{"gene":"KDM4A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2006,"finding":"KDM4A (JMJD2A/JHDM3A) demethylates trimethylated histone H3K9 and H3K36 (H3K9me3→H3K9me2; H3K36me3→H3K36me2) in vitro and in cultured cells; catalytically inactive mutant lacks this activity. Overexpression reduces H3K9/K36me3 levels; C. elegans JMJD2A homolog depletion increases H3K9me3 and H3K36me3 and triggers p53-dependent germline apoptosis.","method":"In vitro demethylase assay, cell overexpression/RNAi, site-directed mutagenesis, C. elegans genetics","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with catalytic mutant controls, replicated by independent group in Nature (PMID:16732292) in same year","pmids":["16603238","16732292"],"is_preprint":false},{"year":2006,"finding":"Overexpression of KDM4A (JHDM3A) abrogates HP1 recruitment to heterochromatin, indicating KDM4A antagonizes H3K9me3-nucleated HP1 events. siRNA knockdown of JHDM3A increases H3K9 methylation and upregulates the target gene ASCL2, demonstrating euchromatic demethylation of active-transcription marks.","method":"siRNA knockdown, overexpression, immunofluorescence, RT-PCR","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function with clear molecular readouts, replicated by Whetstine et al. (PMID:16603238)","pmids":["16732292"],"is_preprint":false},{"year":2006,"finding":"X-ray crystal structures of the KDM4A catalytic core (JmjN + JmjC + C-terminal domain + zinc finger) with and without α-ketoglutarate and Fe²⁺ defined the substrate-binding pocket; site-directed mutagenesis combined with demethylase activity assays established a molecular model for substrate selection by the JMJD2 family.","method":"X-ray crystallography, site-directed mutagenesis, demethylase activity assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus activity assay in single study","pmids":["16677698"],"is_preprint":false},{"year":2007,"finding":"Crystal structures of KDM4A bound to tri-, di-, and monomethyl H3K9 and trimethyl H3K36 peptides revealed a lysyl-binding pocket where substrates adopt distinct bent conformations involving the Zn-binding site, providing a structural mechanism for methylation-state selectivity and sequence specificity for H3K9 versus H3K36.","method":"X-ray crystallography with peptide substrate co-crystals","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple co-crystal structures defining selectivity mechanism, independent structural study","pmids":["17589501"],"is_preprint":false},{"year":2007,"finding":"KDM4A catalytic core complexed with methylated H3K36 peptides (Fe²⁺/N-oxalylglycine) showed that peptide-binding specificity is largely determined by main-chain contacts and primary peptide structure, explaining selectivity for H3K9 and H3K36 but not H3K27; methyl-state selectivity is influenced by space and electrostatic environment in the catalytic center.","method":"X-ray crystallography of substrate complexes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with two substrates, independent validation of mechanism from PMID:17589501","pmids":["17567753"],"is_preprint":false},{"year":2005,"finding":"KDM4A (JMJD2A) associates in vivo with pRb and class I HDACs (co-immunoprecipitation) and mediates repression of E2F-regulated promoters; the tandem Tudor domain is required for repression of the target gene ASCL2 via the N-CoR complex.","method":"Co-immunoprecipitation, reporter gene assay, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with multiple partners, functional reporter assays, single lab","pmids":["15927959"],"is_preprint":false},{"year":2005,"finding":"KDM4A directly interacts with N-CoR through a defined NID (N-CoR interaction domain) both in vitro and in vivo; this interaction is required for JMJD2A-mediated repression of ASCL2 and requires a functional N-CoR complex and the tandem Tudor domain.","method":"GST pulldown (in vitro), co-immunoprecipitation (in vivo), chromatin immunoprecipitation, domain deletion mapping","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro pulldown plus reciprocal Co-IP plus ChIP, single lab","pmids":["16024779"],"is_preprint":false},{"year":2007,"finding":"KDM4A forms a complex with ligand-bound androgen receptor (AR) through its catalytic domain or C-terminus; overexpression of KDM4A stimulates AR transcriptional activity in a catalytic-activity-dependent manner; knockdown reduces PSA expression in LNCaP cells.","method":"Co-immunoprecipitation, reporter assay, domain mapping, siRNA knockdown, RT-PCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, catalytic mutant control, functional reporter assay; single lab","pmids":["17555712"],"is_preprint":false},{"year":2009,"finding":"G9a/KMT1C methylates histone H1.4K26, and KDM4 family members (including KDM4A) demethylate H1.4K26 in vitro and in vivo, establishing KDM4A as a histone H1.4K26 demethylase.","method":"In vitro methylation/demethylation assay, cellular overexpression/knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay plus cellular validation, single lab","pmids":["19144645"],"is_preprint":false},{"year":2008,"finding":"Drosophila KDM4A (dKDM4A) specifically demethylates H3K36me2 and H3K36me3 in vitro and in vivo; HP1a associates with dKDM4A (chromo shadow domain of HP1a binds HP1-interacting motif of dKDM4A) and stimulates its H3K36 demethylase activity in a manner dependent on the H3K9me-binding motif of HP1a.","method":"Affinity purification/mass spectrometry, in vitro demethylase assay, domain mapping, in vivo ChIP/western","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, AP-MS interaction, domain-level mutagenesis, in vivo corroboration; single lab but multiple orthogonal methods","pmids":["19061644"],"is_preprint":false},{"year":2010,"finding":"KDM4A protein levels oscillate in a cell cycle-dependent manner; overexpression increases chromatin accessibility, accelerates S-phase progression, and alters replication timing in an enzymatic-activity-dependent manner. HP1γ overexpression antagonizes these KDM4A-dependent effects, placing KDM4A upstream of HP1γ in controlling chromatin accessibility during DNA replication.","method":"Cell cycle synchronization/western blot, FACS, BrdU incorporation, replication timing assay, epistasis via HP1γ overexpression","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal phenotypic assays with enzymatic mutant controls plus genetic epistasis, replicated in C. elegans","pmids":["21145482"],"is_preprint":false},{"year":2011,"finding":"KDM4A (JMJD2A) tandem Tudor domain binds dimethylated histone H4K20 (H4K20me2); KDM4A is ubiquitinated by RNF8 and RNF168 and degraded by the proteasome following DNA damage in an RNF8-dependent manner. This RNF8-dependent degradation is required to allow 53BP1 recruitment to DNA damage sites; ectopic KDM4A expression blocks 53BP1 