockdown/rescue with domain mutants, genetic epistasis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, genome-wide ChIP, functional domain mutagenesis rescue; replicated by independent labs\",\n      \"pmids\": [\"23395003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Kdm2b maintains mESC pluripotency by binding CpG islands via its CxxC-ZF domain and recruiting PRC1 to repress lineage-specific genes; Oct4 and Sox2 directly regulate Kdm2b transcription, defining an Oct4-Sox2-Kdm2b-PRC1-CGI regulatory axis.\",\n      \"method\": \"ChIP, Co-IP, CxxC domain mutants, loss-of-function (knockdown), gene expression analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, Co-IP, domain mutants, KD phenotype), replicated finding\",\n      \"pmids\": [\"23502314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KDM2B (Jhdm1b) is a histone H3 lysine 36 demethylase (H3K36me1/me2) that targets the p15(Ink4b) locus to repress its expression in an enzymatic activity-dependent manner, thereby regulating cell proliferation and cellular senescence.\",\n      \"method\": \"In vitro histone demethylase assay, ChIP, shRNA knockdown with p15Ink4b rescue epistasis, cell proliferation assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assay, ChIP, genetic epistasis rescue; replicated across multiple labs\",\n      \"pmids\": [\"18836456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JHDM1B/KDM2B is a nucleolar protein that binds the transcribed region of ribosomal DNA and represses ribosomal RNA gene transcription through JmjC domain-dependent demethylation of H3K4me3 in the nucleolus.\",\n      \"method\": \"Subcellular fractionation/localization, ChIP on rDNA, RNAi knockdown, in vitro demethylase assay with JmjC domain mutants, cell size/proliferation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assay with domain mutants, ChIP, localization with functional consequence; highly cited foundational paper\",\n      \"pmids\": [\"17994099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KDM2B (Fbxl10/JHDM1B) forms a novel complex with Ring1B/Rnf2 that also includes BCOR (BcoR), CK2α, Skp1, and Nspc1/PCGF1; this was identified as a distinct ncPRC1-like complex separate from canonical PRC1 and E2F6 complexes.\",\n      \"method\": \"In vivo biotinylation tagging, streptavidin pulldown, mass spectrometry proteomics, iterative complex purification\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — high-throughput proteomics with iterative purification; replicated by subsequent independent studies\",\n      \"pmids\": [\"17296600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM2B (NDY1) synergizes with EZH2 to repress miR-101 by co-binding its promoter; EZH2 binding to the miR-101 promoter depends on KDM2B, but KDM2B binds independently; this axis mediates FGF-2-driven cell proliferation, migration, and angiogenesis downstream of CREB/DYRK1A.\",\n      \"method\": \"ChIP, Co-IP, promoter reporter assays, shRNA knockdown, epistasis experiments, cell proliferation/migration/angiogenesis assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal ChIP, functional epistasis, multiple orthogonal assays\",\n      \"pmids\": [\"21777817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM2B/JHDM1b silences p15(Ink4b) through active demethylation of H3K36me2 at the locus; ectopic KDM2B expression is sufficient to transform hematopoietic progenitors, and its depletion in leukemic stem cells impairs self-renewal in vitro and in vivo.\",\n      \"method\": \"Retroviral overexpression, shRNA knockdown, in vitro and in vivo transplantation assays, ChIP for H3K36me2\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss-of-function with defined molecular mechanism (H3K36me2 at p15Ink4b), in vivo validation\",\n      \"pmids\": [\"21310926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ndy1/KDM2B represses the Ink4a/Arf locus by: (1) counteracting senescence-associated down-regulation of EZH2 via JmjC domain-dependent global H3K27me3 upregulation; (2) directly binding the Ink4a/Arf locus to demethylate H3K36me2 and H3K4me3; (3) promoting Bmi1 binding and blocking RNA Pol II recruitment.\",\n      \"method\": \"ChIP, Co-IP (Ndy1-Ezh2 interaction), demethylase assays, MEF immortalization assays, knockdown/overexpression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple ChIP experiments, Co-IP, functional mechanistic epistasis, replicated\",\n      \"pmids\": [\"19202064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the KDM2B/SKP1/BCORL1/PCGF1 tetrameric complex reveals that the BCORL1 PUFD domain positions residues preceding the PCGF1 RAWUL domain to create an extended interface for KDM2B interaction unique to PRC1.1; in vitro assembly identifies the minimal four-component PRC1.1 complex as two heterodimers (KDM2B/SKP1 and BCORL1/PCGF1).\",\n      \"method\": \"Crystal structure determination, in vitro complex assembly, biochemical pulldown assays, analytical ultracentrifugation\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with biochemical validation of assembly requirements\",\n      \"pmids\": [\"27568929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Complete inactivation of Fbxl10 leads to dense de novo DNA methylation specifically at promoters co-occupied by FBXL10 and Polycomb repressive complexes, establishing FBXL10 as the first factor whose loss causes gain of genomic DNA methylation; this protection requires FBXL10 but not Polycomb components alone.