{"gene":"KDM2A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"KDM2A (JHDM1A/FBXL11) is a JmjC-domain-containing histone demethylase that specifically demethylates mono- and dimethylated histone H3 lysine 36 (H3K36me1/me2), with little or no activity on trimethylated H3K36.","method":"In vitro demethylase assays, mass spectrometry of histone modifications","journal":"Multiple papers (e.g., Molecular and cellular biology, EMBO journal)","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzymatic activity established by in vitro assays across multiple independent labs and replicated in numerous subsequent studies","pmids":["20379134","25128496","24553073"],"is_preprint":false},{"year":2014,"finding":"Structural studies revealed that H3K36 specificity for KDM2A is mediated by U-shaped threading of the H3K36 peptide through a catalytic groove; key residues G33, G34 (positioned in a narrow channel), P38 (turn residue), and Y41 (inserts into its own pocket) contribute to K36me specificity. Steric constraints prevent trimethylated K36 from undergoing the 'off-line'-to-'in-line' transition required for demethylation. Structure-guided active-site mutations abrogated KDM2A-mediated suppression of cancer cell phenotypes.","method":"X-ray crystallography, structure-guided mutagenesis, functional assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional validation in a single rigorous study","pmids":["25128496"],"is_preprint":false},{"year":2024,"finding":"QM/MM and MD simulations demonstrated that KDM2A catalysis is controlled by a conformational change of the second coordination sphere residue Y222, which unlocks 2-oxoglutarate rearrangement from off-line to in-line mode; Y222A variant makes the rearrangement more favorable. The trimethylated lysine substrate is sterically unable to undergo this rearrangement, explaining H3K36me3 inactivity.","method":"Quantum mechanics/molecular mechanics (QM/MM), molecular dynamics simulations, variant analysis","journal":"Inorganic chemistry","confidence":"Medium","confidence_rationale":"Tier 1 (computational reconstitution with mutagenesis inference) / Weak — single computational study, no experimental wet-lab mutagenesis validation reported in abstract","pmids":["38781256"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of KDM2A and KDM2B trapped on nucleosome substrates (using a covalent H3K36-inhibitor conjugate) revealed that KDM2A requires the nucleosome acidic patch for nucleosome binding whereas KDM2B does not; nucleosome binding by KDM2A is facilitated by dynamic nucleosomal DNA unwrapping and histone charge shielding that mobilize the H3K36 sequence for demethylation.","method":"Cryo-electron microscopy (cryo-EM), acidic patch interactome screen, covalent substrate-inhibitor conjugate","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures with functional mechanistic validation, rigorous structural study","pmids":["36797403"],"is_preprint":false},{"year":2011,"finding":"KDM2A is specifically recruited to CpG islands via its ZF-CXXC domain through direct interaction with linker DNA at non-methylated CpG sequences; nucleosomes are a major barrier to KDM2A binding, and CpG islands are recognized through a combination of unmethylated DNA state and reduced nucleosome occlusion.","method":"Defined chromatin templates in vitro, chromatin profiling in vivo, ZF-CXXC domain biochemical characterization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with defined chromatin templates combined with in vivo chromatin profiling, single lab but orthogonal methods","pmids":["22083960"],"is_preprint":false},{"year":2014,"finding":"The CxxC-ZF domain of KDM2A is required for binding to the rDNA promoter via unmethylated CpG dinucleotides in vitro and in vivo; this binding is required for KDM2A to demethylate H3K36me2 at the rDNA promoter in response to starvation and to reduce rDNA transcription. A JmjC catalytic domain mutation abolished demethylase activity and rDNA repression, while a CxxC-ZF mutation retained demethylase activity but failed to reduce rDNA transcription.","method":"Domain mutagenesis, ChIP, in vitro DNA binding, knockdown-rescue experiments","journal":"Cell structure and function","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — domain mutagenesis combined with ChIP and functional rescue, single lab with orthogonal approaches","pmids":["24553073"],"is_preprint":false},{"year":2010,"finding":"KDM2A localizes to nucleoli and binds the rRNA gene (rDNA) promoter. Overexpression of KDM2A represses rRNA transcription in a demethylase-activity-dependent manner. Under starvation, KDM2A activity is stimulated, reducing H3K36me1/me2 at the rDNA promoter and suppressing rRNA transcription. Cell-permeable succinate inhibits KDM2A demethylase activity and prevents starvation-induced rRNA transcription reduction.","method":"Overexpression, knockdown, ChIP assays, nucleolar localization by microscopy, succinate inhibitor treatment","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, localization, enzymatic inhibition, knockdown/overexpression) replicated by subsequent independent labs","pmids":["20379134"],"is_preprint":false},{"year":2015,"finding":"Mild glucose starvation activates KDM2A through AMPK signaling to reduce H3K36me2 at the rDNA promoter and suppress rRNA transcription and cell proliferation; this pathway is distinct from TIF-IA regulation by AMPK and operates in both ER+ and triple-negative breast cancer cells.","method":"2-DG treatment, AMPK inhibition, KDM2A knockdown, ChIP assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epistasis via pharmacological pathway dissection and knockdown with ChIP in multiple cell lines, single lab","pmids":["26416883"],"is_preprint":false},{"year":2019,"finding":"Metformin activates KDM2A to reduce rRNA transcription and cell proliferation by a dual mechanism requiring both AMPK activation and reduction of intracellular succinate levels; AMPK activation alone is insufficient without the succinate reduction, as succinate replenishment blocks KDM2A activation but not AMPK activation.","method":"Metformin treatment, AMPK inhibition, metabolite (succinate, α-ketoglutarate) supplementation, ChIP assays, KDM2A knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dissection of dual metabolic inputs with pharmacological and genetic tools combined with ChIP, single lab","pmids":["31822720"],"is_preprint":false},{"year":2017,"finding":"KDM2A integrates DNA methylation and H3K9me3 histone modification signals through a nucleosome interaction module comprising a CXXC zinc finger, a PHD domain, and a directly identified HP1-binding motif (LxVxL-type). KDM2A directly binds HP1 and can be recruited to H3K9me3-modified chromatin through HP1, while HP1 can also be recruited to unmethylated chromatin by KDM2A. A KDM2A mutant deficient in HP1-binding is inactive in an in vivo zebrafish overexpression assay.","method":"Biochemical pulldown, direct binding assays, HP1-binding motif mutagenesis, in vivo zebrafish functional assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical reconstitution with domain mutagenesis and in vivo functional validation, single lab with multiple orthogonal approaches","pmids":["28180290"],"is_preprint":false},{"year":2019,"finding":"HP1γ directly binds KDM2A via the LxVxL motif (valine 801) of KDM2A and is required for nucleolar accumulation of KDM2A; knockdown of HP1γ or mutation of V801 reduces nucleolar KDM2A and suppresses starvation-induced reduction of rRNA transcription.","method":"Co-IP, point mutagenesis, HP1γ knockdown, nucleolar localization microscopy, ChIP","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding defined by mutagenesis and knockdown with functional consequence, single lab","pmids":["31413816"],"is_preprint":false},{"year":2008,"finding":"KDM2A associates with heterochromatin and directly interacts with HP1, promoting HP1 localization to chromatin. KDM2A is required to maintain the heterochromatic state (demonstrated by epigenetic reporter), associates with centromeres, and represses transcription of small non-coding RNAs encoded by centromeric satellite repeats. Forced expression of satellite RNAs compromised HP1 localization and the heterochromatic state.","method":"siRNA knockdown, epigenetic reporter system, co-IP, centromere association by immunofluorescence/ChIP, satellite RNA overexpression","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter, co-IP, functional rescue) in single lab","pmids":["19001877"],"is_preprint":false},{"year":2015,"finding":"ATM interacts with KDM2A; their interaction increases in response to DNA double-strand breaks. ATM specifically phosphorylates KDM2A at threonine 632 (T632) following DNA damage. T632 phosphorylation does not alter KDM2A demethylase activity but abrogates its chromatin-binding capacity, leading to increased H3K36me2 near DNA damage sites. Enriched H3K36me2 recruits the MRE11 complex via direct interaction with the BRCT2 domain of NBS1, enabling efficient DNA damage repair.","method":"Co-IP, ATM interaction assay, mutagenesis (T632 site), mass spectrometry, ChIP, DNA damage assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — phospho-site identification by mutagenesis + mass spectrometry, ChIP, and mechanistic epistasis in single rigorous study","pmids":["25823024"],"is_preprint":false},{"year":2020,"finding":"SIRT6 mono-ADP ribosylates KDM2A, leading to rapid displacement of KDM2A from chromatin, resulting in increased H3K36me2 levels at DNA damage sites; H3K36me2 then promotes H3K9 trimethylation via HP1α binding, which transiently suppresses RNA Pol II transcription initiation and recruits NHEJ factors to DSBs.","method":"SIRT6 enzymatic assay, chromatin displacement assay, H3K36me2/H3K9me3 ChIP, NHEJ factor recruitment assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzymatic modification identified with downstream chromatin and transcriptional consequence, single lab","pmids":["32584788"],"is_preprint":false},{"year":2013,"finding":"KDM2A epigenetically represses DUSP3 expression by demethylating H3K36me2 at the DUSP3 locus in NSCLC cells. DUSP3 dephosphorylates ERK1/2, so KDM2A overexpression activates ERK1/2 signaling through epigenetic suppression of DUSP3.","method":"KDM2A knockdown/overexpression, catalytic mutant, ChIP at DUSP3 locus, ERK1/2 phosphorylation assays, rescue experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — catalytic mutant compared to WT in defined pathway with ChIP and biochemical readout, replicated in cell lines and xenografts","pmids":["24200691"],"is_preprint":false},{"year":2014,"finding":"KDM2A transcriptionally represses HDAC3 by removing H3K36me2 at the HDAC3 promoter in NSCLC cells. HDAC3 in turn represses cell cycle (CDK6) and invasion (NANOS1) genes; thus KDM2A promotes NSCLC tumorigenicity through the KDM2A→HDAC3 repression→CDK6/NANOS1 de-repression axis.","method":"KDM2A knockdown/overexpression (catalytic mutant controls), ChIP at HDAC3 promoter, HDAC3 knockdown rescue experiments, xenograft models","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — catalytic mutant + ChIP + genetic epistasis (double KD rescue), single lab with orthogonal methods","pmids":["24482232"],"is_preprint":false},{"year":2017,"finding":"KDM2A interacts with RelA (NF-κB subunit) and co-occupies the TET2 gene promoter to repress TET2 transcription, reducing 5'-hydroxymethylcytosine levels in genomic DNA. Depletion of RelA or KDM2A restores TET2 expression, leading to re-activation of TET2 downstream targets (EpCAM, E-cadherin) and inhibition of breast cancer invasion.","method":"Co-IP, ChIP, knockdown-rescue assays, 5-hmc level measurement, invasion assays","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional evidence with Co-IP and ChIP, single lab","pmids":["28785073"],"is_preprint":false},{"year":2015,"finding":"Kdm2a and Kdm2b regulate the turnover of non-phosphorylated β-catenin specifically within the nucleus via direct interaction with the fourth and fifth armadillo repeats of β-catenin; the lysine residues in this region are required for methylation of non-phosphorylated β-catenin, which is demethylated by Kdm2a/b and subsequently ubiquitylated. Kdm2a/b knockdown in Xenopus embryos increases non-phosphorylated and methylated β-catenin and upregulates β-catenin target genes.","method":"Direct interaction assays (Co-IP/pulldown), β-catenin methylation-ubiquitylation assays, Xenopus embryo knockdown with phenotypic and molecular readouts","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct protein interaction mapped to specific domains, coupled biochemical modification (methylation→ubiquitylation) assays, in vivo Xenopus model with axis readout","pmids":["26004508"],"is_preprint":false},{"year":2023,"finding":"KDM2A promotes proteasomal degradation of TCF/LEF transcription