foci.","method":"Co-immunoprecipitation, pulldown, ubiquitination assay, laser-induced DNA damage/immunofluorescence, siRNA epistasis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding assay, ubiquitination assay, cellular imaging, genetic epistasis), single lab","pmids":["22373579"],"is_preprint":false},{"year":2011,"finding":"SCF(FbxL4) ubiquitin ligase complex interacts with KDM4A and targets it for proteasomal degradation; ubiquitin overexpression restores KDM4A turnover and blocks KDM4A-dependent faster S-phase progression in a cullin-1-dependent manner.","method":"Co-immunoprecipitation, ubiquitin overexpression rescue, BrdU incorporation, siRNA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue with ubiquitin, single lab","pmids":["21757720"],"is_preprint":false},{"year":2011,"finding":"SCF(FBXO22) ubiquitin ligase complex targets KDM4A for proteasomal degradation; FBXO22 recognizes KDM4A through its FIST domain binding the JmjN/JmjC catalytic domains. Modulation of FBXO22 levels correspondingly alters histone H3K9 and H3K36 methylation levels and ASCL2 transcription.","method":"Co-immunoprecipitation, RNAi, domain mapping, western blot for histone marks, RT-PCR","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus functional readouts; single lab","pmids":["21768309"],"is_preprint":false},{"year":2011,"finding":"Heart-specific Jmjd2a deletion attenuates hypertrophic response to pressure overload; Jmjd2a transgenic overexpression exacerbates cardiac hypertrophy. KDM4A binds the FHL1 promoter in response to TAC stress, upregulates FHL1 expression via SRF/myocardin, and reduces H3K9me3 at the FHL1 promoter—effects requiring demethylase activity.","method":"Conditional knockout/transgenic mouse, ChIP, co-immunoprecipitation, reporter assay, catalytic mutant","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic models (KO and Tg), ChIP, catalytic mutant, multiple orthogonal readouts; single lab","pmids":["21555854"],"is_preprint":false},{"year":2012,"finding":"KDM4A (JMJD2A) overexpression leads to site-specific copy number gain (1q12, 1q21, Xq13.1) through rereplication within a single S phase; this requires enzymatic activity and is suppressed by Suv39h1/KMT1A or HP1γ overexpression. Sites with increased copy number show increased KDM4A, MCM, and DNA polymerase occupancy.","method":"FISH, BrdU incorporation, ChIP, enzymatic mutant, genetic suppression by Suv39h1/HP1γ overexpression","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including FISH, ChIP, replication assays, genetic epistasis; single lab with rigorous controls","pmids":["23871696"],"is_preprint":false},{"year":2012,"finding":"KDM4A interacts with p53 (in vitro and in HCT116 cells) and is co-recruited with p53 to the p21 promoter upon DNA damage. KDM4A knockdown increases p21 and PUMA expression and decreases Bcl-2, inducing apoptosis; the effect is partially p53-dependent.","method":"GST pulldown, co-immunoprecipitation, ChIP, siRNA, western blot, flow cytometry","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro pulldown plus Co-IP plus ChIP, single lab","pmids":["22134899"],"is_preprint":false},{"year":2012,"finding":"KDM4A (JMJD2A) promotes cellular transformation by repressing CHD5 (a tumor suppressor regulating p53 activity), thereby inhibiting Ras-induced senescence and collaborating with oncogenic Ras; depletion of KDM4A in K-Ras-expressing A549 cells triggers senescence.","method":"Lentiviral overexpression, siRNA, ChIP, senescence assays (SA-β-gal), co-operation with Ras in transformation assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct target identification, functional epistasis in transformation assay, single lab","pmids":["23168260"],"is_preprint":false},{"year":2013,"finding":"KDM4A overexpression promotes KSHV reactivation through H3K9me3 demethylase activity; KSHV-encoded K-bZIP protein physically interacts with KDM4A and inhibits its demethylase activity both in vivo and in vitro by blocking substrate accessibility, increasing global H3K9me3.","method":"Co-immunoprecipitation, in vitro demethylase inhibition assay, KSHV reactivation/titer assay, catalytic mutant rescue","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro inhibition assay, catalytic mutant, single lab","pmids":["21228229"],"is_preprint":false},{"year":2016,"finding":"SCF(Fbxo22) forms a complex with KDM4A that ubiquitylates methylated p53 for proteasomal degradation; a catalytic mutant of KDM4A stabilizes p53 and enhances its interaction with PHF20. This SCF(Fbxo22)-KDM4A complex is required for p16 induction and SASP during late-phase senescence.","method":"Co-immunoprecipitation, ubiquitination assay, catalytic mutant, Fbxo22 knockout mice, western blot","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assay, catalytic mutant, in vivo genetic model (KO mice), multiple orthogonal methods","pmids":["26868148"],"is_preprint":false},{"year":2015,"finding":"KDM4A interacts with the translation initiation complex in the cytoplasm (co-immunoprecipitation) and affects distribution of translation initiation factors within polysome fractions; KDM4A depletion reduces protein synthesis and enhances sensitivity to mTOR inhibitors.","method":"Co-immunoprecipitation, polysome fractionation, protein synthesis assay (35S-Met), cell viability","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional polysome fractionation plus synthesis assay, single lab","pmids":["25564516"],"is_preprint":false},{"year":2016,"finding":"KDM4A functions as an E2F1 coactivator: it associates with E2F1 on target gene promoters and enhances E2F1 chromatin binding and transcriptional activity. PDK1 and PDK3 are direct KDM4A/E2F1 targets regulating the switch between glycolytic and mitochondrial metabolism; KDM4A depletion elevates pyruvate dehydrogenase activity and ROS.","method":"Co-immunoprecipitation, ChIP, reporter assay, metabolic flux assays, siRNA rescue","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, metabolic assay with PDK rescue, single lab","pmids":["27626669"],"is_preprint":false},{"year":2016,"finding":"KDM4A drives prostate tumorigenesis by interacting with ETS transcription factor ETV1; ETV1 recruits KDM4A to the YAP1 promoter, reducing H3K9me3 and increasing YAP1 expression. YAP1 largely rescues growth inhibitory effects of KDM4A depletion, establishing a JMJD2A/ETV1/YAP1 axis.","method":"Co-immunoprecipitation, ChIP, mouse xenograft, siRNA, overexpression, rescue experiment","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, in vivo mouse model, genetic rescue; single lab","pmids":["26731476"],"is_preprint":false},{"year":2016,"finding":"KDM4A associates with RNA Polymerase I at active ribosomal DNA genes and is required for serum-induced activation of rDNA transcription. PI3K/SGK1 signaling controls KDM4A