\",\n      \"method\": \"Fbxl10 knockout mouse model, whole-genome bisulfite sequencing/methylation analysis, genetic epistasis with PRC1/PRC2 component knockouts\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — complete KO with genome-wide methylation analysis, genetic epistasis\",\n      \"pmids\": [\"25848754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM2B drives pancreatic cancer through two distinct transcriptional mechanisms: (1) repression of developmental genes via co-binding with PcG proteins at transcriptional start sites; (2) activation of metabolic genes (protein synthesis, mitochondrial function) via co-binding with MYC and KDM5A.\",\n      \"method\": \"Gain/loss-of-function in cell lines and mouse models, genome-wide ChIP-seq, gene expression profiling, mouse PDAC model (KrasG12D cooperation)\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP, in vivo mouse models, gain and loss of function; multiple orthogonal approaches\",\n      \"pmids\": [\"23321669\"],\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 at the beginning of reprogramming; this capacity depends on both demethylase and DNA-binding activities but is largely independent of its anti-senescence role.\",\n      \"method\": \"Retroviral overexpression in reprogramming, domain mutant rescue (demethylase-dead, DNA-binding mutants), ChIP for H3K36me2, gene expression during reprogramming time course\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain mutant epistasis, ChIP, mechanistic dissection of demethylase vs. DNA-binding requirements\",\n      \"pmids\": [\"22522173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM2B is a histone H3K79 di- and trimethyl demethylase that induces transcriptional repression of HOXA7 and MEIS1 via occupancy of their promoters and H3K79 demethylation; KDM2B-knockdown increases global H3K79 methylation; KDM2B loss displaces SIRT1 from chromatin, increasing H4K16 acetylation.\",\n      \"method\": \"In vitro demethylase assay, genome-wide H3K79 methylation analysis (ChIP-seq), KDM2B knockdown stable cell lines, Co-IP for SIRT1\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assay plus genome-wide ChIP, single lab\",\n      \"pmids\": [\"29763382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The FRRUC complex (FBXL10-RNF68-RNF2) is rapidly and transiently recruited to DNA damage sites in a PARP1- and TIMELESS-dependent manner, where it promotes H2AK119 mono-ubiquitylation, local H2A.Z incorporation, transcriptional repression, DSB signaling, and homologous recombination repair.\",\n      \"method\": \"Live-cell imaging at laser-induced DNA damage sites, Co-IP, ChIP, genetic knockdowns, epistasis with BMI1-RNF2 and MEL18-RNF2 complexes, HR repair assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence, epistasis, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"29985131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In synovial sarcoma, SS18-SSX1 oncoprotein physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B on unmethylated CpG islands; via KDM2B, SS18-SSX1 aberrantly activates developmental genes normally silenced by polycomb; KDM2B depletion restores repression and causes irreversible mesenchymal differentiation.\",\n      \"method\": \"Co-IP, ChIP-seq, functional genomics screen, loss-of-function differentiation assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, genome-wide ChIP-seq, functional genomics; rigorous mechanistic study\",\n      \"pmids\": [\"29502955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM2B counteracts senescence-associated downregulation of EZH2 by silencing let-7b and miR-101 via locus-specific H3K36me2 demethylation at their genomic loci, thereby maintaining EZH2 levels and promoting cellular proliferation/immortalization.\",\n      \"method\": \"Retroviral overexpression, ChIP for H3K36me2 at miRNA loci, let-7b overexpression epistasis, KDM2B knockdown in multiple primary cell types\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, genetic epistasis (let-7b rescue), multiple cell types, mechanistic dissection\",\n      \"pmids\": [\"21757686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fbl10/KDM2B interacts with c-Jun and represses c-Jun-mediated transcription; KDM2B binds unmethylated CpG sequences in the c-jun promoter via its CxxC zinc finger, tethers transcriptional repressor complexes, and requires c-Jun for its promoter recruitment; KDM2B protein is down-regulated in response to UV inversely correlating with c-Jun induction.\",\n      \"method\": \"Co-IP, ChIP, siRNA knockdown, luciferase reporter assays, UV treatment experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, reporter assays, functional knockdown; multiple orthogonal methods\",\n      \"pmids\": [\"17704768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM2B, via its F-box domain, functions as a substrate recognition subunit of the SCF(KDM2B)/CRL1 E3 ubiquitin ligase complex to target c-Fos for polyubiquitylation and degradation; EGF-induced c-Fos S374 phosphorylation dissociates c-Fos from KDM2B, stabilizing c-Fos and enabling cell proliferation.\",\n      \"method\": \"Co-IP, in vitro ubiquitylation assay, phosphomimetic/non-phosphorylatable c-Fos mutants, EGF stimulation experiments, tumor-derived KDM2B mutation analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro ubiquitylation assay, domain mutants, phospho-mutant epistasis\",\n      \"pmids\": [\"26725323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NDY1/KDM2B functions as a master regulator of PRC1 and PRC2 by silencing a set of miRNAs that target multiple polycomb complex members; NDY1 knockdown de-represses these miRNAs and down-regulates their polycomb targets, reducing cancer stem cell self-renewal and sphere formation.