factors (including TCF7L2) independently of its demethylase domain; this requires the KDM2A CXXC domain and is neddylation-dependent. The C-terminal region of TCF7L2 and the CXXC domain of KDM2A mediate their direct interaction.","method":"Co-IP, domain deletion/mutagenesis, proteasome inhibition, neddylation inhibition, protein stability assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping by co-IP with multiple functional interventions, single lab","pmids":["37998355"],"is_preprint":false},{"year":2020,"finding":"Alternative short isoform of KDM2A (KDM2A-SF), which lacks the JmjC demethylase domain, binds to CpG island promoters via its CXXC domain and represses canonical Wnt signaling target genes (Axin2, Cyclin D1) in a demethylase-independent manner. KDM2A-SF and KDM2B-SF interact with the Wnt transcriptional mediator TCF7L1.","method":"ChIP at target promoters, luciferase reporter assays, co-IP with TCF7L1, domain deletion analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP, reporter, Co-IP with functional domain dissection, single lab","pmids":["33104714"],"is_preprint":false},{"year":2017,"finding":"The short isoform of KDM2A (SF-KDM2A), lacking the JmjC domain, localizes to nucleoli, binds the rDNA promoter via its zf-CXXC domain, reduces H4K20me3 at the rDNA promoter, and activates rRNA transcription; CXXC domain mutation abolishes both promoter binding and rRNA transcription activation.","method":"Nucleolar localization assays, ChIP at rDNA promoter, CXXC domain mutagenesis, H4K20me3 ChIP, SF-KDM2A knockdown/overexpression","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis combined with ChIP and functional readout, single lab","pmids":["28350064"],"is_preprint":false},{"year":2023,"finding":"KDM2A is required for dissolution of ALT-specific telomere clusters following recombination-directed telomere DNA synthesis; mechanistically, KDM2A promotes de-clustering of ALT multitelomeres by facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Loss of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and causes chromosome missegregation and mitotic cell death.","method":"CRISPR/Cas9 genetic screens, KDM2A/SENP6 co-epistasis, telomere SUMO assays, chromosome segregation analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double inactivation), biochemical SUMO assays, and functional cellular phenotype in a rigorous study with orthogonal methods","pmids":["36991019"],"is_preprint":false},{"year":2014,"finding":"Fbxl11/Kdm2a knockout mice die at E10.5-12.5 with severe growth defects, decreased cell proliferation, and increased apoptosis. Loss of Fbxl11 reduces Polycomb group protein Ezh2 and PcG-mediated H2A ubiquitination, and upregulates the CDK inhibitor p21Cip1.","method":"Knockout mouse generation, histology, Western blot, immunostaining for H2A ubiquitination and p21Cip1","journal":"Mechanisms of development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO mouse with defined molecular phenotype (Ezh2, H2AUb, p21) across multiple endpoints","pmids":["25463925"],"is_preprint":false},{"year":2013,"finding":"KDM2A depletion in stem cells from apical papilla (SCAPs) inhibits cell proliferation and arrests the cell cycle at G1/S by de-repressing the CDK inhibitors p15INK4B and p27Kip1. ChIP assays showed that KDM2A knockdown increases H3K4 trimethylation at p15INK4B and p27Kip1 loci.","method":"shRNA knockdown, cell cycle analysis by flow cytometry, ChIP for H3K4me3 at target loci","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — knockdown with ChIP defining epigenetic mechanism, single lab","pmids":["23559091"],"is_preprint":false},{"year":2016,"finding":"KDM2A silencing in SCAPs de-represses SFRP2 transcription by increasing H3K4 and H3K36 methylation at the SFRP2 promoter; SFRP2 enhances osteo/dentinogenic differentiation via Osterix transcription factor. BCOR functions as a co-factor of KDM2A in this regulation.","method":"KDM2A knockdown, ChIP for H3K4me/H3K36me at SFRP2 promoter, differentiation assays, BCOR knockdown","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP at specific locus with functional differentiation outcome, single lab","pmids":["27074224"],"is_preprint":false},{"year":2013,"finding":"KDM2A knockdown in SCAPs increases H3K4me3 at SOX2 and NANOG loci and upregulates these stemness genes. Co-factor BCOR knockdown similarly increases SOX2 and NANOG mRNA, suggesting BCOR acts with KDM2A to repress stemness genes. KDM2A depletion enhances adipogenic and chondrogenic differentiation.","method":"shRNA knockdown of KDM2A and BCOR, ChIP for H3K4me3, differentiation assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP evidence combined with knockdown and differentiation phenotype, single lab","pmids":["23872478"],"is_preprint":false},{"year":2014,"finding":"KDM2A physically binds Rb and E2F1 in a cell cycle-dependent manner and represses E2F1 transcriptional activity. ChIP assays demonstrate KDM2A associates with E2F1-regulated proliferative promoters (CDC25A, TS) in early G-phase and dissociates in S-phase. KDM2A also occupies MMP9, 14, 15, FLT1, and KDR promoters and suppresses E2F1-mediated induction of these promoters.","method":"Co-IP, ChIP at promoters, cell cycle synchronization, luciferase reporter assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ChIP with functional reporter assays, single lab","pmids":["25029110"],"is_preprint":false},{"year":2021,"finding":"Myeloid-specific knockout of Kdm2a increases H3K36me2 levels at the Pparg locus with augmented chromatin accessibility and Stat6 recruitment, rendering macrophages with preferential M2 polarization. Kdm2a-deficient mice are protected from HFD-induced obesity and insulin resistance.","method":"Conditional KO (LysM-Cre), H3K36me2 ChIP at Pparg locus, ATAC-seq for chromatin accessibility, Stat6 ChIP, metabolic phenotyping","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with ChIP, ATAC-seq, and mechanistic epistasis linking H3K36me2 to macrophage fate and metabolic phenotype","pmids":["33462408"],"is_preprint":false},{"year":2024,"finding":"In male germ cells, KDM2A acts as a lysine demethylase targeting H3K36me3 (in addition to H3K36me2). Conditional deletion of Kdm2a in pre-meiotic germ cells causes complete male sterility with spermatogenesis arrested at the zygotene stage. KDM2A deficiency disrupts H3K36me2/3 balance (reducing H3K36me2 and increasing H3K36me3 in c-KIT+ germ cells). KDM2A recruits transcription factor E2F1 and co-factor HCFC1 to promoters of meiosis entry/progression genes (Stra8, Meiosin, Spo11, Sycp1).","method":"Conditional KO mice (pre-meiotic specific), ChIP-seq for H3K36me2/3, Co-IP for E2F1/HCFC1, ChIP at meiotic gene promoters","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with ChIP-seq and Co-IP defining the molecular mechanism, multiple orthogonal approaches","pmids":["39160277"],"is_preprint":false},{"year":2025,"finding":"Conditional deletion of Kdm2a in spermatogonia using a different Cre system demonstrates Kdm2a is required for Polycomb-mediated repression during spermatogonial differentiation: KO spermatogonia show increased H3K36me2 and reduced H3K27me3 at CpG-rich gene promoters, with failed gene repression of 750+ genes. In spermatocytes, Kdm2a loss disrupts meiotic prophase, chromosome synapsis, processing of meiotic DSBs, and X-linked gene repression.","method":"Conditional KO (spermatogonia-specific Cre), RNA-seq, ChIP-seq for H3K36me2 and H3K27me3, DSB repair analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with ChIP-seq and RNA-seq establishing mechanistic link between KDM2A, H3K36me2, H3K27me3, and Polycomb-dependent gene repression","pmids":["40701999"],"is_preprint":false},{"year":2021,"finding":"KDM2A targets PFKFB3 (6-phosphofructo-2-kinase) for ubiquitylation and proteasomal degradation through its ubiquitin ligase (F-box) activity, suppressing myeloma cell proliferation and angiogenesis; this is independent of KDM2A histone demethylase activity.","method":"Co-IP, ubiquitylation assays, PFKFB3 stability/degradation assays, KDM2A overexpression/knockdown in multiple myeloma cells","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ubiquitylation assays with functional readout, single lab","pmids":["34079757"],"is_preprint":false},{"year":2025,"finding":"In skeletal muscle, Kdm2a deficiency increases H3K36me2 levels at the Esrrg locus, promoting recruitment of Mrg15 to process Esrrg precursor mRNA splicing, thereby reshaping skeletal muscle metabolic profiles to induce slow-twitch myofiber transition. Deletion or inhibition of Kdm2a shifts fuel use and protects mice against cold insults and HFD-induced obesity.","method":"Conditional KO (muscle-specific), H3K36me2 ChIP at Esrrg, Mrg15 co-IP/ChIP, mRNA splicing analysis, metabolic phenotyping","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo with ChIP, RNA processing mechanistic follow-up, and metabolic phenotyping providing strong mechanistic support","pmids":["39870955"],"is_preprint":false},{"year":2024,"finding":"KDM2A and KDM2B redundantly protect a subset of CpG islands from DNA methylation in an H3K36me2 demethylation-dependent manner; double KO of Kdm2a/2b causes stronger increase in CGI DNA methylation than single KOs. JmjC domain mutations that abolish demethylase activity phenocopy the double KO, confirming the catalytic mechanism underlies CGI protection from aberrant methylation.","method":"Kdm2a/2b single and double KO, JmjC domain catalytic mutations, DNA methylation profiling","journal":"Journal of genetics and genomics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — genetic and catalytic mutagenesis with genome-wide methylation readout, dual KO epistasis","pmids":["39522683"],"is_preprint":false},{"year":2025,"finding":"PHF8 interacts with KDM2A via two regions including an intrinsically disordered region (IDR) of KDM2A and negatively regulates KDM2A activity toward rRNA transcription; AMPK-mediated dephosphorylation of KDM2A at Ser731 (located N-terminal to the PHF8-binding region) reduces PHF8 binding and activates KDM2A. A S731A KDM2A mutant shows decreased PHF8 binding and reduced rRNA transcription.","method":"Co-IP, domain deletion mapping, S731A mutagenesis, AMPK activator treatment, rRNA transcription assays","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis-defined phospho-site with Co-IP and functional rRNA assay, single lab","pmids":["40427554"],"is_preprint":false},{"year":2025,"finding":"De novo variants in KDM2A that cause intellectual disability affect KDM2A subcellular distribution, expression, and stability in human cells. Genetic epistasis in Drosophila indicated that some variants act through loss of nuclear function, while at least one variant (c.704C>T, p.Pro235Leu) also confers cytoplasmic gain-of-function toxicity, as eliminating endogenous Drosophila Kdm2 does not reproduce the neurodevelopmental phenotype.","method":"Human cell expression/localization assays for pathogenic variants, Drosophila KDM2A variant expression and Kdm2 endogenous KO epistasis, enzymatic-methylation sequencing of patient blood","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — variant functional characterization in human cells and Drosophila genetic epistasis, single study but two orthogonal model systems","pmids":["41468891"],"is_preprint":false},{"year":2023,"finding":"Hepatitis B virus core protein (HBC) interacts with RANGAP1 and stabilizes it by disrupting the RANGAP1-SYVN1 (E3 ligase) interaction; stabilized RANGAP1 then interacts with KDM2A and promotes KDM2A stabilization by disrupting the KDM2A-SYVN1 interaction, thereby upregulating KDM2A to facilitate HCC cell growth and migration.","method":"Co-IP, Western blot, SYVN1-KDM2A interaction assays, stability/ubiquitination assays","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP mapping protein interactions with stability assays, single lab","pmids":["37845585"],"is_preprint":false},{"year":2023,"finding":"KDM2A knockdown in NSD1-deficient HNSCC reverses decreased H3K36me2 and elevated H3K27me3 at CXCL9 and CXCL10 promoters, restores T-cell chemokine expression, and enables T-cell infiltration into the tumor microenvironment. KDM2A suppression inhibited tumor growth only in immunocompetent mice, establishing KDM2A as the primary H3K36me2 demethylase whose activity is antagonistic to NSD1-dependent H3K36me2 writing.","method":"KDM2A knockdown, ChIP for H3K36me2/H3K27me3 at chemokine promoters, immunocompetent vs immunodeficient mouse tumor models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with KDM2A and NSD1, ChIP-defined histone mark changes, in vivo immunocompetent vs. immunodeficient comparison","pmids":["37311054"],"is_preprint":false},{"year":2025,"finding":"STAT3 forms a complex specifically with NFκB p50 (not p65) that occupies the KDM2A promoter at an NFκB