cytoplasmic-to-nuclear localization and thereby its occupancy on rDNA.","method":"Co-immunoprecipitation, ChIP, subcellular fractionation, siRNA, reporter assay, kinase inhibition","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with Pol I, ChIP at rDNA, localization experiment linked to rDNA transcription function, single lab","pmids":["26729372"],"is_preprint":false},{"year":2014,"finding":"GPS2/KDM4A pioneering activity is required for promoter-specific recruitment of PPARγ in adipocytes; GPS2 inhibits RNF8 ubiquitin ligase activity, stabilizing KDM4A, which demethylates H3K9 to prime PPARγ-responsive genes including ATGL and HSL. Genome-wide profiling confirms the GPS2/KDM4A requirement for this specific transcriptional program.","method":"Co-immunoprecipitation, ChIP-seq, siRNA, ubiquitination assay, lipolysis assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genome-wide ChIP-seq, functional rescue; single lab","pmids":["24953653"],"is_preprint":false},{"year":2017,"finding":"KDM4A demethylase activity has a high KM(app) for O₂ of ~173 μM (recombinant enzyme), indicating its H3K9me3 demethylase activity responds sensitively to physiological reductions in oxygen concentration; cellular KDM4A activity against H3K9me3 shows a graded response to decreasing O₂ concentrations consistent with biochemical data.","method":"Kinetic analysis of recombinant enzyme, immunofluorescence in cells under graded hypoxia","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinetic analysis plus cellular activity assay, single lab, two orthogonal methods","pmids":["28051298"],"is_preprint":false},{"year":2017,"finding":"KDM4A demethylates H3K9me3 at the HIF-1α locus; depletion or inactivation of KDM4A causes H3K9me3 accumulation at the HIF-1α gene, reducing HIF-1α mRNA and protein, and decreasing hypoxic transcriptional response, invasion, and migration.","method":"ChIP, siRNA, RT-PCR, western blot, invasion/migration assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing H3K9me3 accumulation at locus, multiple functional readouts, single lab","pmids":["28894274"],"is_preprint":false},{"year":2017,"finding":"KSHV K-bZIP acts as a viral SUMO-2/3-specific E3 ligase that SUMOylates KDM4A at lysine 471 via a SIM-dependent mechanism; SUMOylation stabilizes KDM4A chromatin association and is required for viral gene transactivation and virion production, as well as for KDM4A-dependent cell proliferation.","method":"In vitro and in vivo SUMOylation assay, site-directed mutagenesis (K471), co-immunoprecipitation, RNA-seq, virion production assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo SUMOylation, K471 mutant, RNA-seq comparison; single lab","pmids":["28212444"],"is_preprint":false},{"year":2016,"finding":"Combined deficiency for Jmjd2a and Jmjd2c (but not individual knockouts) causes early embryonic lethality and impaired ESC self-renewal with spontaneous primitive endoderm differentiation; both demethylases localize to H3K4me3-positive promoters and have redundant roles in preventing H3K9me3 and H3K36me3 accumulation. Catalytic activity is required for ESC maintenance.","method":"Conditional triple-KO mouse ESCs, ChIP-seq, RNA-seq, differentiation assays, catalytic mutant rescue","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic models (single/double/triple KO), ChIP-seq, catalytic mutant, multiple phenotypic readouts","pmids":["27266524"],"is_preprint":false},{"year":2016,"finding":"Jmjd2/Kdm4 demethylases are required for MLL-AF9 AML in vivo and in vitro; their activity maintains expression of Il3ra (CD123) by removing H3K9me3 from its promoter. Ectopic Il3ra re-expression rescues AML cell survival in Jmjd2/Kdm4 triple-knockout cells, establishing Il3ra as a critical downstream target.","method":"Conditional triple-KO mice, ChIP, lentiviral re-expression rescue, in vivo AML model","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic models, ChIP, genetic rescue, multiple orthogonal assays","pmids":["27257215"],"is_preprint":false},{"year":2020,"finding":"KDM4A-mediated H3K9me3 demethylation at broad H3K4me3 domains in oocytes is essential for normal pre-implantation development and zygotic genome activation; loss of KDM4A causes aberrant H3K9me3 spreading over bdH3K4me3 domains, resulting in insufficient transcriptional activation of genes and endogenous retroviral elements. Catalytic activity of KDM4A is essential for this function.","method":"Conditional oocyte KO, ChIP-seq, RNA-seq, catalytic mutant, embryo development assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, genome-wide ChIP-seq, catalytic mutant, multiple phenotypic readouts in vivo","pmids":["32231309"],"is_preprint":false},{"year":2021,"finding":"KDM4A inhibition promotes formation of liquid-like HP1γ puncta on heterochromatin, stalls DNA replication forks, and activates tumor-cell-intrinsic cGAS-STING signaling through replication-stress-induced cytosolic DNA accumulation, enabling antitumor immunity.","method":"KDM4A inhibition (chemical/genetic), live-cell imaging of HP1γ puncta, DNA fiber assay, cGAS-STING pathway assays, CD8+ T cell recruitment assays, in vivo lineage tracing","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays in vitro and in vivo, single lab","pmids":["33743195"],"is_preprint":false},{"year":2021,"finding":"KDM4A promotes myogenesis by demethylating H3K9me3 at the MyoD, MyoG, and Myf5 gene loci; conditional KDM4A deletion impairs embryonic and postnatal muscle formation; KDM4A-deficient myoblasts show inhibited differentiation, reduced proliferation, increased p21, and decreased Cyclin D1.","method":"Conditional knockout mouse, ChIP, western blot, differentiation assay, satellite cell isolation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model, ChIP for direct target loci, multiple functional readouts; single lab","pmids":["34011940"],"is_preprint":false},{"year":2021,"finding":"KDM4A regulates SLC7A11 transcription by demethylating H3K9me3 in the SLC7A11 promoter; KDM4A knockdown increases H3K9me3 at the SLC7A11 promoter, decreases SLC7A11 expression, and promotes ferroptotic cell death in osteosarcoma cells.","method":"ChIP assay, siRNA, western blot, ferroptosis assays (iron, MDA, GSH), in vivo xenograft","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter regulation, multiple functional readouts, single lab","pmids":["33689883"],"is_preprint":false},{"year":2017,"finding":"Drosophila KDM4A (dKDM4A) localizes predominantly to heterochromatin and regulates heterochromatin position-effect variegation and organization of repetitive DNA; its enzymatic activity is dispensable for PEV but required for relocation of heterochromatic DSBs outside the domain and for demethylation of H3K56me3 following DNA damage to facilitate repair.","method":"Immunofluorescence, PEV assay, FISH, DNA