\",\n      \"method\": \"shRNA knockdown in multiple tumor cell lines, mammosphere assays, stem cell marker analysis (ALDH, CD44/CD24), miRNA profiling, epistasis (miRNA re-expression)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell lines, miRNA epistasis, CSC phenotype; single lab\",\n      \"pmids\": [\"24853546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fbxl10/KDM2B deficiency in mouse neural progenitor cells causes increased apoptosis, upregulation of p19ARF (an apoptosis inducer), increased neural progenitor mitosis, and neural tube closure failure leading to exencephaly.\",\n      \"method\": \"Fbxl10 knockout mouse generation, in situ hybridization, TUNEL assay, mitotic cell counting, p19ARF qRT-PCR in embryos and MEFs\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype and molecular mechanism (p19ARF), in vivo\",\n      \"pmids\": [\"21220025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM2B promotes IL-6 production in macrophages independently of its demethylase activity by interacting with Brg1 (SWI/SNF ATPase subunit) to facilitate chromatin accessibility at the Il6 promoter and directly recruiting RNA Polymerase II; KDM2B-deficient mice show decreased IL-6 and resistance to endotoxin shock.\",\n      \"method\": \"Co-IP (KDM2B-Brg1 interaction), ChIP for chromatin accessibility and Pol II, KDM2B conditional KO mice, ELISA for IL-6, ATAC-seq\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, in vivo KO, demethylase-independent mechanism established by domain mutants\",\n      \"pmids\": [\"31197256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FBXL10/KDM2B recruits a noncanonical PRC1 complex containing RING1B, SKP1, PCGF1, and BCOR to specific genomic loci (including Cdk1, Pparg1/2) to repress adipogenesis; this function requires the F-box and leucine-rich repeat domains but not the JmjC demethylase domain.\",\n      \"method\": \"ChIP-seq, Co-IP, domain deletion mutants, siRNA knockdown of RING1B/SKP1, 3T3-L1 differentiation assays\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq, domain mutant dissection, genetic epistasis with complex components\",\n      \"pmids\": [\"25533466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM2B cooperates with polycomb and trithorax complexes to regulate hematopoietic stem and progenitor cell differentiation, lineage choice, cytokine signaling, and cell cycle; KDM2B has a dichotomous role—maintaining lymphoid leukemias but restraining RAS-driven myeloid transformation—depending on cellular context.\",\n      \"method\": \"Kdm2b-null mice, RNA-seq, ChIP-seq in human leukemias, HSPC transplantation assays\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with RNA-seq and genome-wide ChIP-seq, in vivo transplantation\",\n      \"pmids\": [\"26808549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM2B regulates somatic reprogramming through PRC1.1 recruitment to CpG islands; BMP-SMAD signaling attenuates PRC1.1 occupancy and H2AK119 ubiquitylation at developmental gene loci, activating mesendodermal factors and suppressing reprogramming.\",\n      \"method\": \"ChIP for PRC1.1 components and H2AK119ub1, BMP4 treatment epistasis, reprogramming efficiency assays with domain mutants\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, genetic epistasis with BMP pathway; single lab\",\n      \"pmids\": [\"29166607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM2B in PRC1.1 acts as a tumor suppressor in T-cell leukemogenesis by binding nonmethylated CpG island promoters via its CxxC domain and restricting excessive NOTCH1-mediated transcriptional activation via H2AK119ub1 deposition; Kdm2b-deficient mice develop NOTCH1-dependent T-ALL.\",\n      \"method\": \"Hematopoietic-specific CxxC domain deletion mice, ChIP-seq (KDM2B, BCOR, EZH2, H2AK119ub1, H3K4me3, H3K27me3), comparison with NOTCH1 target genes in human T-ALL\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific KO, genome-wide ChIP-seq, in vivo leukemia model\",\n      \"pmids\": [\"31471323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM2B demethylates serum response factor (SRF) at K165 (non-histone target) to negatively regulate skeletal muscle differentiation; SET7 counteracts this by methylating SRF K165; SRF K165 methylation is required for transcriptional activation of SRF-dependent muscle genes and promoter occupancy.\",\n      \"method\": \"Co-IP (KDM2B-SRF interaction), in vitro demethylation assay on SRF, SET7 inhibitor treatment, ChIP for SRF at target promoters, gain/loss-of-function differentiation assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro demethylase assay on non-histone substrate, Co-IP, ChIP; single lab\",\n      \"pmids\": [\"33564100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM2B mediates H2AK119 monoubiquitylation as a PRC1 component by recognizing regulatory regions of CDH1, miR200a, and CGN genes via its DNA-recognition property (not demethylase activity), inducing H2AK119ub1 and subsequent EZH2 recruitment and H3K27 methylation required for EMT-related gene repression during TGF-β-induced EMT.\",\n      \"method\": \"ChIP for H2AK119ub1 and H3K27me3, KDM2B domain mutants (DNA-binding vs. demethylase), knockdown/overexpression in lung/pancreatic cancer lines, TGF-β treatment\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, domain mutant dissection, functional EMT phenotype; single lab\",\n      \"pmids\": [\"33779563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ELKS1 stabilizes KDM2B protein in mast cells, and KDM2B is an essential transcriptional regulator of Syntaxin 4 (STX4) and Stxbp2 expression required for mast cell degranulation.\",\n      \"method\": \"Mast cell-specific Elks1 conditional KO mice, Co-IP (ELKS1-KDM2B interaction), ChIP for KDM2B at Stx4/Stxbp2 promoters, degranulation assays in vitro and in vivo\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO in vivo, Co-IP, ChIP, functional degranulation assay; single lab\",\n      \"pmids\": [\"32937583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM2B-mediated H3K79 demethylation facilitates PCNA dissociation from chromatin during S phase by abolishing H3K79me-dependent PCNA chromatin binding; KDM2B depletion causes aberrant PCNA retention on chromatin and impairs DNA replication efficiency.\",\n      \"method\": \"PCNA-H3K79me peptide pulldown, isothermal titration calorimetry (ITC), ChIP, iPOND, DNA fiber assay, flow cytometry, KDM2B-depleted cells and H3K79R histone mutants\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — ITC quantitative binding, in vitro pulldown, multiple functional assays; single lab\",\n      \"pmids\": [\"33029857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tip60 acetyltransferase acetylates KDM2B at lysine 758, which decreases KDM2B's ability to bind nucleosomes and reduces its demethylase activity toward nucleosomal (but not bulk) histone substrates, diminishing KDM2B occupancy at p21 and puma promoters and promoting tumor growth.\",\n      \"method\": \"Co-IP, in vitro acetylation/demethylase assays with nucleosome vs. bulk histone substrates, K758 acetylation mutants, ChIP for KDM2B binding, tumor xenograft models\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro acetylation and demethylase assays, site-specific mutants, ChIP; single lab\",\n      \"pmids\": [\"31218831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXL10/KDM2B stabilizes ERRα protein by reducing its polyubiquitylation and promoting its mono-ubiquitylation, thereby increasing ERRα transcriptional activity and promoter occupancy at ERRα target genes to facilitate breast cancer cell proliferation.\",\n      \"method\": \"Co-IP (mass spectrometry identification then validated), ubiquitylation assays (poly vs. mono-Ub), reporter gene assay, ChIP for ERRα, in vitro and in vivo proliferation/tumor assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitylation assays, ChIP, in vivo tumor model; single lab\",\n      \"pmids\": [\"33450359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXL10/KDM2B promotes EMT and breast cancer metastasis by interacting with SNAI1 and facilitating SNAI1-HDAC1 interaction, resulting in SNAI1 deacetylation and enhanced transcriptional repression of CDH1/E-cadherin.\",\n      \"method\": \"Co-IP (FBXL10-SNAI1-HDAC1 ternary complex), reporter assays for CDH1 transcription, E-cadherin protein level measurements, lung metastasis mouse model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ternary complex Co-IP, reporter assay, in vivo metastasis model; single lab\",\n      \"pmids\": [\"34718323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Alternative short isoforms of KDM2B (KDM2B-SF), lacking the N-terminal demethylase domain but retaining CxxC and other domains, negatively regulate canonical Wnt signaling by binding Axin2 and cyclin D1 promoters and interacting with TCF7L1, repressing Wnt target gene transcription in a DNA-binding domain-dependent manner.\",\n      \"method\": \"Luciferase reporter assays (Wnt-responsive element), ChIP, Co-IP with TCF7L1, domain deletion mutant analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP, ChIP, reporter assays, domain mutants; single lab\",\n      \"pmids\": [\"33104714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM2B controls hippocampal morphogenesis and neurogenesis by transcriptionally silencing Wnt signaling genes in neural progenitors through CxxC domain-dependent chromatin association and recruitment of Polycomb repressive complexes; loss of CxxC domain (Kdm2b∆CxxC mice) causes de-repression of Wnt genes, impaired neural progenitor migration/differentiation, and spatial memory deficits.\",\n      \"method\": \"Conditional CxxC domain deletion mice, ChIP for PRC marks, RNA-seq, behavioral testing (spatial memory, fear conditioning), lineage tracing, Wnt pathway activation rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific KO in vivo, genome-wide ChIP, RNA-seq, genetic rescue; mechanistically rigorous\",\n      \"pmids\": [\"37838801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of KDM2B CxxC-ZF domain impairs PRC1 recruitment to chromatin in neural stem cells (NSCs), causing de-repression of apoptosis and cell-cycle arrest genes, NSC senescence, loss of NSC populations in mouse brain, and ASD/ID-like behavioral and memory deficits.\",\n      \"method\": \"CxxC domain mutant knock-in mice, ChIP for PRC1/H2AK119ub1, RNA-seq, NSC culture assays, behavioral phenotyping\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific KI mouse, genome-wide ChIP, functional NSC assays, in vivo behavioral phenotype\",\n      \"pmids\": [\"35128353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EBNA3C (EBV nuclear antigen) interacts with KDM2B, and this interaction is required for H3K4me3 removal at EBNA3C target gene promoters (COBLL1, ADAM28-ADAMDEC1 locus) and for full EBNA3C-mediated transcriptional repression in lymphoblastoid cells.\",\n      \"method\": \"Co-IP (EBNA3C-KDM2B), ChIP for H3K4me3 at target loci, recombinant EBV with EBNA3C RBPJ-motif mutants, gene expression analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, recombinant virus genetic analysis; single lab\",\n      \"pmids\": [\"30135119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM2B represses Choline Kinase α (CKα) expression by binding to its promoter (Box2) during neuroblast proliferation, maintaining the undifferentiated state; KDM2B knockdown enhances CKα expression and induces neuronal differentiation even without retinoic acid.