p50 binding motif, upregulating KDM2A expression in cancer-associated fibroblasts in response to IL-6. KDM2A-expressing CAFs secrete CXCR2-associated chemokines promoting M2 macrophage polarization.","method":"Co-IP for STAT3-NFκB p50 complex, ChIP at KDM2A promoter, pharmacological/genetic inhibition of pathway components, flow cytometry for macrophage markers","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ChIP defining transcriptional mechanism, single lab","pmids":["37821959"],"is_preprint":false},{"year":2024,"finding":"DUX4-mediated transcription of HSATII pericentromeric satellite repeats causes nuclear foci formation of KDM2A/B-PRC1 complexes, sequestering them and causing global loss of PRC1-mediated monoubiquitination of histone H2A; this loss of PRC1-H2Aub signaling severely impairs DNA damage response.","method":"DUX4 expression, immunofluorescence for KDM2A/B-PRC1 nuclear foci, H2A ubiquitination assays, DNA damage response assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional sequestration mechanism defined by nuclear foci formation with downstream H2Aub and DDR readout, single lab","pmids":["38451221"],"is_preprint":false},{"year":2023,"finding":"KDM2A-mediated reduction of H3K36me2 at MAPK pathway gene loci (particularly p38 MAPK pathway genes) in neural progenitor cells impairs NPC proliferation, increases apoptosis, and causes premature neuronal differentiation. De novo mutations in KDM2A identified in intellectual disability patients significantly decrease KDM2A protein levels. ChIP-seq shows KDM2A binding at transcription start sites of neurogenesis genes and H3K36me2 reduction at downstream regulatory elements upon KDM2A knockdown.","method":"KDM2A knockdown, ChIP-seq for KDM2A binding and H3K36me2, RNA-seq in neural stem cells and cerebral organoids, characterization of patient variants","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and RNA-seq integrated with patient variant characterization in neural model, single lab","pmids":["38060137"],"is_preprint":false},{"year":2025,"finding":"RBM15-mediated m6A modification upregulates KDM2A mRNA, leading to increased KDM2A protein; elevated KDM2A reduces H3K36me2 enrichment at the HOXA2 promoter (by ChIP) to inhibit HOXA2 expression, promoting chondrocyte ferroptosis in an OA cell model.","method":"RIP assay for m6A on KDM2A mRNA, dual-luciferase assay, ChIP for H3K36me2 at HOXA2 promoter, rescue experiments","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP-defined locus-specific mechanism with upstream m6A regulation validated by RIP and reporter assay, single lab","pmids":["41349348"],"is_preprint":false}],"current_model":"KDM2A is a JmjC-domain-containing histone demethylase that specifically removes mono- and di-methyl groups from H3K36 (H3K36me1/me2) by threading the substrate peptide through a catalytic groove in a U-shaped conformation, with trimethylated H3K36 excluded by steric constraints on 2-OG rearrangement; it is recruited genome-wide to unmethylated CpG islands through its ZF-CXXC domain binding linker DNA, and to heterochromatin through direct HP1 interaction via an LxVxL motif in its intrinsically disordered region. At rDNA promoters, KDM2A demethylates H3K36me2 in response to energy deprivation (glucose starvation, metformin) via AMPK activation and reduction of intracellular succinate, repressing rRNA transcription and cell proliferation; regulation involves phosphorylation of Ser731 controlling interaction with PHF8. In response to DNA DSBs, ATM phosphorylates KDM2A at T632, displacing it from chromatin, elevating H3K36me2 near damage sites to recruit the MRE11/NBS1 complex for repair; SIRT6 additionally mono-ADP-ribosylates KDM2A to promote chromatin displacement and NHEJ. KDM2A also acts as an F-box-containing SCF E3 ligase to ubiquitylate non-phosphorylated nuclear β-catenin (after its demethylation) and to degrade PFKFB3 and TCF/LEF transcription factors. In cancers, oncogenic KDM2A overexpression epigenetically silences tumor-suppressor loci (DUSP3, HDAC3, TET2, RARRES3) via H3K36me2 demethylation; in ALT-dependent cancers, KDM2A uniquely promotes telomere de-clustering by facilitating SENP6-mediated SUMO deconjugation at telomeres. In macrophages, Kdm2a deletion increases H3K36me2 at the Pparg locus to drive M2 polarization, and in skeletal muscle, Kdm2a deletion increases H3K36me2 at Esrrg to recruit Mrg15 for alternative splicing, promoting slow-twitch fiber transition and metabolic flexibility."},"narrative":{"mechanistic_narrative":"KDM2A is a JmjC-domain histone demethylase that selectively removes mono- and di-methyl marks from histone H3 lysine 36 (H3K36me1/me2), with H3K36me3 normally excluded by steric constraints on substrate rearrangement in the catalytic groove [PMID:20379134, PMID:25128496, PMID:24553073, PMID:38781256]. Genome-wide targeting is achieved through its ZF-CXXC domain, which reads non-methylated CpG dinucleotides on linker DNA and recognizes CpG islands by combining unmethylated DNA state with reduced nucleosome occlusion; productive nucleosome engagement additionally depends on the acidic patch and DNA unwrapping [PMID:36797403, PMID:22083960, PMID:39522683]. Together with KDM2B, KDM2A protects CpG islands from aberrant DNA methylation in a catalysis-dependent manner [PMID:39522683], and it integrates heterochromatin signals by binding HP1 through an LxVxL motif, coupling H3K9me3-marked chromatin to its demethylase function [PMID:28180290, PMID:19001877]. At rDNA promoters KDM2A localizes to nucleoli and represses rRNA transcription by demethylating H3K36me2 in response to energy deprivation, an activity stimulated by AMPK signaling and by reduction of intracellular succinate following glucose starvation or metformin, and modulated by Ser731 phosphorylation that governs PHF8 binding [PMID:20379134, PMID:26416883, PMID:31822720, PMID:40427554]. KDM2A participates in the DNA double-strand break response: ATM phosphorylates it at T632 and SIRT6 mono-ADP-ribosylates it, both displacing KDM2A from chromatin to raise local H3K36me2 that recruits the MRE11/NBS1 complex and NHEJ machinery [PMID:25823024, PMID:32584788]. Beyond demethylation, KDM2A functions through its F-box/CXXC-dependent activities to direct ubiquitin- and neddylation-coupled degradation of nuclear non-phosphorylated β-catenin, PFKFB3, and TCF/LEF factors [PMID:26004508, PMID:37998355, PMID:34079757]. In oncogenic contexts KDM2A silences tumor-suppressor loci including DUSP3, HDAC3, and TET2 via H3K36me2 demethylation [PMID:24200691, PMID:24482232, PMID:28785073], antagonizes NSD1-dependent H3K36me2 writing to suppress T-cell chemokine expression [PMID:37311054], and promotes de-clustering of ALT telomeres via SENP6-mediated SUMO deconjugation [PMID:36991019]. In vivo, KDM2A is essential for embryogenesis [PMID:25463925] and shapes cell fate across tissues, restraining macrophage M2 polarization at the Pparg locus, controlling slow-twitch myofiber identity through Esrrg splicing, and governing meiotic gene programs in male germ cells [PMID:33462408, PMID:39160277, PMID:39870955]. De novo KDM2A variants cause intellectual disability through altered protein stability and localization [PMID:41468891, PMID:38060137].","teleology":[{"year":2007,"claim":"Established the founding biochemical identity of KDM2A by showing it is an enzyme that erases a specific histone mark, defining its molecular activity.","evidence":"In vitro demethylase assays and mass spectrometry of histone modifications","pmids":["20379134","25128496","24553073"],"confidence":"High","gaps":["Did not explain the structural basis of H3K36me1/2 selectivity versus me3 exclusion","Genomic targeting mechanism not yet addressed"]},{"year":2014,"claim":"Resolved how KDM2A discriminates methylation states, showing substrate threading and active-site geometry enforce H3K36me1/me2 specificity and exclude me3.","evidence":"X-ray crystallography with structure-guided mutagenesis and cancer-phenotype functional assays","pmids":["25128496"],"confidence":"High","gaps":["Did not capture KDM2A engaging an intact nucleosome","Catalytic chemistry of the off-line-to-in-line transition not directly observed"]},{"year":2024,"claim":"Defined the catalytic chemistry of state selectivity, identifying Y222 conformational control of 2-oxoglutarate rearrangement as the basis for H3K36me3 inactivity.","evidence":"QM/MM and molecular dynamics simulations with variant analysis","pmids":["38781256"],"confidence":"Medium","gaps":["Computational only; no experimental wet-lab Y222 mutagenesis validation reported","Relevance of predicted variants to cellular activity untested"]},{"year":2023,"claim":"Revealed how KDM2A reaches its substrate on chromatin, showing nucleosome binding requires the acidic patch and DNA unwrapping — distinguishing it from KDM2B.","evidence":"Cryo-EM of KDM2A trapped on nucleosomes via a covalent H3K36-inhibitor conjugate plus acidic-patch interactome screen","pmids":["36797403"],"confidence":"High","gaps":["Did not address regulation of nucleosome engagement in vivo","Interplay with CpG-island targeting not resolved structurally"]},{"year":2011,"claim":"Identified the genomic targeting principle, showing the ZF-CXXC domain recruits KDM2A to unmethylated CpG islands via linker DNA with nucleosomes as a barrier.","evidence":"Defined chromatin templates in vitro combined with in vivo chromatin profiling and ZF-CXXC biochemistry","pmids":["22083960"],"confidence":"High","gaps":["Did not establish functional consequence of CGI binding genome-wide","Did not separate targeting from catalytic requirement"]},{"year":2010,"claim":"Connected KDM2A catalysis to nucleolar rRNA control and metabolic state, showing it represses rRNA transcription under starvation and is inhibited by succinate.","evidence":"Overexpression/knockdown, ChIP, nucleolar microscopy, and succinate inhibition at the rDNA promoter","pmids":["20379134"],"confidence":"High","gaps":["Upstream signaling linking starvation to KDM2A activity not defined","Did not separate CpG-binding from catalytic requirement at rDNA"]},{"year":2015,"claim":"Mapped the energy-sensing pathway, showing AMPK signaling and CxxC-ZF-dependent rDNA binding are both required for starvation-induced rRNA repression.","evidence":"2-DG/AMPK inhibition with domain mutagenesis, ChIP, and knockdown-rescue in breast cancer cells","pmids":["26416883","24553073"],"confidence":"High","gaps":["Did not resolve how AMPK mechanistically modifies KDM2A","Succinate contribution not yet separated from AMPK"]},{"year":2019,"claim":"Dissected the dual metabolic inputs, showing metformin activates KDM2A only when AMPK activation is combined with succinate reduction.","evidence":"Metformin treatment with metabolite supplementation, AMPK inhibition, and ChIP","pmids":["31822720"],"confidence":"Medium","gaps":["Direct molecular target of AMPK on KDM2A not identified here","Single-lab pharmacological dissection"]},{"year":2025,"claim":"Identified a phospho-switch regulating rDNA activity, showing AMPK-driven Ser731 dephosphorylation reduces inhibitory PHF8 binding to activate KDM2A.","evidence":"Co-IP, domain mapping, S731A mutagenesis, and rRNA transcription assays","pmids":["40427554"],"confidence":"Medium","gaps":["Direct kinase/phosphatase acting on Ser731 not fully defined","Single-lab finding awaiting independent confirmation"]},{"year":2008,"claim":"Linked KDM2A to heterochromatin maintenance, showing it interacts with HP1, associates with centromeres, and represses satellite RNA transcription.","evidence":"siRNA knockdown, epigenetic reporter, co-IP, centromere ChIP/IF, and satellite-RNA overexpression","pmids":["19001877"],"confidence":"Medium","gaps":["The HP1-binding motif was not mapped here","Causal direction between HP1 localization and heterochromatin state incompletely resolved"]},{"year":2017,"claim":"Defined the molecular HP1 interface, mapping an LxVxL-type motif that couples DNA methylation and H3K9me3 signals through a multivalent nucleosome module.","evidence":"Biochemical pulldown, direct binding assays, motif mutagenesis, and in vivo zebrafish assay","pmids":["28180290"],"confidence":"High","gaps":["Did not establish which HP1 paralog dominates in vivo","Functional output of HP1 coupling at native loci not fully resolved"]},{"year":2019,"claim":"Connected HP1 binding to nucleolar function, showing HP1γ binding at V801 is required for nucleolar accumulation and starvation-induced rRNA repression.","evidence":"Co-IP, V801 point mutagenesis, HP1γ knockdown, and nucleolar microscopy/ChIP","pmids":["31413816"],"confidence":"Medium","gaps":["Mechanism linking HP1γ to nucleolar retention not detailed","Single-lab finding"]},{"year":2015,"claim":"Established KDM2A's role in the DSB response, showing ATM-mediated T632 phosphorylation displaces it from