damage assays, enzymatic mutant, Drosophila genetics","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization by imaging, enzymatic mutant for functional dissection, genetic assays; Drosophila ortholog study","pmids":["28743002"],"is_preprint":false},{"year":2012,"finding":"HP1a targets dKDM4A to a subset of heterochromatic genes in Drosophila to regulate H3K36me3 levels; HP1a binding is required for dKDM4A-mediated H3K36me3 demethylation specifically at this gene subset, shown by ChIP-chip in wild-type vs. dkdm4a mutant embryos.","method":"ChIP-chip, dkdm4a mutant embryos, genetic epistasis with HP1a","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-chip with genetic mutant, Drosophila ortholog study; single lab","pmids":["22761891"],"is_preprint":false},{"year":2019,"finding":"KDM4A promotes adipogenic and inhibits osteogenic differentiation by directly binding the promoters of Sfrp4 and C/ebpα, removing H3K9me3, and reducing DNA methylation; overexpression inactivates canonical Wnt signaling via Sfrp4 upregulation. Silencing Sfrp4 rescues the osteogenesis block, placing Sfrp4 downstream of KDM4A in this pathway.","method":"ChIP, overexpression/knockdown, catalytic mutant, siRNA rescue, differentiation assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct promoter binding, catalytic mutant controls, genetic rescue; single lab","pmids":["31515577"],"is_preprint":false},{"year":2020,"finding":"KDM4A depletion leads to global H3K9me3 and H3K27me3 accumulation at KDM4A-targeted loci in AML cells and downregulates a KDM4A-PAF1-controlled transcriptional program essential for leukemogenesis; KDM4A interacts with the PAF1 complex (distinct from KDM4C-dependent targets).","method":"ChIP-seq, RNA-seq, siRNA/shRNA, co-immunoprecipitation, apoptosis assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq, Co-IP, loss-of-function with defined transcriptional phenotype; single lab","pmids":["34083515"],"is_preprint":false},{"year":2020,"finding":"QM/MM computational analysis shows KDM4A catalysis generates a reactive Fe(IV)-oxo intermediate; substrate binding mode, correlated protein-histone motions, and molecular orbital control synergistically determine reactivity. K241A substitution (consistent with experimental studies) abolishes activity by altering substrate orientation; Ser288 and Thr289 contribute through correlated motions.","method":"Molecular dynamics + QM/MM calculations with in silico mutagenesis validated against experimental activity data","journal":"Chemical science","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — computational study validated only against published experimental data, no new experimental results","pmids":["34094257"],"is_preprint":false},{"year":2024,"finding":"Hypoxia-like conditions promote SUMO1 modification of KDM4A at lysine K471 (K471 is the primary SUMOylation site, confirmed by mutation), which enhances KDM4A chromatin association, reduces H3K9me3 at the SLC7A11 promoter, and upregulates SLC7A11/GPX4 to confer ferroptosis resistance in cervical cancer cells.","method":"Co-immunoprecipitation, site-directed mutagenesis (K471), ChIP, western blot, ferroptosis assays","journal":"Environmental toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K471 mutation, ChIP validation, multiple functional assays; single lab","pmids":["38727079"],"is_preprint":false},{"year":2016,"finding":"KDM4A inhibition (KDM4A-silencing or compound C-4) induces TRAIL and DR5 expression by switching promoter-bound histone-modifying complexes: dissociating KDM4A and NCoR-HDAC complex and recruiting histone acetylase CBP at the CHOP gene promoter, thereby de-repressing TRAIL and DR5 transcription.","method":"ChIP, siRNA, small-molecule inhibitor, co-immunoprecipitation, apoptosis assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing complex switching, Co-IP, functional apoptosis readout; single lab","pmids":["27612013"],"is_preprint":false},{"year":2018,"finding":"KDM4A and KDM4C co-occupy promoters with NF-κB p65 (ChIP-seq/motif analysis) and co-target Wdr5, a MLL complex member; their depletion in B cells potentiates activation and upregulates cell cycle inhibitors Cdkn2c and Cdkn3 via WDR5-dependent H3K4 methylation.","method":"ChIP-seq, de novo motif analysis, siRNA, co-immunoprecipitation, B cell activation assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq, Co-IP, functional B cell assays; single lab","pmids":["29718303"],"is_preprint":false},{"year":2019,"finding":"USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitination and protein stability; USP1 inhibition reduces KDM4A levels and suppresses c-Myc expression (a downstream effector of the USP1-KDM4A/androgen receptor axis) in prostate cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA, western blot, proliferation assay","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue; single lab","pmids":["32133742"],"is_preprint":false}],"current_model":"KDM4A is a JmjC-domain, Fe(II)- and 2-oxoglutarate-dependent dioxygenase that removes di- and tri-methyl marks from histone H3K9 and H3K36 (and H1.4K26), thereby modulating chromatin accessibility, DNA replication timing, transcription factor recruitment (AR, ERα, E2F1, ETV1, PPARγ), and DNA damage repair; its abundance is tightly cell-cycle-regulated through proteasomal degradation mediated by at least two SCF complexes (SCF-FbxL4 and SCF-FBXO22) and by RNF8/RNF168-dependent ubiquitination, while its chromatin occupancy and activity are further tuned by SUMO modification at K471, HP1 interaction, and oxygen availability; through these mechanisms KDM4A controls gene expression programs in development, differentiation, and oncogenesis."},"narrative":{"mechanistic_narrative":"KDM4A (JMJD2A/JHDM3A) is a JmjC-domain, Fe(II)- and 2-oxoglutarate-dependent histone demethylase that removes di- and tri-methyl marks from histone H3K9 and H3K36 (and H1.4K26), and through this catalysis controls chromatin accessibility, replication, and transcriptional programs across development, differentiation, and oncogenesis [PMID:16603238, PMID:16732292, PMID:19144645, PMID:23871696]. Crystal structures of its catalytic core (JmjN+JmjC+zinc finger) bound to methylated H3K9 and H3K36 peptides define a lysyl-binding pocket whose main-chain contacts and bent substrate conformations dictate methylation-state and sequence selectivity, including exclusion of H3K27 [PMID:16677698, PMID:17589501, PMID:17567753]. By erasing H3K9me3, KDM4A antagonizes HP1-nucleated heterochromatin, and its overexpression accelerates S-phase, alters replication timing, and drives site-specific rereplication and copy-number gain in an enzymatic-activity-dependent manner that is opposed by Suv39h1/HP1γ [PMID:16732292, PMID:21145482, PMID:23871696]; KDM4A inhibition conversely stabilizes liquid-like HP1γ puncta, stalls replication forks, and triggers cGAS-STING-dependent antitumor immunity [PMID:33743195]. KDM4A is recruited to specific loci by transcription factors and corepressor/coactivator complexes—pRb/HDAC and N-CoR for E2F- and ASCL2-target repression, and AR, E2F1, ETV1, PPARγ (via GPS2), and the PAF1 complex for target activation—linking demethylation to androgen signaling, metabolic gene control, leukemogenesis, and tumorigenesis [PMID:15927959, PMID:16024779, PMID:17555712, PMID:27626669, PMID:26731476, PMID:24953653, PMID:34083515]. KDM4A redundantly with KDM4C maintains ESC self-renewal and is required for oocyte zygotic genome activation, myogenesis, and adipo-/osteogenic lineage choice through demethylation of defined target loci [PMID:27266524, PMID:32231309, PMID:34011940, PMID:31515577]. Its abundance is tightly controlled by ubiquitin-proteasome turnover via SCF(FbxL4) and SCF(FBXO22) and by RNF8/RNF168, the latter degradation permitting 53BP1 recruitment at DNA damage sites, while USP1 deubiquitination, SUMOylation at K471, and oxygen availability further tune its chromatin occupancy and activity [PMID:22373579, PMID:21757720, PMID:21768309, PMID:28051298, PMID:38727079, PMID:32133742].","teleology":[{"year":2006,"claim":"Established the founding enzymatic identity—that KDM4A is a histone demethylase—answering whether trimethyl-lysine marks are reversible and defining its H3K9me3/H3K36me3 substrates.","evidence":"In vitro demethylase assays with catalytic-mutant controls, cellular over/knockdown, and C. elegans genetics","pmids":["16603238","16732292"],"confidence":"High","gaps":["Did not resolve atomic basis of substrate selection","In vivo locus-specific targeting not yet mapped"]},{"year":2006,"claim":"Connected demethylase activity to chromatin state by showing KDM4A antagonizes HP1 recruitment and de-represses active genes, establishing functional consequences of erasing H3K9me3.","evidence":"Reciprocal siRNA/overexpression with immunofluorescence and RT-PCR readouts","pmids":["16732292"],"confidence":"High","gaps":["Mechanism of locus selection unaddressed","Direct HP1 binding vs indirect competition not distinguished here"]},{"year":2007,"claim":"Resolved the structural mechanism of methylation-state and sequence selectivity, explaining why KDM4A acts on H3K9 and H3K36 but not H3K27.","evidence":"X-ray co-crystal structures of catalytic core with tri-/di-/monomethyl peptides plus mutagenesis and activity assays","pmids":["16677698","17589501","17567753"],"confidence":"High","gaps":["Full-length enzyme/reader-domain architecture not resolved","Dynamics of catalysis not captured by static structures"]},{"year":2005,"claim":"Identified KDM4A as a transcriptional corepressor that engages pRb/HDAC and N-CoR via its tandem Tudor domain, showing it functions beyond bulk demethylation in targeted gene repression.","evidence":"Co-IP, GST pulldown, ChIP, reporter assays, and domain deletion mapping","pmids":["15927959","16024779"],"confidence":"Medium","gaps":["Single-lab interactions without independent structural validation","Whether repression requires demethylase activity unclear"]},{"year":2007,"claim":"Linked KDM4A to nuclear-receptor signaling by showing catalytic-activity-dependent coactivation of androgen receptor target genes.","evidence":"Co-IP, domain mapping, catalytic-mutant reporter assays, and siRNA in LNCaP cells","pmids":["17555712"],"confidence":"Medium","gaps":["Direct histone substrate at AR target promoters not defined here","Single-lab evidence"]},{"year":2008,"claim":"Defined HP1 as a regulator of KDM4A targeting and activity, showing HP1 binding stimulates H3K36 demethylation at specific heterochromatic genes.","evidence":"AP-MS, in vitro demethylase assays, domain mapping, and ChIP in Drosophila","pmids":["19061644","22761891"],"confidence":"High","gaps":["Conservation of HP1 stimulation in mammalian KDM4A not fully established","Ortholog-based mechanism"]},{"year":2009,"claim":"Expanded the substrate repertoire to linker histone H1.4K26, showing KDM4A reverses G9a-deposited marks beyond core histones.","evidence":"In vitro methylation/demethylation assays with cellular over/knockdown","pmids":["19144645"],"confidence":"Medium","gaps":["Physiological consequence of H1.4K26 demethylation not defined","Single-lab evidence"]},{"year":2011,"claim":"Established cell-cycle-coupled proteasomal turnover of KDM4A via SCF(FbxL4) and SCF(FBXO22), linking enzyme abundance to S-phase progression and histone-mark homeostasis.","evidence":"Co-IP, domain mapping, ubiquitin-rescue, BrdU incorporation, and histone-mark westerns","pmids":["21757720","21768309"],"confidence":"Medium","gaps":["Degron and signal controlling F-box recognition undefined","Single-lab Co-IP-based ligase assignments"]},{"year":2011,"claim":"Placed KDM4A in the DNA damage response, showing its tandem Tudor binds H4K20me2 and that RNF8/RNF168-dependent degradation is required to clear KDM4A and permit 53BP1 recruitment.","evidence":"Binding/ubiquitination assays, laser micro-irradiation imaging, and siRNA epistasis","pmids":["22373579"],"confidence":"High","gaps":["Whether demethylase activity contributes to repair distinct from chromatin occlusion unresolved","Single lab"]},{"year":2011,"claim":"Demonstrated an in vivo developmental/disease role in cardiac hypertrophy, with KDM4A activating FHL1 via H3K9me3 removal in a demethylase-dependent manner.","evidence":"Conditional KO and transgenic mice, ChIP, reporter assays, and catalytic mutant","pmids":["21555854"],"confidence":"High","gaps":["Upstream signals recruiting KDM4A to FHL1 under stress not fully defined"]},{"year":2012,"claim":"Showed KDM4A overexpression drives site-specific rereplication and copy-number gain, mechanistically linking demethylase-driven chromatin opening to genomic instability.","evidence":"FISH, BrdU, ChIP, enzymatic mutant, and genetic suppression by Suv39h1/HP1γ","pmids":["23871696"],"confidence":"High","gaps":["How specific amplicon loci are selected unresolved","Relevance to spontaneous tumor amplification not directly tested"]},{"year":2012,"claim":"Connected KDM4A to p53/oncogenic programs, showing interaction with p53 at p21 and repression of CHD5 to suppress Ras-induced senescence.","evidence":"Pulldown, Co-IP, ChIP, senescence and transformation assays","pmids":["22134899","23168260"],"confidence":"Medium","gaps":["Direct catalytic mechanism at these loci versus scaffolding unclear","Single-lab data"]},{"year":2016,"claim":"Reframed KDM4A-p53 interplay as ubiquitin-mediated, showing SCF(Fbxo22)-KDM4A degrades methylated p53 to drive p16 induction and SASP in late senescence.","evidence":"Co-IP, ubiquitination assays, catalytic mutant, and Fbxo22-KO mice","pmids":["26868148"],"confidence":"High","gaps":["How methylation state