\",\n      \"method\": \"ChIP (KDM2B at Chka promoter), siRNA knockdown, gain-of-function, retinoic acid differentiation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, gain/loss-of-function with defined promoter binding; single lab\",\n      \"pmids\": [\"30629659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM2B, functioning in the ncPRC1.1 context, regulates amino acid metabolism (SGOC, glutamate, GSH pathways) by enhancing chromatin accessibility and expression of MYC and ATF4, with KDM2B co-occupying promoters of metabolic genes together with MYC and ATF4.\",\n      \"method\": \"Multi-omics (RNA-seq, quantitative TMT proteomics, metabolomics, ATAC-seq, ChIP-seq), shRNA knockdown in TNBC cell lines\",\n      \"journal\": \"Metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics with ChIP-seq; single lab but comprehensive approach\",\n      \"pmids\": [\"37935302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FBXL10 maintains silencing of DUSP6 (a phosphatase for ERK1/2) via recruitment of Polycomb group proteins and deposition of repressive histone modifications at the DUSP6 promoter, thereby maintaining ERK1/2 phosphorylation and promoting DLBCL cell proliferation.\",\n      \"method\": \"ChIP for PcG marks at DUSP6 promoter, RNA-seq, DUSP6 knockdown rescue of FBXL10-depleted cells, xenograft tumor model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, RNA-seq, genetic rescue epistasis, in vivo model; single lab\",\n      \"pmids\": [\"29352142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM2B directly binds the MOB1 promoter and suppresses its transcriptional activity, thereby regulating the Hippo pathway; KDM2B promotes PDAC proliferation, migration, and invasion via MOB1 suppression.\",\n      \"method\": \"ChIP for KDM2B at MOB1 promoter, promoter luciferase assay, gain/loss-of-function with MOB1 epistasis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase reporter with genetic epistasis; single lab\",\n      \"pmids\": [\"31941533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LncKdm2b (Kancr), divergently transcribed from a bidirectional promoter of Kdm2b, positively regulates Kdm2b transcription in cis by associating with hnRNPAB to facilitate a permissive chromatin environment at the Kdm2b promoter; LncKdm2b and Kdm2b are both required for proper differentiation and migration of cortical projection neurons.\",\n      \"method\": \"In vivo lineage tracing, phenotypic analysis, RNA-protein interaction (hnRNPAB pulldown), chromatin accessibility assays, CRISPRi knockdown\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo lineage tracing, RNA-protein interaction, chromatin assay; single lab\",\n      \"pmids\": [\"31317506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DHX9 helicase enhances H3K9 chromatin demethylation by KDM2B at the YAP1 promoter and facilitates RNA Polymerase II recruitment, promoting YAP1 expression in Ewing sarcoma; DHX9 and KDM2B form a functional complex, and this axis is counteracted by EWS-FLI1 binding to the YAP1 promoter.\",\n      \"method\": \"Co-IP (DHX9-KDM2B), ChIP for H3K9me and Pol II at YAP1 promoter, transcriptome profiling, functional transformation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, transcriptome; single lab\",\n      \"pmids\": [\"38017132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM2B inactivation via CRISPR-Cas9 genome-wide screen suppresses multiple heparan sulfate (HS) sulfotransferases and upregulates SULF1 sulfatase, altering HS structure and protein binding; KDM2B-deficient cell growth defects are rescued by SULF1 inactivation, establishing KDM2B as a master regulator of extracellular matrix gene expression.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, RNA-seq, HS sulfotransferase activity assays, SULF1 genetic epistasis\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide CRISPR screen with genetic epistasis and functional HS assays; single lab\",\n      \"pmids\": [\"33846619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM2B CxxC domain missense variants significantly reduce its DNA-binding ability (measured functionally in vitro) while allowing protein expression; this DNA-binding impairment is the molecular mechanism distinguishing CxxC variants from haploinsufficiency variants, associated with a distinct neurodevelopmental syndrome phenotype.\",\n      \"method\": \"Functional DNA-binding assays with mutant KDM2B proteins, protein expression assays in vitro, clinical cohort correlation with episignature analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro DNA-binding assays with patient variants; clinical correlation supports mechanism\",\n      \"pmids\": [\"40420380\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM2B is a multifunctional chromatin regulator that: (1) specifically recognizes unmethylated CpG islands via its CxxC zinc-finger domain to recruit a noncanonical PRC1.1 complex (containing RING1B, PCGF1, BCOR/BCORL1, and SKP1) that catalyzes H2AK119 monoubiquitylation and gene repression of developmental and lineage-specific genes; (2) acts as an H3K36me1/me2 demethylase (and also H3K79me2/3 demethylase) to regulate transcription at specific loci including p15Ink4b, Ink4a/Arf, and ribosomal RNA genes; (3) functions as an F-box subunit of SCF-E3 ubiquitin ligase to target substrates like c-Fos for proteasomal degradation; (4) is recruited to DNA damage sites via PARP1/TIMELESS to promote H2AK119ub1-dependent H2A.Z loading and homologous recombination repair; and (5) serves as a non-histone demethylase targeting SRF K165 to regulate muscle differentiation, collectively placing KDM2B at the intersection of Polycomb-mediated silencing, H3K36/K79/K4 demethylation, ubiquitin ligase activity, and DNA damage response.