chromatin, raising H3K36me2 to recruit MRE11/NBS1.","evidence":"Co-IP, ATM interaction, T632 mutagenesis/mass spectrometry, ChIP, and DNA-damage repair assays","pmids":["25823024"],"confidence":"High","gaps":["How elevated H3K36me2 is specifically read by NBS1 at damage sites not fully resolved","Kinetics of re-loading after repair unaddressed"]},{"year":2020,"claim":"Added a second displacement mechanism, showing SIRT6 mono-ADP-ribosylates KDM2A to elevate H3K36me2, drive H3K9me3/HP1α, and recruit NHEJ factors.","evidence":"SIRT6 enzymatic assay, chromatin displacement, H3K36me2/H3K9me3 ChIP, and NHEJ recruitment assays","pmids":["32584788"],"confidence":"Medium","gaps":["ADP-ribosylation site on KDM2A not defined","Relationship between SIRT6 and ATM-driven displacement not reconciled"]},{"year":2015,"claim":"Revealed a non-histone catalytic axis, showing KDM2A demethylates and then ubiquitylates nuclear non-phosphorylated β-catenin to control Wnt signaling.","evidence":"Domain-mapped interaction assays, coupled methylation-ubiquitylation assays, and Xenopus embryo knockdown","pmids":["26004508"],"confidence":"High","gaps":["The methyltransferase generating the β-catenin methyl mark not identified","Demethylase-versus-F-box contributions not fully partitioned"]},{"year":2023,"claim":"Extended demethylase-independent degradation activity, showing CXXC- and neddylation-dependent KDM2A degrades TCF/LEF factors including TCF7L2.","evidence":"Co-IP, domain deletion, proteasome and neddylation inhibition, and stability assays","pmids":["37998355","33104714"],"confidence":"Medium","gaps":["E3 complex composition not biochemically reconstituted","In vivo relevance of TCF/LEF turnover untested"]},{"year":2021,"claim":"Generalized the E3 ligase function to metabolism, showing F-box-dependent KDM2A ubiquitylates PFKFB3 to suppress myeloma proliferation independent of demethylase activity.","evidence":"Co-IP, ubiquitylation and stability assays in myeloma cells","pmids":["34079757"],"confidence":"Medium","gaps":["SCF complex assembly not directly demonstrated","Single-lab finding"]},{"year":2013,"claim":"Defined oncogenic gene silencing, showing KDM2A demethylates H3K36me2 to repress DUSP3 and thereby activate ERK1/2 signaling in NSCLC.","evidence":"Catalytic mutant comparison, ChIP at DUSP3, ERK1/2 phosphorylation, and rescue assays","pmids":["24200691"],"confidence":"High","gaps":["Did not address breadth of repressed loci genome-wide","Selectivity of locus targeting not explained"]},{"year":2014,"claim":"Extended the silencing program, showing KDM2A represses HDAC3 to de-repress CDK6/NANOS1 and promote NSCLC tumorigenicity, and physically engages Rb/E2F1 to control proliferative promoters.","evidence":"Catalytic-mutant knockdown/overexpression, ChIP, double-knockdown rescue, xenografts, and cell-cycle-synchronized Co-IP","pmids":["24482232","25029110"],"confidence":"High","gaps":["Mechanism directing KDM2A to specific repressive targets unresolved","E2F1 regulation mechanism only partly defined"]},{"year":2017,"claim":"Linked KDM2A to DNA hydroxymethylation control, showing KDM2A co-occupies the TET2 promoter with RelA to repress TET2 and promote breast cancer invasion.","evidence":"Co-IP, ChIP, knockdown-rescue, 5-hmC measurement, and invasion assays","pmids":["28785073"],"confidence":"Medium","gaps":["Whether repression requires demethylase activity not fully resolved","Single-lab finding"]},{"year":2023,"claim":"Identified a unique telomere maintenance role, showing KDM2A enables SENP6-mediated SUMO deconjugation to de-cluster ALT telomeres and preserve chromosome segregation.","evidence":"CRISPR screens, KDM2A/SENP6 epistasis, telomere SUMO assays, and segregation analysis","pmids":["36991019"],"confidence":"High","gaps":["Molecular link between KDM2A and SENP6 activity not defined","Whether this requires demethylase or F-box activity unresolved"]},{"year":2014,"claim":"Established organismal essentiality, showing Fbxl11/Kdm2a knockout is embryonic lethal with reduced Ezh2/H2Aub and elevated p21.","evidence":"Knockout mouse generation with histology and molecular profiling","pmids":["25463925"],"confidence":"High","gaps":["Causal chain from KDM2A loss to Ezh2 reduction not mechanistically defined","Tissue-specific contributions not separated"]},{"year":2016,"claim":"Defined a stem/progenitor differentiation role, showing KDM2A with co-factor BCOR represses cell-cycle inhibitors, stemness genes, and differentiation regulators in SCAPs.","evidence":"shRNA knockdown of KDM2A and BCOR, ChIP for H3K4me3/H3K36me, and differentiation assays","pmids":["23559091","23872478","27074224"],"confidence":"Medium","gaps":["Relationship between H3K4me3 changes and KDM2A's H3K36me2 catalysis unclear","BCOR-KDM2A complex not biochemically reconstituted"]},{"year":2021,"claim":"Linked KDM2A catalysis to immunometabolic cell fate, showing myeloid Kdm2a loss raises H3K36me2 at Pparg to drive M2 polarization and protect against obesity.","evidence":"Conditional KO with Pparg H3K36me2 ChIP, ATAC-seq, Stat6 ChIP, and metabolic phenotyping","pmids":["33462408"],"confidence":"High","gaps":["Did not establish direct KDM2A recruitment mechanism to Pparg","Demethylase-versus-other-activity contribution not isolated"]},{"year":2024,"claim":"Defined germline and CpG-island roles, showing KDM2A balances H3K36me2/3, recruits E2F1/HCFC1 to meiotic genes, and (with KDM2B) protects CpG islands from DNA methylation through catalysis.","evidence":"Conditional KO mice with ChIP-seq/Co-IP, plus Kdm2a/2b single/double KO and JmjC catalytic mutants with methylation profiling","pmids":["39160277","39522683","40701999"],"confidence":"High","gaps":["The reported H3K36me3 activity in germ cells differs from the canonical me1/2 specificity and is not structurally explained","Polycomb coupling mechanism at CpG islands not fully defined"]},{"year":2025,"claim":"Extended catalytic control to muscle metabolism, showing Kdm2a loss raises H3K36me2 at Esrrg to recruit Mrg15 for splicing and drive slow-twitch transition.","evidence":"Muscle-specific conditional KO with Esrrg H3K36me2 ChIP, Mrg15 co-IP/ChIP, splicing analysis, and metabolic phenotyping","pmids":["39870955"],"confidence":"High","gaps":["How H3K36me2 mechanistically recruits Mrg15 to splicing not fully resolved","Direct KDM2A targeting to Esrrg not mapped"]},{"year":2023,"claim":"Defined immune-evasion and regulatory contexts, showing KDM2A antagonizes NSD1 H3K36me2 writing to suppress chemokine expression and is itself stabilized or transcriptionally induced in tumor microenvironments.","evidence":"KDM2A knockdown with ChIP and immunocompetent/immunodeficient tumor models; Co-IP/ChIP for SYVN1-RANGAP1 stability and STAT3/NFκB p50 promoter regulation","pmids":["37311054","37845585","37821959","38451221"],"confidence":"Medium","gaps":["Stability and transcriptional findings rest largely on single-lab Co-IP/ChIP","Whether chemokine repression is purely catalytic not fully isolated"]},{"year":2025,"claim":"Connected KDM2A to human disease, showing de novo variants cause intellectual disability via altered stability, localization, and impaired regulation of neurodevelopmental gene programs.","evidence":"Human cell variant localization/stability assays, Drosophila epistasis, and ChIP-seq/RNA-seq in neural models","pmids":["41468891","38060137"],"confidence":"Medium","gaps":["Loss- versus gain-of-function contributions differ across variants and are not fully reconciled","Mechanism connecting MAPK-locus H3K36me2 to neuronal phenotype incomplete"]},{"year":null,"claim":"How KDM2A's distinct activities — H3K36me2 demethylase, CpG-island reader, and F-box/SCF ubiquitin ligase — are partitioned, coordinated, and selectively deployed at specific loci and substrates in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model partitioning catalytic versus ligase functions across contexts","Mechanism selecting specific repressive target loci genome-wide undefined","Reported H3K36me3 activity conflicts with canonical me1/2 specificity"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,3,6]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,6,8]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,5,32]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[17,18,30]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[17,30]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[14,15,16,26]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[6,10,20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,12,17]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[11,12,21]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,4,32]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,7,14,15]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[12,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[17,30,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[22,28,31]}],"complexes":["SCF (F-box) ubiquitin ligase","KDM2A/B-PRC1"],"partners":["HP1","ATM","SIRT6","PHF8","CTNNB1","TCF7L2","E2F1","NBS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y2K7","full_name":"Lysine-specific demethylase 2A","aliases":["CXXC-type zinc finger protein 8","F-box and leucine-rich repeat protein 11","F-box protein FBL7","F-box protein Lilina","F-box/LRR-repeat protein 11","JmjC domain-containing histone demethylation protein 1A","[Histone-H3]-lysine-36 demethylase 1A"],"length_aa":1162,"mass_kda":132.8,"function":"Histone demethylase that specifically demethylates 'Lys-36' of histone H3, thereby playing a central role in histone code. Preferentially demethylates dimethylated H3 'Lys-36' residue while it has weak or no activity for mono- and tri-methylated H3 'Lys-36'. May also recognize and bind to some phosphorylated proteins and promote their ubiquitination and degradation. Required to maintain the heterochromatic state. Associates with centromeres and represses transcription of small non-coding RNAs that are encoded by the clusters of satellite repeats at the centromere. Required to sustain centromeric integrity and genomic stability, particularly during mitosis. Regulates circadian gene expression by repressing the transcriptional activator activity of CLOCK-BMAL1 heterodimer and RORA in a catalytically-independent manner (PubMed:26037310)","subcellular_location":"Nucleus, nucleoplasm; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9Y2K7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM2A","classification":"Common Essential","n_dependent_lines":820,"n_total_lines":1208,"dependency_fraction":0.6788079470198676},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KDM2A","total_profiled":1310},"omim":[{"mim_id":"615607","title":"IMMUNODEFICIENCY 17; IMD17","url":"https://www.omim.org/entry/615607"},{"mim_id":"605657","title":"LYSINE DEMETHYLASE 2A; KDM2A","url":"https://www.omim.org/entry/605657"}],"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/KDM2A"},"hgnc":{"alias_symbol":["KIAA1004","FBL11","LILINA","DKFZP434M1735","FBL7","FLJ00115","CXXC8","JHDM1A"],"prev_symbol":["FBXL11"]},"alphafold":{"accession":"Q9Y2K7","domains":[{"cath_id":"2.60.120.650","chopping":"37-326","consensus_level":"high","plddt":95.4732,"start":37,"end":326},{"cath_id":"1.20.58.1360","chopping":"328-355_450-519","consensus_level":"medium","plddt":92.8372,"start":328,"end":519},{"cath_id":"-","chopping":"566-613","consensus_level":"medium","plddt":87.391,"start":566,"end":613},{"cath_id":"3.30.40.10","chopping":"619-676","consensus_level":"medium","plddt":82.9024,"start":619,"end":676},{"cath_id":"3.80.10.10","chopping":"904-1159","consensus_level":"medium","plddt":89.8891,"start":904,"end":1159}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2K7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2K7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2K7-F1-predicted_aligned_error_v6.png","plddt_mean":73.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM2A","jax_strain_url":"https://www.jax.org/strain/search?query=KDM2A"},"sequence":{"accession":"Q9Y2K7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2K7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2K7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2K7"}},"corpus_meta":[{"pmid":"24200691","id":"PMC_24200691","title":"KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24200691","citation_count":155,"is_preprint":false},{"pmid":"19001877","id":"PMC_19001877","title":"KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19001877","citation_count":103,"is_preprint":false},{"pmid":"20379134","id":"PMC_20379134","title":"JmjC enzyme KDM2A is a regulator of rRNA transcription in response to starvation.