of p53 is read by the complex not fully resolved"]},{"year":2016,"claim":"Broadened KDM4A's transcription-factor partnerships and outputs, identifying E2F1, ETV1, and Pol I associations governing metabolism, prostate tumorigenesis, and rDNA transcription.","evidence":"Co-IP, ChIP, metabolic flux/reporter assays, xenografts, and fractionation with kinase inhibition","pmids":["27626669","26731476","26729372"],"confidence":"Medium","gaps":["Whether each axis requires demethylase activity at the implicated promoter not uniformly tested","Single-lab studies"]},{"year":2016,"claim":"Established essential, partly KDM4C-redundant developmental and leukemic roles, showing requirement for ESC self-renewal and MLL-AF9 AML via Il3ra maintenance.","evidence":"Conditional double/triple-KO mice/ESCs, ChIP-seq, RNA-seq, and genetic rescue","pmids":["27266524","27257215"],"confidence":"High","gaps":["Degree of paralog redundancy in other tissues not mapped"]},{"year":2017,"claim":"Defined oxygen sensitivity of KDM4A catalysis, establishing it as an O2-responsive demethylase that can act on the HIF-1α locus to shape the hypoxic response.","evidence":"Kinetic analysis of recombinant enzyme (high KM for O2) plus cellular activity and ChIP under hypoxia","pmids":["28051298","28894274"],"confidence":"Medium","gaps":["Quantitative contribution of KDM4A among O2-sensing enzymes in physiological hypoxia unresolved"]},{"year":2017,"claim":"Identified SUMOylation at K471 as a post-translational switch enhancing KDM4A chromatin association, initially via a KSHV SUMO E3 ligase.","evidence":"In vitro/in vivo SUMOylation assays, K471 mutant, Co-IP, and RNA-seq","pmids":["28212444"],"confidence":"Medium","gaps":["Endogenous (non-viral) SUMO machinery acting on K471 defined only later","Single-lab"]},{"year":2020,"claim":"Demonstrated catalytically essential roles in zygotic genome activation and lineage differentiation, showing KDM4A clears H3K9me3 spread over broad H3K4me3 domains and controls myogenic and adipo/osteogenic programs.","evidence":"Conditional KO mice, ChIP-seq, RNA-seq, catalytic mutant, and differentiation assays","pmids":["32231309","34011940","31515577"],"confidence":"High","gaps":["Targeting determinants directing KDM4A to broad domains incompletely defined"]},{"year":2021,"claim":"Revealed therapeutic and ferroptosis-linked consequences of KDM4A loss, showing inhibition stabilizes HP1γ condensates to trigger cGAS-STING immunity and that KDM4A controls SLC7A11 to modulate ferroptosis.","evidence":"Chemical/genetic inhibition, live-cell imaging, DNA fiber and ferroptosis assays, and in vivo immunity readouts","pmids":["33743195","33689883"],"confidence":"Medium","gaps":["Single-lab mechanistic chains","Direct demethylation versus indirect effects on SLC7A11 not fully separated"]},{"year":2024,"claim":"Closed the loop on K471 regulation by showing hypoxia-driven endogenous SUMO1 modification enhances chromatin binding and confers ferroptosis resistance via SLC7A11/GPX4.","evidence":"Co-IP, K471 mutagenesis, ChIP, and ferroptosis assays","pmids":["38727079"],"confidence":"Medium","gaps":["Host SUMO E3 ligase for K471 not identified","Single-lab"]},{"year":null,"claim":"How the many recruitment cues (transcription factors, HP1, SUMO, oxygen, F-box ligases) are integrated to select specific genomic loci and dictate activation versus repression by a single KDM4A enzyme remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM state to locus targeting","Catalytic versus scaffolding contributions vary by context and are not reconciled","Full-length structure with reader domains and partners not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,8,9]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,25,38]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[11,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,7,21,22,24]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[25]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,23,30]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,15,34]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[20,23]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,7,21,24]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10,12,15]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[11,34]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[28,30,32,36]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[17,22,29,37]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,12,13,19,42]}],"complexes":["SCF(FBXO22)","SCF(FbxL4)","N-CoR/HDAC corepressor complex","PAF1 complex"],"partners":["HP1 (CBX/HP1Γ)","AR","E2F1","ETV1","TP53","FBXO22","GPS2","USP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75164","full_name":"Lysine-specific demethylase 4A","aliases":["JmjC domain-containing histone demethylation protein 3A","Jumonji domain-containing protein 2A","[histone H3]-trimethyl-L-lysine(36) demethylase 4A","[histone H3]-trimethyl-L-lysine(9) demethylase 4A"],"length_aa":1064,"mass_kda":120.7,"function":"Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code (PubMed:16603238, PubMed:26741168, PubMed:21768309). Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20' (PubMed:16603238, PubMed:26741168, PubMed:21768309). Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues (PubMed:16603238, PubMed:26741168, PubMed:21768309). Demethylation of Lys residue generates formaldehyde and succinate (PubMed:16603238). Also able to demethylate histone H1-4 methylated at 'Lys-26' (H1.4K26me1, H1.4K26me2 and H1.4K26me3) (PubMed:19144645, PubMed:30156264). Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively (PubMed:16024779) Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O75164/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM4A","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"H2AFZ","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KDM4A","total_profiled":1310},"omim":[{"mim_id":"609764","title":"LYSINE DEMETHYLASE 4A; KDM4A","url":"https://www.omim.org/entry/609764"},{"mim_id":"609096","title":"F-BOX ONLY PROTEIN 22; FBXO22","url":"https://www.omim.org/entry/609096"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli fibrillar center","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KDM4A"},"hgnc":{"alias_symbol":["KIAA0677","JHDM3A","TDRD14A"],"prev_symbol":["JMJD2","JMJD2A"]},"alphafold":{"accession":"O75164","domains":[{"cath_id":"2.60.120.650","chopping":"5-351","consensus_level":"high","plddt":94.177,"start":5,"end":351},{"cath_id":"3.30.40.10","chopping":"639-683_702-715_726-886","consensus_level":"high","plddt":86.2422,"start":639,"end":886},{"cath_id":"3.10.330.70","chopping":"891-1017","consensus_level":"medium","plddt":85.4339,"start":891,"end":1017}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75164","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75164-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75164-F1-predicted_aligned_error_v6.png","plddt_mean":71.