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KDM2B is a multifunctional chromatin regulator that operates at the intersection of Polycomb-mediated gene silencing, histone demethylation, and ubiquitin ligase signaling to control cell fate decisions including pluripotency, differentiation, senescence, and DNA damage repair. Through its CxxC zinc-finger domain, KDM2B recognizes unmethylated CpG islands and recruits a noncanonical PRC1.1 complex (RING1B, PCGF1, BCOR/BCORL1, SKP1) that catalyzes H2AK119 monoubiquitylation to silence developmental and lineage-specific genes, a function essential for embryonic stem cell self-renewal, neural progenitor maintenance, hematopoietic differentiation, and protection of CpG island promoters from aberrant DNA methylation [PMID:23256043, PMID:23395003, PMID:23502314, PMID:25848754, PMID:35128353]. Its JmjC domain demethylates H3K36me1/me2, H3K4me3, and H3K79me2/me3 at specific loci—including Ink4a/Arf, p15Ink4b, ribosomal RNA genes, and HOXA7—to regulate proliferation, senescence bypass, and transcriptional repression, while also acting as a non-histone demethylase targeting SRF K165 to modulate muscle differentiation [PMID:18836456, PMID:17994099, PMID:29763382, PMID:33564100]. KDM2B additionally functions as an F-box subunit of an SCF E3 ubiquitin ligase that targets c-Fos for proteasomal degradation, is recruited to DNA double-strand breaks via PARP1/TIMELESS to promote H2AK119ub1-dependent homologous recombination repair, and its CxxC domain variants cause a neurodevelopmental syndrome [PMID:26725323, PMID:29985131, PMID:40420380].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of KDM2B's core biochemical activities and interaction partners established it as both a histone demethylase and a PRC1-associated chromatin regulator, resolving what molecular functions this JmjC-domain protein performs.\",\n      \"evidence\": \"Proteomic identification of Ring1B/PCGF1/BCOR/SKP1 complex via biotin tagging and mass spectrometry; nucleolar localization and JmjC-dependent H3K4me3 demethylation at rDNA; CxxC-dependent binding to unmethylated CpG at the c-jun promoter with transcriptional repression\",\n      \"pmids\": [\"17296600\", \"17994099\", \"17704768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic specificity toward different histone marks not yet systematically compared\", \"Whether demethylase and PRC1 functions act at the same or distinct loci was unclear\", \"No structural basis for complex assembly\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing KDM2B as an H3K36me2 demethylase at the p15Ink4b locus linked its enzymatic activity to a defined cell proliferation/senescence regulatory pathway.\",\n      \"evidence\": \"In vitro histone demethylase assay, ChIP at p15Ink4b, shRNA knockdown with epistasis rescue\",\n      \"pmids\": [\"18836456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H3K36me2 demethylation is sufficient or requires concurrent PRC1 activity at this locus\", \"Substrate specificity in vivo beyond Ink4b not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that KDM2B represses the Ink4a/Arf locus through a multi-layered mechanism—direct H3K36me2/H3K4me3 demethylation, indirect EZH2 stabilization, and Bmi1 recruitment—revealed how a single factor coordinates PRC1, PRC2, and demethylase activities to bypass senescence.\",\n      \"evidence\": \"ChIP for multiple histone marks, Co-IP for Ndy1-Ezh2, MEF immortalization with gain/loss-of-function\",\n      \"pmids\": [\"19202064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each mechanism to senescence bypass not quantified\", \"Whether EZH2 stabilization is direct or via miRNA-mediated mechanism not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Clarifying the miRNA-mediated axis through which KDM2B maintains EZH2 levels (by silencing let-7b and miR-101 via H3K36me2 demethylation) and demonstrating KDM2B-EZH2 co-occupancy at miR-101 connected KDM2B's demethylase function to a broader Polycomb maintenance circuit.\",\n      \"evidence\": \"ChIP at miRNA loci, epistasis with let-7b overexpression, Co-IP and ChIP for KDM2B-EZH2 co-binding at miR-101 promoter, functional proliferation/migration assays\",\n      \"pmids\": [\"21757686\", \"21777817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EZH2 regulation is the primary or accessory function of KDM2B in proliferating cells\", \"Generality of this miRNA axis beyond the cell types tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"In vivo knockout revealed that KDM2B is required for neural tube closure through regulation of p19ARF, establishing its physiological necessity in development beyond cultured cells.\",\n      \"evidence\": \"Fbxl10 knockout mouse, TUNEL and mitotic assays in neural progenitors, p19ARF qRT-PCR\",\n      \"pmids\": [\"21220025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the neural tube phenotype reflects demethylase or PRC1 function not resolved\", \"Contribution of other Ink4a/Arf locus products not fully dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genome-wide demonstration that KDM2B's CxxC domain targets it to unmethylated CpG islands to recruit PRC1 and deposit H2AK119ub1 genome-wide resolved the long-standing question of how PRC1 finds its targets independently of PRC2.\",\n      \"evidence\": \"Genome-wide ChIP-seq for KDM2B and PRC1 components, CxxC domain binding assays, Co-IP\",\n      \"pmids\": [\"23256043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CpG island targeting is modulated at different loci not addressed\", \"Contribution of other CxxC-containing proteins to the same pathway\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"KDM2B's role in somatic cell reprogramming was shown to depend on H3K36me2 demethylation at early-responsive gene promoters rather than its anti-senescence activity, functionally separating its demethylase and Ink4a/Arf regulatory roles.