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20379134","citation_count":90,"is_preprint":false},{"pmid":"26004508","id":"PMC_26004508","title":"Kdm2a/b Lysine Demethylases Regulate Canonical Wnt Signaling by Modulating the Stability of Nuclear β-Catenin.","date":"2015","source":"Developmental 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/41648535","citation_count":0,"is_preprint":false},{"pmid":"41192032","id":"PMC_41192032","title":"Vitamin C rescues embryonic developmental arrest caused by maternal Kdm2a deficiency via regulating PTEN/PI3K/AKT axis.","date":"2025","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/41192032","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.31.25324695","title":"De novo variants in<i>KDM2A</i>cause a syndromic neurodevelopmental disorder","date":"2025-04-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.31.25324695","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.26.25338579","title":"Ensilication preserves high-molecular weight native DNA for clinical long-read sequencing","date":"2025-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.26.25338579","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.14.25340263","title":"Interactions with polygenic background impact quantitative traits in the UK Biobank","date":"2025-11-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.14.25340263","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51559,"output_tokens":11063,"usd":0.160311,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21564,"output_tokens":8206,"usd":0.156485,"stage2_stop_reason":"end_turn"},"total_usd":0.316796,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"KDM2A (JHDM1A/FBXL11) is a JmjC-domain-containing histone demethylase that specifically demethylates mono- and dimethylated histone H3 lysine 36 (H3K36me1/me2), with little or no activity on trimethylated H3K36.\",\n      \"method\": \"In vitro demethylase assays, mass spectrometry of histone modifications\",\n      \"journal\": \"Multiple papers (e.g., Molecular and cellular biology, EMBO journal)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzymatic activity established by in vitro assays across multiple independent labs and replicated in numerous subsequent studies\",\n      \"pmids\": [\"20379134\", \"25128496\", \"24553073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Structural studies revealed that H3K36 specificity for KDM2A is mediated by U-shaped threading of the H3K36 peptide through a catalytic groove; key residues G33, G34 (positioned in a narrow channel), P38 (turn residue), and Y41 (inserts into its own pocket) contribute to K36me specificity. Steric constraints prevent trimethylated K36 from undergoing the 'off-line'-to-'in-line' transition required for demethylation. Structure-guided active-site mutations abrogated KDM2A-mediated suppression of cancer cell phenotypes.\",\n      \"method\": \"X-ray crystallography, structure-guided mutagenesis, functional assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional validation in a single rigorous study\",\n      \"pmids\": [\"25128496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"QM/MM and MD simulations demonstrated that KDM2A catalysis is controlled by a conformational change of the second coordination sphere residue Y222, which unlocks 2-oxoglutarate rearrangement from off-line to in-line mode; Y222A variant makes the rearrangement more favorable. The trimethylated lysine substrate is sterically unable to undergo this rearrangement, explaining H3K36me3 inactivity.\",\n      \"method\": \"Quantum mechanics/molecular mechanics (QM/MM), molecular dynamics simulations, variant analysis\",\n      \"journal\": \"Inorganic chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (computational reconstitution with mutagenesis inference) / Weak — single computational study, no experimental wet-lab mutagenesis validation reported in abstract\",\n      \"pmids\": [\"38781256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of KDM2A and KDM2B trapped on nucleosome substrates (using a covalent H3K36-inhibitor conjugate) revealed that KDM2A requires the nucleosome acidic patch for nucleosome binding whereas KDM2B does not; nucleosome binding by KDM2A is facilitated by dynamic nucleosomal DNA unwrapping and histone charge shielding that mobilize the H3K36 sequence for demethylation.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM), acidic patch interactome screen, covalent substrate-inhibitor conjugate\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures with functional mechanistic validation, rigorous structural study\",\n      \"pmids\": [\"36797403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM2A is specifically recruited to CpG islands via its ZF-CXXC domain through direct interaction with linker DNA at non-methylated CpG sequences; nucleosomes are a major barrier to KDM2A binding, and CpG islands are recognized through a combination of unmethylated DNA state and reduced nucleosome occlusion.\",\n      \"method\": \"Defined chromatin templates in vitro, chromatin profiling in vivo, ZF-CXXC domain biochemical characterization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with defined chromatin templates combined with in vivo chromatin profiling, single lab but orthogonal methods\",\n      \"pmids\": [\"22083960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The CxxC-ZF domain of KDM2A is required for binding to the rDNA promoter via unmethylated CpG dinucleotides in vitro and in vivo; this binding is required for KDM2A to demethylate H3K36me2 at the rDNA promoter in response to starvation and to reduce rDNA transcription. A JmjC catalytic domain mutation abolished demethylase activity and rDNA repression, while a CxxC-ZF mutation retained demethylase activity but failed to reduce rDNA transcription.\",\n      \"method\": \"Domain mutagenesis, ChIP, in vitro DNA binding, knockdown-rescue experiments\",\n      \"journal\": \"Cell structure and function\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain mutagenesis combined with ChIP and functional rescue, single lab with orthogonal approaches\",\n      \"pmids\": [\"24553073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KDM2A localizes to nucleoli and binds the rRNA gene (rDNA) promoter. Overexpression of KDM2A represses rRNA transcription in a demethylase-activity-dependent manner. Under starvation, KDM2A activity is stimulated, reducing H3K36me1/me2 at the rDNA promoter and suppressing rRNA transcription. Cell-permeable succinate inhibits KDM2A demethylase activity and prevents starvation-induced rRNA transcription reduction.\",\n      \"method\": \"Overexpression, knockdown, ChIP assays, nucleolar localization by microscopy, succinate inhibitor treatment\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, localization, enzymatic inhibition, knockdown/overexpression) replicated by subsequent independent labs\",\n      \"pmids\": [\"20379134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mild glucose starvation activates KDM2A through AMPK signaling to reduce H3K36me2 at the rDNA promoter and suppress rRNA transcription and cell proliferation; this pathway is distinct from TIF-IA regulation by AMPK and operates in both ER+ and triple-negative breast cancer cells.\",\n      \"method\": \"2-DG treatment, AMPK inhibition, KDM2A knockdown, ChIP assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via pharmacological pathway dissection and knockdown with ChIP in multiple cell lines, single lab\",\n      \"pmids\": [\"26416883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Metformin activates KDM2A to reduce rRNA transcription and cell proliferation by a dual mechanism requiring both AMPK activation and reduction of intracellular succinate levels; AMPK activation alone is insufficient without the succinate reduction, as succinate replenishment blocks KDM2A activation but not AMPK activation.\",\n      \"method\": \"Metformin treatment, AMPK inhibition, metabolite (succinate, α-ketoglutarate) supplementation, ChIP assays, KDM2A knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dissection of dual metabolic inputs with pharmacological and genetic tools combined with ChIP, single lab\",\n      \"pmids\": [\"31822720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM2A integrates DNA methylation and H3K9me3 histone modification signals through a nucleosome interaction module comprising a CXXC zinc finger, a PHD domain, and a directly identified HP1-binding motif (LxVxL-type). KDM2A directly binds HP1 and can be recruited to H3K9me3-modified chromatin through HP1, while HP1 can also be recruited to unmethylated chromatin by KDM2A. A KDM2A mutant deficient in HP1-binding is inactive in an in vivo zebrafish overexpression assay.\",\n      \"method\": \"Biochemical pulldown, direct binding assays, HP1-binding motif mutagenesis, in vivo zebrafish functional assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical reconstitution with domain mutagenesis and in vivo functional validation, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"28180290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HP1γ directly binds KDM2A via the LxVxL motif (valine 801) of KDM2A and is required for nucleolar accumulation of KDM2A; knockdown of HP1γ or mutation of V801 reduces nucleolar KDM2A and suppresses starvation-induced reduction of rRNA transcription.\",\n      \"method\": \"Co-IP, point mutagenesis, HP1γ knockdown, nucleolar localization microscopy, ChIP\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding defined by mutagenesis and knockdown with functional consequence, single lab\",\n      \"pmids\": [\"31413816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KDM2A associates with heterochromatin and directly interacts with HP1, promoting HP1 localization to chromatin. KDM2A is required to maintain the heterochromatic state (demonstrated by epigenetic reporter), associates with centromeres, and represses transcription of small non-coding RNAs encoded by centromeric satellite repeats. Forced expression of satellite RNAs compromised HP1 localization and the heterochromatic state.\",\n      \"method\": \"siRNA knockdown, epigenetic reporter system, co-IP, centromere association by immunofluorescence/ChIP, satellite RNA overexpression\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter, co-IP, functional rescue) in single lab\",\n      \"pmids\": [\"19001877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATM interacts with KDM2A; their interaction increases in response to DNA double-strand breaks. ATM specifically phosphorylates KDM2A at threonine 632 (T632) following DNA damage. T632 phosphorylation does not alter KDM2A demethylase activity but abrogates its chromatin-binding capacity, leading to increased H3K36me2 near DNA damage sites. Enriched H3K36me2 recruits the MRE11 complex via direct interaction with the BRCT2 domain of NBS1, enabling efficient DNA damage repair.\",\n      \"method\": \"Co-IP, ATM interaction assay, mutagenesis (T632 site), mass spectrometry, ChIP, DNA damage assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — phospho-site identification by mutagenesis + mass spectrometry, ChIP, and mechanistic epistasis in single rigorous study\",\n      \"pmids\": [\"25823024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIRT6 mono-ADP ribosylates KDM2A, leading to rapid displacement of KDM2A from chromatin, resulting in increased H3K36me2 levels at DNA damage sites; H3K36me2 then promotes H3K9 trimethylation via HP1α binding, which transiently suppresses RNA Pol II transcription initiation and recruits NHEJ factors to DSBs.\",\n      \"method\": \"SIRT6 enzymatic assay, chromatin displacement assay, H3K36me2/H3K9me3 ChIP, NHEJ factor recruitment assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzymatic modification identified with downstream chromatin and transcriptional consequence, single lab\",\n      \"pmids\": [\"32584788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM2A epigenetically represses DUSP3 expression by demethylating H3K36me2 at the DUSP3 locus in NSCLC cells. DUSP3 dephosphorylates ERK1/2, so KDM2A overexpression activates ERK1/2 signaling through epigenetic suppression of DUSP3.\",\n      \"method\": \"KDM2A knockdown/overexpression, catalytic mutant, ChIP at DUSP3 locus, ERK1/2 phosphorylation assays, rescue experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — catalytic mutant compared to WT in defined pathway with ChIP and biochemical readout, replicated in cell lines and xenografts\",\n      \"pmids\": [\"24200691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM2A transcriptionally represses HDAC3 by removing H3K36me2 at the HDAC3 promoter in NSCLC cells. HDAC3 in turn represses cell cycle (CDK6) and invasion (NANOS1) genes; thus KDM2A promotes NSCLC tumorigenicity through the KDM2A→HDAC3 repression→CDK6/NANOS1 de-repression axis.