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM4A","jax_strain_url":"https://www.jax.org/strain/search?query=KDM4A"},"sequence":{"accession":"O75164","fasta_url":"https://rest.uniprot.org/uniprotkb/O75164.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75164/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75164"}},"corpus_meta":[{"pmid":"16603238","id":"PMC_16603238","title":"Reversal 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Overexpression reduces H3K9/K36me3 levels; C. elegans JMJD2A homolog depletion increases H3K9me3 and H3K36me3 and triggers p53-dependent germline apoptosis.\",\n      \"method\": \"In vitro demethylase assay, cell overexpression/RNAi, site-directed mutagenesis, C. elegans genetics\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with catalytic mutant controls, replicated by independent group in Nature (PMID:16732292) in same year\",\n      \"pmids\": [\"16603238\", \"16732292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpression of KDM4A (JHDM3A) abrogates HP1 recruitment to heterochromatin, indicating KDM4A antagonizes H3K9me3-nucleated HP1 events. siRNA knockdown of JHDM3A increases H3K9 methylation and upregulates the target gene ASCL2, demonstrating euchromatic demethylation of active-transcription marks.\",\n      \"method\": \"siRNA knockdown, overexpression, immunofluorescence, RT-PCR\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function with clear molecular readouts, replicated by Whetstine et al. (PMID:16603238)\",\n      \"pmids\": [\"16732292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"X-ray crystal structures of the KDM4A catalytic core (JmjN + JmjC + C-terminal domain + zinc finger) with and without α-ketoglutarate and Fe²⁺ defined the substrate-binding pocket; site-directed mutagenesis combined with demethylase activity assays established a molecular model for substrate selection by the JMJD2 family.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, demethylase activity assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus activity assay in single study\",\n      \"pmids\": [\"16677698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structures of KDM4A bound to tri-, di-, and monomethyl H3K9 and trimethyl H3K36 peptides revealed a lysyl-binding pocket where substrates adopt distinct bent conformations involving the Zn-binding site, providing a structural mechanism for methylation-state selectivity and sequence specificity for H3K9 versus H3K36.\",\n      \"method\": \"X-ray crystallography with peptide substrate co-crystals\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple co-crystal structures defining selectivity mechanism, independent structural study\",\n      \"pmids\": [\"17589501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KDM4A catalytic core complexed with methylated H3K36 peptides (Fe²⁺/N-oxalylglycine) showed that peptide-binding specificity is largely determined by main-chain contacts and primary peptide structure, explaining selectivity for H3K9 and H3K36 but not H3K27; methyl-state selectivity is influenced by space and electrostatic environment in the catalytic center.\",\n      \"method\": \"X-ray crystallography of substrate complexes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with two substrates, independent validation of mechanism from PMID:17589501\",\n      \"pmids\": [\"17567753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KDM4A (JMJD2A) associates in vivo with pRb and class I HDACs (co-immunoprecipitation) and mediates repression of E2F-regulated promoters; the tandem Tudor domain is required for repression of the target gene ASCL2 via the N-CoR complex.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assay, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with multiple partners, functional reporter assays, single lab\",\n      \"pmids\": [\"15927959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KDM4A directly interacts with N-CoR through a defined NID (N-CoR interaction domain) both in vitro and in vivo; this interaction is required for JMJD2A-mediated repression of ASCL2 and requires a functional N-CoR complex and the tandem Tudor domain.\",\n      \"method\": \"GST pulldown (in vitro), co-immunoprecipitation (in vivo), chromatin immunoprecipitation, domain deletion mapping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro pulldown plus reciprocal Co-IP plus ChIP, single lab\",\n      \"pmids\": [\"16024779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KDM4A forms a complex with ligand-bound androgen receptor (AR) through its catalytic domain or C-terminus; overexpression of KDM4A stimulates AR transcriptional activity in a catalytic-activity-dependent manner; knockdown reduces PSA expression in LNCaP cells.\",\n      \"method\": \"Co-immunoprecipitation, reporter assay, domain mapping, siRNA knockdown, RT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, catalytic mutant control, functional reporter assay; single lab\",\n      \"pmids\": [\"17555712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"G9a/KMT1C methylates histone H1.4K26, and KDM4 family members (including KDM4A) demethylate H1.4K26 in vitro and in vivo, establishing KDM4A as a histone H1.4K26 demethylase.\",\n      \"method\": \"In vitro methylation/demethylation assay, cellular overexpression/knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay plus cellular validation, single lab\",\n      \"pmids\": [\"19144645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Drosophila KDM4A (dKDM4A) specifically demethylates H3K36me2 and H3K36me3 in vitro and in vivo; HP1a associates with dKDM4A (chromo shadow domain of HP1a binds HP1-interacting motif of dKDM4A) and stimulates its H3K36 demethylase activity in a manner dependent on the H3K9me-binding motif of HP1a.\",\n      \"method\": \"Affinity purification/mass spectrometry, in vitro demethylase assay, domain mapping, in vivo ChIP/western\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, AP-MS interaction, domain-level mutagenesis, in vivo corroboration; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19061644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KDM4A protein levels oscillate in a cell cycle-dependent manner; overexpression increases chromatin accessibility, accelerates S-phase progression, and alters replication timing in an enzymatic-activity-dependent manner. HP1γ overexpression antagonizes these KDM4A-dependent effects, placing KDM4A upstream of HP1γ in controlling chromatin accessibility during DNA replication.