\",\n      \"evidence\": \"Retroviral overexpression in reprogramming, demethylase-dead and DNA-binding mutant rescue, ChIP for H3K36me2 during reprogramming time course\",\n      \"pmids\": [\"22522173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRC1 recruitment also contributes to reprogramming efficiency\", \"Generality beyond mouse reprogramming system\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining the PRC1.1 complex composition and demonstrating its requirement for H2AK119ub1 in ESCs, combined with the finding that Oct4/Sox2 regulate Kdm2b transcription, placed KDM2B at the center of a core pluripotency-Polycomb regulatory circuit.\",\n      \"evidence\": \"Reciprocal Co-IP, genome-wide ChIP-seq in mESCs, knockdown/rescue with domain mutants\",\n      \"pmids\": [\"23395003\", \"23502314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with other ncPRC1 complexes in ESCs not fully resolved\", \"How Kdm2b expression is regulated beyond Oct4/Sox2\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of KDM2B's dual transcriptional role—repressing developmental genes with Polycomb while activating metabolic genes with MYC/KDM5A—in pancreatic cancer established it as a bifunctional chromatin regulator rather than a dedicated repressor.\",\n      \"evidence\": \"Genome-wide ChIP-seq, gene expression profiling, gain/loss-of-function in mouse PDAC model\",\n      \"pmids\": [\"23321669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for switching between repressive and activating complexes unknown\", \"Whether MYC interaction is direct or chromatin-proximity-mediated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Complete Fbxl10 inactivation caused de novo DNA methylation specifically at Polycomb/FBXL10-co-occupied promoters, establishing KDM2B as the first factor whose loss causes gain of DNA methylation and revealing an unexpected link between CpG island PRC1 recruitment and DNA methylation protection.\",\n      \"evidence\": \"Fbxl10 knockout mouse, whole-genome bisulfite sequencing, genetic epistasis with PRC1/PRC2 knockouts\",\n      \"pmids\": [\"25848754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which KDM2B/PRC1 prevents DNMT access not elucidated\", \"Whether this is a direct or indirect effect of H2AK119ub1 loss\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Crystal structure of the KDM2B/SKP1/BCORL1/PCGF1 tetramer revealed the architectural basis for PRC1.1 assembly, showing that BCORL1 creates a unique extended interface for KDM2B recruitment distinct from other PRC1 variants.\",\n      \"evidence\": \"Crystal structure determination, in vitro complex assembly, analytical ultracentrifugation\",\n      \"pmids\": [\"27568929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of full PRC1.1 with RING1B or DNA/nucleosome substrate\", \"How the F-box/LRR region integrates with SCF versus PRC1 architecturally\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of KDM2B as an SCF E3 ubiquitin ligase F-box subunit that targets c-Fos for degradation established a non-chromatin enzymatic function and revealed a phosphorylation-dependent switch controlling substrate release.\",\n      \"evidence\": \"In vitro ubiquitylation assay, Co-IP, phosphomimetic c-Fos mutants, EGF stimulation\",\n      \"pmids\": [\"26725323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate repertoire of SCF(KDM2B) unknown\", \"How cells balance KDM2B between PRC1.1 and SCF complexes\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Comprehensive analysis of Kdm2b-null hematopoietic stem cells revealed context-dependent roles—maintaining lymphoid leukemias but restraining RAS-driven myeloid transformation—demonstrating that KDM2B's function is not uniformly oncogenic or tumor-suppressive.\",\n      \"evidence\": \"Kdm2b-null mice, RNA-seq, ChIP-seq in human leukemias, HSPC transplantation\",\n      \"pmids\": [\"26808549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for cell-type-specific oncogenic versus tumor-suppressive switching not defined\", \"Role of specific KDM2B domains in each context not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that the FRRUC complex (FBXL10-RNF68-RNF2) is recruited to DNA damage sites via PARP1/TIMELESS to catalyze H2AK119ub1 and promote H2A.Z loading and homologous recombination extended KDM2B's function beyond transcriptional regulation into the DNA damage response.\",\n      \"evidence\": \"Live-cell imaging at laser-induced damage sites, Co-IP, ChIP, epistasis with canonical PRC1, HR repair assays\",\n      \"pmids\": [\"29985131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for PARP1/TIMELESS-mediated recruitment unknown\", \"Whether FRRUC and PRC1.1 are the same or distinct complexes at damage sites\", \"Relative contribution versus canonical PRC1 in DDR\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating KDM2B demethylase activity toward H3K79me2/me3 expanded its substrate repertoire beyond H3K36/K4 and identified HOXA7/MEIS1 repression as a functional consequence, with implications for leukemia gene regulation.\",\n      \"evidence\": \"In vitro demethylase assay on H3K79 substrates, genome-wide H3K79me ChIP-seq, SIRT1 displacement analysis\",\n      \"pmids\": [\"29763382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"H3K79 demethylase activity not independently confirmed by a second lab\", \"Relative catalytic efficiency toward H3K79 versus H3K36 not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"KDM2B was shown to activate IL-6 transcription independently of its demethylase activity by recruiting Brg1 (SWI/SNF) and RNA Polymerase II, revealing a scaffolding/transcriptional activation mode distinct from its canonical repressive functions.