\",\n      \"method\": \"KDM2A knockdown/overexpression (catalytic mutant controls), ChIP at HDAC3 promoter, HDAC3 knockdown rescue experiments, xenograft models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant + ChIP + genetic epistasis (double KD rescue), single lab with orthogonal methods\",\n      \"pmids\": [\"24482232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM2A interacts with RelA (NF-κB subunit) and co-occupies the TET2 gene promoter to repress TET2 transcription, reducing 5'-hydroxymethylcytosine levels in genomic DNA. Depletion of RelA or KDM2A restores TET2 expression, leading to re-activation of TET2 downstream targets (EpCAM, E-cadherin) and inhibition of breast cancer invasion.\",\n      \"method\": \"Co-IP, ChIP, knockdown-rescue assays, 5-hmc level measurement, invasion assays\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional evidence with Co-IP and ChIP, single lab\",\n      \"pmids\": [\"28785073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kdm2a and Kdm2b regulate the turnover of non-phosphorylated β-catenin specifically within the nucleus via direct interaction with the fourth and fifth armadillo repeats of β-catenin; the lysine residues in this region are required for methylation of non-phosphorylated β-catenin, which is demethylated by Kdm2a/b and subsequently ubiquitylated. Kdm2a/b knockdown in Xenopus embryos increases non-phosphorylated and methylated β-catenin and upregulates β-catenin target genes.\",\n      \"method\": \"Direct interaction assays (Co-IP/pulldown), β-catenin methylation-ubiquitylation assays, Xenopus embryo knockdown with phenotypic and molecular readouts\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct protein interaction mapped to specific domains, coupled biochemical modification (methylation→ubiquitylation) assays, in vivo Xenopus model with axis readout\",\n      \"pmids\": [\"26004508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM2A promotes proteasomal degradation of TCF/LEF transcription factors (including TCF7L2) independently of its demethylase domain; this requires the KDM2A CXXC domain and is neddylation-dependent. The C-terminal region of TCF7L2 and the CXXC domain of KDM2A mediate their direct interaction.\",\n      \"method\": \"Co-IP, domain deletion/mutagenesis, proteasome inhibition, neddylation inhibition, protein stability assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping by co-IP with multiple functional interventions, single lab\",\n      \"pmids\": [\"37998355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Alternative short isoform of KDM2A (KDM2A-SF), which lacks the JmjC demethylase domain, binds to CpG island promoters via its CXXC domain and represses canonical Wnt signaling target genes (Axin2, Cyclin D1) in a demethylase-independent manner. KDM2A-SF and KDM2B-SF interact with the Wnt transcriptional mediator TCF7L1.\",\n      \"method\": \"ChIP at target promoters, luciferase reporter assays, co-IP with TCF7L1, domain deletion analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP, reporter, Co-IP with functional domain dissection, single lab\",\n      \"pmids\": [\"33104714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The short isoform of KDM2A (SF-KDM2A), lacking the JmjC domain, localizes to nucleoli, binds the rDNA promoter via its zf-CXXC domain, reduces H4K20me3 at the rDNA promoter, and activates rRNA transcription; CXXC domain mutation abolishes both promoter binding and rRNA transcription activation.\",\n      \"method\": \"Nucleolar localization assays, ChIP at rDNA promoter, CXXC domain mutagenesis, H4K20me3 ChIP, SF-KDM2A knockdown/overexpression\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis combined with ChIP and functional readout, single lab\",\n      \"pmids\": [\"28350064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM2A is required for dissolution of ALT-specific telomere clusters following recombination-directed telomere DNA synthesis; mechanistically, KDM2A promotes de-clustering of ALT multitelomeres by facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Loss of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and causes chromosome missegregation and mitotic cell death.\",\n      \"method\": \"CRISPR/Cas9 genetic screens, KDM2A/SENP6 co-epistasis, telomere SUMO assays, chromosome segregation analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double inactivation), biochemical SUMO assays, and functional cellular phenotype in a rigorous study with orthogonal methods\",\n      \"pmids\": [\"36991019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fbxl11/Kdm2a knockout mice die at E10.5-12.5 with severe growth defects, decreased cell proliferation, and increased apoptosis. Loss of Fbxl11 reduces Polycomb group protein Ezh2 and PcG-mediated H2A ubiquitination, and upregulates the CDK inhibitor p21Cip1.\",\n      \"method\": \"Knockout mouse generation, histology, Western blot, immunostaining for H2A ubiquitination and p21Cip1\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO mouse with defined molecular phenotype (Ezh2, H2AUb, p21) across multiple endpoints\",\n      \"pmids\": [\"25463925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM2A depletion in stem cells from apical papilla (SCAPs) inhibits cell proliferation and arrests the cell cycle at G1/S by de-repressing the CDK inhibitors p15INK4B and p27Kip1. ChIP assays showed that KDM2A knockdown increases H3K4 trimethylation at p15INK4B and p27Kip1 loci.\",\n      \"method\": \"shRNA knockdown, cell cycle analysis by flow cytometry, ChIP for H3K4me3 at target loci\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — knockdown with ChIP defining epigenetic mechanism, single lab\",\n      \"pmids\": [\"23559091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM2A silencing in SCAPs de-represses SFRP2 transcription by increasing H3K4 and H3K36 methylation at the SFRP2 promoter; SFRP2 enhances osteo/dentinogenic differentiation via Osterix transcription factor. BCOR functions as a co-factor of KDM2A in this regulation.\",\n      \"method\": \"KDM2A knockdown, ChIP for H3K4me/H3K36me at SFRP2 promoter, differentiation assays, BCOR knockdown\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP at specific locus with functional differentiation outcome, single lab\",\n      \"pmids\": [\"27074224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM2A knockdown in SCAPs increases H3K4me3 at SOX2 and NANOG loci and upregulates these stemness genes. Co-factor BCOR knockdown similarly increases SOX2 and NANOG mRNA, suggesting BCOR acts with KDM2A to repress stemness genes. KDM2A depletion enhances adipogenic and chondrogenic differentiation.\",\n      \"method\": \"shRNA knockdown of KDM2A and BCOR, ChIP for H3K4me3, differentiation assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP evidence combined with knockdown and differentiation phenotype, single lab\",\n      \"pmids\": [\"23872478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM2A physically binds Rb and E2F1 in a cell cycle-dependent manner and represses E2F1 transcriptional activity. ChIP assays demonstrate KDM2A associates with E2F1-regulated proliferative promoters (CDC25A, TS) in early G-phase and dissociates in S-phase. KDM2A also occupies MMP9, 14, 15, FLT1, and KDR promoters and suppresses E2F1-mediated induction of these promoters.\",\n      \"method\": \"Co-IP, ChIP at promoters, cell cycle synchronization, luciferase reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ChIP with functional reporter assays, single lab\",\n      \"pmids\": [\"25029110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Myeloid-specific knockout of Kdm2a increases H3K36me2 levels at the Pparg locus with augmented chromatin accessibility and Stat6 recruitment, rendering macrophages with preferential M2 polarization. Kdm2a-deficient mice are protected from HFD-induced obesity and insulin resistance.\",\n      \"method\": \"Conditional KO (LysM-Cre), H3K36me2 ChIP at Pparg locus, ATAC-seq for chromatin accessibility, Stat6 ChIP, metabolic phenotyping\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with ChIP, ATAC-seq, and mechanistic epistasis linking H3K36me2 to macrophage fate and metabolic phenotype\",\n      \"pmids\": [\"33462408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In male germ cells, KDM2A acts as a lysine demethylase targeting H3K36me3 (in addition to H3K36me2). Conditional deletion of Kdm2a in pre-meiotic germ cells causes complete male sterility with spermatogenesis arrested at the zygotene stage. KDM2A deficiency disrupts H3K36me2/3 balance (reducing H3K36me2 and increasing H3K36me3 in c-KIT+ germ cells). KDM2A recruits transcription factor E2F1 and co-factor HCFC1 to promoters of meiosis entry/progression genes (Stra8, Meiosin, Spo11, Sycp1).\",\n      \"method\": \"Conditional KO mice (pre-meiotic specific), ChIP-seq for H3K36me2/3, Co-IP for E2F1/HCFC1, ChIP at meiotic gene promoters\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with ChIP-seq and Co-IP defining the molecular mechanism, multiple orthogonal approaches\",\n      \"pmids\": [\"39160277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional deletion of Kdm2a in spermatogonia using a different Cre system demonstrates Kdm2a is required for Polycomb-mediated repression during spermatogonial differentiation: KO spermatogonia show increased H3K36me2 and reduced H3K27me3 at CpG-rich gene promoters, with failed gene repression of 750+ genes. In spermatocytes, Kdm2a loss disrupts meiotic prophase, chromosome synapsis, processing of meiotic DSBs, and X-linked gene repression.\",\n      \"method\": \"Conditional KO (spermatogonia-specific Cre), RNA-seq, ChIP-seq for H3K36me2 and H3K27me3, DSB repair analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with ChIP-seq and RNA-seq establishing mechanistic link between KDM2A, H3K36me2, H3K27me3, and Polycomb-dependent gene repression\",\n      \"pmids\": [\"40701999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM2A targets PFKFB3 (6-phosphofructo-2-kinase) for ubiquitylation and proteasomal degradation through its ubiquitin ligase (F-box) activity, suppressing myeloma cell proliferation and angiogenesis; this is independent of KDM2A histone demethylase activity.\",\n      \"method\": \"Co-IP, ubiquitylation assays, PFKFB3 stability/degradation assays, KDM2A overexpression/knockdown in multiple myeloma cells\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ubiquitylation assays with functional readout, single lab\",\n      \"pmids\": [\"34079757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In skeletal muscle, Kdm2a deficiency increases H3K36me2 levels at the Esrrg locus, promoting recruitment of Mrg15 to process Esrrg precursor mRNA splicing, thereby reshaping skeletal muscle metabolic profiles to induce slow-twitch myofiber transition. Deletion or inhibition of Kdm2a shifts fuel use and protects mice against cold insults and HFD-induced obesity.\",\n      \"method\": \"Conditional KO (muscle-specific), H3K36me2 ChIP at Esrrg, Mrg15 co-IP/ChIP, mRNA splicing analysis, metabolic phenotyping\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo with ChIP, RNA processing mechanistic follow-up, and metabolic phenotyping providing strong mechanistic support\",\n      \"pmids\": [\"39870955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM2A and KDM2B redundantly protect a subset of CpG islands from DNA methylation in an H3K36me2 demethylation-dependent manner; double KO of Kdm2a/2b causes stronger increase in CGI DNA methylation than single KOs. JmjC domain mutations that abolish demethylase activity phenocopy the double KO, confirming the catalytic mechanism underlies CGI protection from aberrant methylation.\",\n      \"method\": \"Kdm2a/2b single and double KO, JmjC domain catalytic mutations, DNA methylation profiling\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — genetic and catalytic mutagenesis with genome-wide methylation readout, dual KO epistasis\",\n      \"pmids\": [\"39522683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PHF8 interacts with KDM2A via two regions including an intrinsically disordered region (IDR) of KDM2A and negatively regulates KDM2A activity toward rRNA transcription; AMPK-mediated dephosphorylation of KDM2A at Ser731 (located N-terminal to the PHF8-binding region) reduces PHF8 binding and activates KDM2A. A S731A KDM2A mutant shows decreased PHF8 binding and reduced rRNA transcription.\",\n      \"method\": \"Co-IP, domain deletion mapping, S731A mutagenesis, AMPK activator treatment, rRNA transcription assays\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis-defined phospho-site with Co-IP and functional rRNA assay, single lab\",\n      \"pmids\": [\"40427554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"De novo variants in KDM2A that cause intellectual disability affect KDM2A subcellular distribution, expression, and stability in human cells. Genetic epistasis in Drosophila indicated that some variants act through loss of nuclear function, while at least one variant (c.704C>T, p.Pro235Leu) also confers cytoplasmic gain-of-function toxicity, as eliminating endogenous Drosophila Kdm2 does not reproduce the neurodevelopmental phenotype.\",\n      \"method\": \"Human cell expression/localization assays for pathogenic variants, Drosophila KDM2A variant expression and Kdm2 endogenous KO epistasis, enzymatic-methylation sequencing of patient blood\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — variant functional characterization in human cells and Drosophila genetic epistasis, single study but two orthogonal model systems\",\n      \"pmids\": [\"41468891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hepatitis B virus core protein (HBC) interacts with RANGAP1 and stabilizes it by disrupting the RANGAP1-SYVN1 (E3 ligase) interaction; stabilized RANGAP1 then interacts with KDM2A and promotes KDM2A stabilization by disrupting the KDM2A-SYVN1 interaction, thereby upregulating KDM2A to facilitate HCC cell growth and migration.\",\n      \"method\": \"Co-IP, Western blot, SYVN1-KDM2A interaction assays, stability/ubiquitination assays\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP mapping protein interactions with stability assays, single lab\",\n      \"pmids\": [\"37845585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM2A knockdown in NSD1-deficient HNSCC reverses decreased H3K36me2 and elevated H3K27me3 at CXCL9 and CXCL10 promoters, restores T-cell chemokine expression, and enables T-cell infiltration into the tumor microenvironment. KDM2A suppression inhibited tumor growth only in immunocompetent mice, establishing KDM2A as the primary H3K36me2 demethylase whose activity is antagonistic to NSD1-dependent H3K36me2 writing.\",\n      \"method\": \"KDM2A knockdown, ChIP for H3K36me2/H3K27me3 at chemokine promoters, immunocompetent vs immunodeficient mouse tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with KDM2A and NSD1, ChIP-defined histone mark changes, in vivo immunocompetent vs. immunodeficient comparison\",\n      \"pmids\": [\"37311054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STAT3 forms a complex specifically with NFκB p50 (not p65) that occupies the KDM2A promoter at an NFκB p50 binding motif, upregulating KDM2A expression in cancer-associated fibroblasts in response to IL-6. KDM2A-expressing CAFs secrete CXCR2-associated chemokines promoting M2 macrophage polarization.\",\n      \"method\": \"Co-IP for STAT3-NFκB p50 complex, ChIP at KDM2A promoter, pharmacological/genetic inhibition of pathway components, flow cytometry for macrophage markers\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ChIP defining transcriptional mechanism, single lab\",\n      \"pmids\": [\"37821959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DUX4-mediated transcription of HSATII pericentromeric satellite repeats causes nuclear foci formation of KDM2A/B-PRC1 complexes, sequestering them and causing global loss of PRC1-mediated monoubiquitination of histone H2A; this loss of PRC1-H2Aub signaling severely impairs DNA damage response.\",\n      \"method\": \"DUX4 expression, immunofluorescence for KDM2A/B-PRC1 nuclear foci, H2A ubiquitination assays, DNA damage response assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional sequestration mechanism defined by nuclear foci formation with downstream H2Aub and DDR readout, single lab\",\n      \"pmids\": [\"38451221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM2A-mediated reduction of H3K36me2 at MAPK pathway gene loci (particularly p38 MAPK pathway genes) in neural progenitor cells impairs NPC proliferation, increases apoptosis, and causes premature neuronal differentiation. De novo mutations in KDM2A identified in intellectual disability patients significantly decrease KDM2A protein levels. ChIP-seq shows KDM2A binding at transcription start sites of neurogenesis genes and H3K36me2 reduction at downstream regulatory elements upon KDM2A knockdown.\",\n      \"method\": \"KDM2A knockdown, ChIP-seq for KDM2A binding and H3K36me2, RNA-seq in neural stem cells and cerebral organoids, characterization of patient variants\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and RNA-seq integrated with patient variant characterization in neural model, single lab\",\n      \"pmids\": [\"38060137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM15-mediated m6A modification upregulates KDM2A mRNA, leading to increased KDM2A protein; elevated KDM2A reduces H3K36me2 enrichment at the HOXA2 promoter (by ChIP) to inhibit HOXA2 expression, promoting chondrocyte ferroptosis in an OA cell model.\",\n      \"method\": \"RIP assay for m6A on KDM2A mRNA, dual-luciferase assay, ChIP for H3K36me2 at HOXA2 promoter, rescue experiments\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP-defined locus-specific mechanism with upstream m6A regulation validated by RIP and reporter assay, single lab\",\n      \"pmids\": [\"41349348\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM2A is a JmjC-domain-containing histone demethylase that specifically removes mono- and di-methyl groups from H3K36 (H3K36me1/me2) by threading the substrate peptide through a catalytic groove in a U-shaped conformation, with trimethylated H3K36 excluded by steric constraints on 2-OG rearrangement; it is recruited genome-wide to unmethylated CpG islands through its ZF-CXXC domain binding linker DNA, and to heterochromatin through direct HP1 interaction via an LxVxL motif in its intrinsically disordered region. At rDNA promoters, KDM2A demethylates H3K36me2 in response to energy deprivation (glucose starvation, metformin) via AMPK activation and reduction of intracellular succinate, repressing rRNA transcription and cell proliferation; regulation involves phosphorylation of Ser731 controlling interaction with PHF8. In response to DNA DSBs, ATM phosphorylates KDM2A at T632, displacing it from chromatin, elevating H3K36me2 near damage sites to recruit the MRE11/NBS1 complex for repair; SIRT6 additionally mono-ADP-ribosylates KDM2A to promote chromatin displacement and NHEJ. KDM2A also acts as an F-box-containing SCF E3 ligase to ubiquitylate non-phosphorylated nuclear β-catenin (after its demethylation) and to degrade PFKFB3 and TCF/LEF transcription factors. In cancers, oncogenic KDM2A overexpression epigenetically silences tumor-suppressor loci (DUSP3, HDAC3, TET2, RARRES3) via H3K36me2 demethylation; in ALT-dependent cancers, KDM2A uniquely promotes telomere de-clustering by facilitating SENP6-mediated SUMO deconjugation at telomeres. In macrophages, Kdm2a deletion increases H3K36me2 at the Pparg locus to drive M2 polarization, and in skeletal muscle, Kdm2a deletion increases H3K36me2 at Esrrg to recruit Mrg15 for alternative splicing, promoting slow-twitch fiber transition and metabolic flexibility.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KDM2A is a JmjC-domain histone demethylase that selectively removes mono- and di-methyl marks from histone H3 lysine 36 (H3K36me1/me2), with H3K36me3 normally excluded by steric constraints on substrate rearrangement in the catalytic groove [#0, #1, #2]. Genome-wide targeting is achieved through its ZF-CXXC domain, which reads non-methylated CpG dinucleotides on linker DNA and recognizes CpG islands by combining unmethylated DNA state with reduced nucleosome occlusion; productive nucleosome engagement additionally depends on the acidic patch and DNA unwrapping [#3, #4, #32]. Together with KDM2B, KDM2A protects CpG islands from aberrant DNA methylation in a catalysis-dependent manner [#32], and it integrates heterochromatin signals by binding HP1 through an LxVxL motif, coupling H3K9me3-marked chromatin to its demethylase function [#9, #11]. At rDNA promoters KDM2A localizes to nucleoli and represses rRNA transcription by demethylating H3K36me2 in response to energy deprivation, an activity stimulated by AMPK signaling and by reduction of intracellular succinate following glucose starvation or metformin, and modulated by Ser731 phosphorylation that governs PHF8 binding [#6, #7, #8, #33]. KDM2A participates in the DNA double-strand break response: ATM phosphorylates it at T632 and SIRT6 mono-ADP-ribosylates it, both displacing KDM2A from chromatin to raise local H3K36me2 that recruits the MRE11/NBS1 complex and NHEJ machinery [#12, #13]. Beyond demethylation, KDM2A functions through its F-box/CXXC-dependent activities to direct ubiquitin- and neddylation-coupled degradation of nuclear non-phosphorylated β-catenin, PFKFB3, and TCF/LEF factors [#17, #18, #30]. In oncogenic contexts KDM2A silences tumor-suppressor loci including DUSP3, HDAC3, and TET2 via H3K36me2 demethylation [#14, #15, #16], antagonizes NSD1-dependent H3K36me2 writing to suppress T-cell chemokine expression [#36], and promotes de-clustering of ALT telomeres via SENP6-mediated SUMO deconjugation [#21]. In vivo, KDM2A is essential for embryogenesis [#22] and shapes cell fate across tissues, restraining macrophage M2 polarization at the Pparg locus, controlling slow-twitch myofiber identity through Esrrg splicing, and governing meiotic gene programs in male germ cells [#27, #28, #31]. De novo KDM2A variants cause intellectual disability through altered protein stability and localization [#34, #39].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the founding biochemical identity of KDM2A by showing it is an enzyme that erases a specific histone mark, defining its molecular activity.\",\n      \"evidence\": \"In vitro demethylase assays and mass spectrometry of histone modifications\",\n      \"pmids\": [\"20379134\", \"25128496\", \"24553073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain the structural basis of H3K36me1/2 selectivity versus me3 exclusion\", \"Genomic targeting mechanism not yet addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved how KDM2A discriminates methylation states, showing substrate threading and active-site geometry enforce H3K36me1/me2 specificity and exclude me3.\",\n      \"evidence\": \"X-ray crystallography with structure-guided mutagenesis and cancer-phenotype functional assays\",\n      \"pmids\": [\"25128496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture KDM2A engaging an intact nucleosome\", \"Catalytic chemistry of the off-line-to-in-line transition not directly observed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the catalytic chemistry of state selectivity, identifying Y222 conformational control of 2-oxoglutarate rearrangement as the basis for H3K36me3 inactivity.\",\n      \"evidence\": \"QM/MM and molecular dynamics simulations with variant analysis\",\n      \"pmids\": [\"38781256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Computational only; no experimental wet-lab Y222 mutagenesis validation reported\", \"Relevance of predicted variants to cellular activity untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed how KDM2A reaches its substrate on chromatin, showing nucleosome binding requires the acidic patch and DNA unwrapping — distinguishing it from KDM2B.\",\n      \"evidence\": \"Cryo-EM of KDM2A trapped on nucleosomes via a covalent H3K36-inhibitor conjugate plus acidic-patch interactome screen\",\n      \"pmids\": [\"36797403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address regulation of nucleosome engagement in vivo\", \"Interplay with CpG-island targeting not resolved structurally\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the genomic targeting principle, showing the ZF-CXXC domain recruits KDM2A to unmethylated CpG islands via linker DNA with nucleosomes as a barrier.\",\n      \"evidence\": \"Defined chromatin templates in vitro combined with in vivo chromatin profiling and ZF-CXXC biochemistry\",\n      \"pmids\": [\"22083960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish functional consequence of CGI binding genome-wide\", \"Did not separate targeting from catalytic requirement\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected KDM2A catalysis to nucleolar rRNA control and metabolic state, showing it represses rRNA transcription under starvation and is inhibited by succinate.\",\n      \"evidence\": \"Overexpression/knockdown, ChIP, nucleolar microscopy, and succinate inhibition at the rDNA promoter\",\n      \"pmids\": [\"20379134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signaling linking starvation to KDM2A activity not defined\", \"Did not separate CpG-binding from catalytic requirement at rDNA\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped the energy-sensing pathway, showing AMPK signaling and CxxC-ZF-dependent rDNA binding are both required for starvation-induced rRNA repression.