\",\n      \"evidence\": \"Co-IP for KDM2B-Brg1, ChIP for Pol II, ATAC-seq, conditional KO mice with endotoxin challenge\",\n      \"pmids\": [\"31197256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SWI/SNF cooperation is widespread or locus-specific\", \"Structural basis for demethylase-independent activation unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing KDM2B CxxC domain deletion as sufficient to cause NOTCH1-dependent T-ALL in mice demonstrated that PRC1.1-mediated silencing at CpG islands restrains oncogenic signaling and identified a tumor suppressor function.\",\n      \"evidence\": \"Hematopoietic-specific CxxC domain deletion, genome-wide ChIP-seq for PRC marks, comparison with NOTCH1 targets in human T-ALL\",\n      \"pmids\": [\"31471323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether pharmacological restoration of PRC1.1 could treat T-ALL\", \"Mechanism by which PRC1.1 specifically restrains NOTCH1 targets not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"KDM2B-mediated H3K79 demethylation was linked to PCNA chromatin dissociation during S phase, connecting KDM2B enzymatic activity to DNA replication control beyond transcriptional regulation.\",\n      \"evidence\": \"PCNA-H3K79me peptide pulldown, ITC binding measurements, iPOND, DNA fiber assay, histone mutant epistasis\",\n      \"pmids\": [\"33029857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"H3K79 demethylase activity of KDM2B still awaits independent replication\", \"In vivo replication phenotype not assessed in animal models\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of SRF K165 as a non-histone demethylation target of KDM2B established that its enzymatic activity extends to transcription factor regulation, modulating skeletal muscle differentiation.\",\n      \"evidence\": \"In vitro demethylation assay on SRF, Co-IP, ChIP for SRF at muscle gene promoters, differentiation assays\",\n      \"pmids\": [\"33564100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full non-histone substrate repertoire unexplored\", \"In vivo muscle phenotype in Kdm2b-deficient animals not reported\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CxxC domain-specific knock-in mice showed that impaired PRC1 recruitment in neural stem cells causes senescence, NSC loss, and ASD/ID-like behavioral deficits, directly linking KDM2B-PRC1.1 to neurodevelopmental phenotypes.\",\n      \"evidence\": \"CxxC domain mutant knock-in mice, ChIP for PRC1/H2AK119ub1, RNA-seq, NSC assays, behavioral phenotyping\",\n      \"pmids\": [\"35128353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phenotype is entirely PRC1-dependent or involves demethylase-independent scaffolding\", \"Human genetic validation not yet available at this time point\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vivo CxxC deletion demonstrated KDM2B controls hippocampal neurogenesis by silencing Wnt signaling genes through Polycomb recruitment, causing spatial memory deficits when lost, and multi-omics in cancer cells revealed KDM2B/PRC1.1 regulates amino acid metabolism via MYC/ATF4 co-occupancy.\",\n      \"evidence\": \"Conditional CxxC deletion mice with behavioral testing and Wnt rescue; multi-omics (RNA-seq, proteomics, metabolomics, ATAC-seq, ChIP-seq) in TNBC cells\",\n      \"pmids\": [\"37838801\", \"37935302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Wnt de-repression is the sole driver of hippocampal defects\", \"Generality of metabolic regulation across cancer types\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Functional characterization of patient-derived KDM2B CxxC missense variants confirmed that reduced DNA-binding ability is the molecular mechanism underlying a neurodevelopmental syndrome, providing the genotype-to-mechanism link for human disease.\",\n      \"evidence\": \"In vitro DNA-binding assays with mutant proteins, protein expression assays, episignature analysis in clinical cohort\",\n      \"pmids\": [\"40420380\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CxxC variants affect PRC1.1 recruitment genome-wide in patient cells not yet shown\", \"Therapeutic approaches not explored\", \"Independent replication of episignature needed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how KDM2B partitions between PRC1.1, SCF, and FRRUC complexes in a single cell; the full non-histone substrate repertoire; the structural basis for switching between repressive and activating transcriptional roles; and whether the H3K79 demethylase activity represents a major or minor catalytic function in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full PRC1.1 on chromatin\", \"Partitioning between PRC1.1 and SCF complexes not measured\", \"H3K79 demethylase activity not independently replicated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 4, 8, 13, 26]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 17, 44]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 4, 8, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 11, 21, 33]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 14]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 8, 10, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 6, 11, 17, 21]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [20, 34, 35]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [18, 31]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [25, 33, 34]}\n    ],\n    \"complexes\": [\n      \"PRC1.1 (ncPRC1)\",\n      \"SCF(KDM2B)/CRL1\",\n      \"FRRUC (FBXL10-RNF68-RNF2)\"\n    ],\n    \"partners\": [\n      \"RING1B\",\n      \"PCGF1\",\n      \"BCOR\",\n      \"BCORL1\",\n      \"SKP1\",\n      \"EZH2\",\n      \"BRG1\",\n      \"SIRT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}