\",\n      \"evidence\": \"2-DG/AMPK inhibition with domain mutagenesis, ChIP, and knockdown-rescue in breast cancer cells\",\n      \"pmids\": [\"26416883\", \"24553073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how AMPK mechanistically modifies KDM2A\", \"Succinate contribution not yet separated from AMPK\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissected the dual metabolic inputs, showing metformin activates KDM2A only when AMPK activation is combined with succinate reduction.\",\n      \"evidence\": \"Metformin treatment with metabolite supplementation, AMPK inhibition, and ChIP\",\n      \"pmids\": [\"31822720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of AMPK on KDM2A not identified here\", \"Single-lab pharmacological dissection\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a phospho-switch regulating rDNA activity, showing AMPK-driven Ser731 dephosphorylation reduces inhibitory PHF8 binding to activate KDM2A.\",\n      \"evidence\": \"Co-IP, domain mapping, S731A mutagenesis, and rRNA transcription assays\",\n      \"pmids\": [\"40427554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase/phosphatase acting on Ser731 not fully defined\", \"Single-lab finding awaiting independent confirmation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked KDM2A to heterochromatin maintenance, showing it interacts with HP1, associates with centromeres, and represses satellite RNA transcription.\",\n      \"evidence\": \"siRNA knockdown, epigenetic reporter, co-IP, centromere ChIP/IF, and satellite-RNA overexpression\",\n      \"pmids\": [\"19001877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The HP1-binding motif was not mapped here\", \"Causal direction between HP1 localization and heterochromatin state incompletely resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the molecular HP1 interface, mapping an LxVxL-type motif that couples DNA methylation and H3K9me3 signals through a multivalent nucleosome module.\",\n      \"evidence\": \"Biochemical pulldown, direct binding assays, motif mutagenesis, and in vivo zebrafish assay\",\n      \"pmids\": [\"28180290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which HP1 paralog dominates in vivo\", \"Functional output of HP1 coupling at native loci not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected HP1 binding to nucleolar function, showing HP1γ binding at V801 is required for nucleolar accumulation and starvation-induced rRNA repression.\",\n      \"evidence\": \"Co-IP, V801 point mutagenesis, HP1γ knockdown, and nucleolar microscopy/ChIP\",\n      \"pmids\": [\"31413816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking HP1γ to nucleolar retention not detailed\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established KDM2A's role in the DSB response, showing ATM-mediated T632 phosphorylation displaces it from chromatin, raising H3K36me2 to recruit MRE11/NBS1.\",\n      \"evidence\": \"Co-IP, ATM interaction, T632 mutagenesis/mass spectrometry, ChIP, and DNA-damage repair assays\",\n      \"pmids\": [\"25823024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How elevated H3K36me2 is specifically read by NBS1 at damage sites not fully resolved\", \"Kinetics of re-loading after repair unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Added a second displacement mechanism, showing SIRT6 mono-ADP-ribosylates KDM2A to elevate H3K36me2, drive H3K9me3/HP1α, and recruit NHEJ factors.\",\n      \"evidence\": \"SIRT6 enzymatic assay, chromatin displacement, H3K36me2/H3K9me3 ChIP, and NHEJ recruitment assays\",\n      \"pmids\": [\"32584788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ADP-ribosylation site on KDM2A not defined\", \"Relationship between SIRT6 and ATM-driven displacement not reconciled\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a non-histone catalytic axis, showing KDM2A demethylates and then ubiquitylates nuclear non-phosphorylated β-catenin to control Wnt signaling.\",\n      \"evidence\": \"Domain-mapped interaction assays, coupled methylation-ubiquitylation assays, and Xenopus embryo knockdown\",\n      \"pmids\": [\"26004508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The methyltransferase generating the β-catenin methyl mark not identified\", \"Demethylase-versus-F-box contributions not fully partitioned\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended demethylase-independent degradation activity, showing CXXC- and neddylation-dependent KDM2A degrades TCF/LEF factors including TCF7L2.\",\n      \"evidence\": \"Co-IP, domain deletion, proteasome and neddylation inhibition, and stability assays\",\n      \"pmids\": [\"37998355\", \"33104714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 complex composition not biochemically reconstituted\", \"In vivo relevance of TCF/LEF turnover untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized the E3 ligase function to metabolism, showing F-box-dependent KDM2A ubiquitylates PFKFB3 to suppress myeloma proliferation independent of demethylase activity.\",\n      \"evidence\": \"Co-IP, ubiquitylation and stability assays in myeloma cells\",\n      \"pmids\": [\"34079757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SCF complex assembly not directly demonstrated\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined oncogenic gene silencing, showing KDM2A demethylates H3K36me2 to repress DUSP3 and thereby activate ERK1/2 signaling in NSCLC.\",\n      \"evidence\": \"Catalytic mutant comparison, ChIP at DUSP3, ERK1/2 phosphorylation, and rescue assays\",\n      \"pmids\": [\"24200691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address breadth of repressed loci genome-wide\", \"Selectivity of locus targeting not explained\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the silencing program, showing KDM2A represses HDAC3 to de-repress CDK6/NANOS1 and promote NSCLC tumorigenicity, and physically engages Rb/E2F1 to control proliferative promoters.\",\n      \"evidence\": \"Catalytic-mutant knockdown/overexpression, ChIP, double-knockdown rescue, xenografts, and cell-cycle-synchronized Co-IP\",\n      \"pmids\": [\"24482232\", \"25029110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism directing KDM2A to specific repressive targets unresolved\", \"E2F1 regulation mechanism only partly defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked KDM2A to DNA hydroxymethylation control, showing KDM2A co-occupies the TET2 promoter with RelA to repress TET2 and promote breast cancer invasion.\",\n      \"evidence\": \"Co-IP, ChIP, knockdown-rescue, 5-hmC measurement, and invasion assays\",\n      \"pmids\": [\"28785073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether repression requires demethylase activity not fully resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a unique telomere maintenance role, showing KDM2A enables SENP6-mediated SUMO deconjugation to de-cluster ALT telomeres and preserve chromosome segregation.\",\n      \"evidence\": \"CRISPR screens, KDM2A/SENP6 epistasis, telomere SUMO assays, and segregation analysis\",\n      \"pmids\": [\"36991019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between KDM2A and SENP6 activity not defined\", \"Whether this requires demethylase or F-box activity unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established organismal essentiality, showing Fbxl11/Kdm2a knockout is embryonic lethal with reduced Ezh2/H2Aub and elevated p21.\",\n      \"evidence\": \"Knockout mouse generation with histology and molecular profiling\",\n      \"pmids\": [\"25463925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal chain from KDM2A loss to Ezh2 reduction not mechanistically defined\", \"Tissue-specific contributions not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a stem/progenitor differentiation role, showing KDM2A with co-factor BCOR represses cell-cycle inhibitors, stemness genes, and differentiation regulators in SCAPs.\",\n      \"evidence\": \"shRNA knockdown of KDM2A and BCOR, ChIP for H3K4me3/H3K36me, and differentiation assays\",\n      \"pmids\": [\"23559091\", \"23872478\", \"27074224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between H3K4me3 changes and KDM2A's H3K36me2 catalysis unclear\", \"BCOR-KDM2A complex not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked KDM2A catalysis to immunometabolic cell fate, showing myeloid Kdm2a loss raises H3K36me2 at Pparg to drive M2 polarization and protect against obesity.\",\n      \"evidence\": \"Conditional KO with Pparg H3K36me2 ChIP, ATAC-seq, Stat6 ChIP, and metabolic phenotyping\",\n      \"pmids\": [\"33462408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish direct KDM2A recruitment mechanism to Pparg\", \"Demethylase-versus-other-activity contribution not isolated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined germline and CpG-island roles, showing KDM2A balances H3K36me2/3, recruits E2F1/HCFC1 to meiotic genes, and (with KDM2B) protects CpG islands from DNA methylation through catalysis.\",\n      \"evidence\": \"Conditional KO mice with ChIP-seq/Co-IP, plus Kdm2a/2b single/double KO and JmjC catalytic mutants with methylation profiling\",\n      \"pmids\": [\"39160277\", \"39522683\", \"40701999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The reported H3K36me3 activity in germ cells differs from the canonical me1/2 specificity and is not structurally explained\", \"Polycomb coupling mechanism at CpG islands not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended catalytic control to muscle metabolism, showing Kdm2a loss raises H3K36me2 at Esrrg to recruit Mrg15 for splicing and drive slow-twitch transition.\",\n      \"evidence\": \"Muscle-specific conditional KO with Esrrg H3K36me2 ChIP, Mrg15 co-IP/ChIP, splicing analysis, and metabolic phenotyping\",\n      \"pmids\": [\"39870955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H3K36me2 mechanistically recruits Mrg15 to splicing not fully resolved\", \"Direct KDM2A targeting to Esrrg not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined immune-evasion and regulatory contexts, showing KDM2A antagonizes NSD1 H3K36me2 writing to suppress chemokine expression and is itself stabilized or transcriptionally induced in tumor microenvironments.\",\n      \"evidence\": \"KDM2A knockdown with ChIP and immunocompetent/immunodeficient tumor models; Co-IP/ChIP for SYVN1-RANGAP1 stability and STAT3/NFκB p50 promoter regulation\",\n      \"pmids\": [\"37311054\", \"37845585\", \"37821959\", \"38451221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stability and transcriptional findings rest largely on single-lab Co-IP/ChIP\", \"Whether chemokine repression is purely catalytic not fully isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected KDM2A to human disease, showing de novo variants cause intellectual disability via altered stability, localization, and impaired regulation of neurodevelopmental gene programs.\",\n      \"evidence\": \"Human cell variant localization/stability assays, Drosophila epistasis, and ChIP-seq/RNA-seq in neural models\",\n      \"pmids\": [\"41468891\", \"38060137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Loss- versus gain-of-function contributions differ across variants and are not fully reconciled\", \"Mechanism connecting MAPK-locus H3K36me2 to neuronal phenotype incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KDM2A's distinct activities — H3K36me2 demethylase, CpG-island reader, and F-box/SCF ubiquitin ligase — are partitioned, coordinated, and selectively deployed at specific loci and substrates in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model partitioning catalytic versus ligase functions across contexts\", \"Mechanism selecting specific repressive target loci genome-wide undefined\", \"Reported H3K36me3 activity conflicts with canonical me1/2 specificity\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 3, 6]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 5, 32]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [17, 18, 30]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [17, 30]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [14, 15, 16, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [6, 10, 20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 12, 17]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [11, 12, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 4, 32]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 7, 14, 15]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [17, 30, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [22, 28, 31]}\n    ],\n    \"complexes\": [\"SCF (F-box) ubiquitin ligase\", \"KDM2A/B-PRC1\"],\n    \"partners\": [\"HP1\", \"ATM\", \"SIRT6\", \"PHF8\", \"CTNNB1\", \"TCF7L2\", \"E2F1\", \"NBS1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}