\",\n      \"method\": \"Cell cycle synchronization/western blot, FACS, BrdU incorporation, replication timing assay, epistasis via HP1γ overexpression\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal phenotypic assays with enzymatic mutant controls plus genetic epistasis, replicated in C. elegans\",\n      \"pmids\": [\"21145482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM4A (JMJD2A) tandem Tudor domain binds dimethylated histone H4K20 (H4K20me2); KDM4A is ubiquitinated by RNF8 and RNF168 and degraded by the proteasome following DNA damage in an RNF8-dependent manner. This RNF8-dependent degradation is required to allow 53BP1 recruitment to DNA damage sites; ectopic KDM4A expression blocks 53BP1 foci.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, ubiquitination assay, laser-induced DNA damage/immunofluorescence, siRNA epistasis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding assay, ubiquitination assay, cellular imaging, genetic epistasis), single lab\",\n      \"pmids\": [\"22373579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SCF(FbxL4) ubiquitin ligase complex interacts with KDM4A and targets it for proteasomal degradation; ubiquitin overexpression restores KDM4A turnover and blocks KDM4A-dependent faster S-phase progression in a cullin-1-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin overexpression rescue, BrdU incorporation, siRNA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue with ubiquitin, single lab\",\n      \"pmids\": [\"21757720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SCF(FBXO22) ubiquitin ligase complex targets KDM4A for proteasomal degradation; FBXO22 recognizes KDM4A through its FIST domain binding the JmjN/JmjC catalytic domains. Modulation of FBXO22 levels correspondingly alters histone H3K9 and H3K36 methylation levels and ASCL2 transcription.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, domain mapping, western blot for histone marks, RT-PCR\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus functional readouts; single lab\",\n      \"pmids\": [\"21768309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Heart-specific Jmjd2a deletion attenuates hypertrophic response to pressure overload; Jmjd2a transgenic overexpression exacerbates cardiac hypertrophy. KDM4A binds the FHL1 promoter in response to TAC stress, upregulates FHL1 expression via SRF/myocardin, and reduces H3K9me3 at the FHL1 promoter—effects requiring demethylase activity.\",\n      \"method\": \"Conditional knockout/transgenic mouse, ChIP, co-immunoprecipitation, reporter assay, catalytic mutant\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic models (KO and Tg), ChIP, catalytic mutant, multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"21555854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM4A (JMJD2A) overexpression leads to site-specific copy number gain (1q12, 1q21, Xq13.1) through rereplication within a single S phase; this requires enzymatic activity and is suppressed by Suv39h1/KMT1A or HP1γ overexpression. Sites with increased copy number show increased KDM4A, MCM, and DNA polymerase occupancy.\",\n      \"method\": \"FISH, BrdU incorporation, ChIP, enzymatic mutant, genetic suppression by Suv39h1/HP1γ overexpression\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including FISH, ChIP, replication assays, genetic epistasis; single lab with rigorous controls\",\n      \"pmids\": [\"23871696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM4A interacts with p53 (in vitro and in HCT116 cells) and is co-recruited with p53 to the p21 promoter upon DNA damage. KDM4A knockdown increases p21 and PUMA expression and decreases Bcl-2, inducing apoptosis; the effect is partially p53-dependent.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, ChIP, siRNA, western blot, flow cytometry\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro pulldown plus Co-IP plus ChIP, single lab\",\n      \"pmids\": [\"22134899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM4A (JMJD2A) promotes cellular transformation by repressing CHD5 (a tumor suppressor regulating p53 activity), thereby inhibiting Ras-induced senescence and collaborating with oncogenic Ras; depletion of KDM4A in K-Ras-expressing A549 cells triggers senescence.\",\n      \"method\": \"Lentiviral overexpression, siRNA, ChIP, senescence assays (SA-β-gal), co-operation with Ras in transformation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct target identification, functional epistasis in transformation assay, single lab\",\n      \"pmids\": [\"23168260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM4A overexpression promotes KSHV reactivation through H3K9me3 demethylase activity; KSHV-encoded K-bZIP protein physically interacts with KDM4A and inhibits its demethylase activity both in vivo and in vitro by blocking substrate accessibility, increasing global H3K9me3.\",\n      \"method\": \"Co-immunoprecipitation, in vitro demethylase inhibition assay, KSHV reactivation/titer assay, catalytic mutant rescue\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro inhibition assay, catalytic mutant, single lab\",\n      \"pmids\": [\"21228229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SCF(Fbxo22) forms a complex with KDM4A that ubiquitylates methylated p53 for proteasomal degradation; a catalytic mutant of KDM4A stabilizes p53 and enhances its interaction with PHF20. This SCF(Fbxo22)-KDM4A complex is required for p16 induction and SASP during late-phase senescence.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, catalytic mutant, Fbxo22 knockout mice, western blot\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assay, catalytic mutant, in vivo genetic model (KO mice), multiple orthogonal methods\",\n      \"pmids\": [\"26868148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KDM4A interacts with the translation initiation complex in the cytoplasm (co-immunoprecipitation) and affects distribution of translation initiation factors within polysome fractions; KDM4A depletion reduces protein synthesis and enhances sensitivity to mTOR inhibitors.\",\n      \"method\": \"Co-immunoprecipitation, polysome fractionation, protein synthesis assay (35S-Met), cell viability\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional polysome fractionation plus synthesis assay, single lab\",\n      \"pmids\": [\"25564516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM4A functions as an E2F1 coactivator: it associates with E2F1 on target gene promoters and enhances E2F1 chromatin binding and transcriptional activity. PDK1 and PDK3 are direct KDM4A/E2F1 targets regulating the switch between glycolytic and mitochondrial metabolism; KDM4A depletion elevates pyruvate dehydrogenase activity and ROS.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, reporter assay, metabolic flux assays, siRNA rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, metabolic assay with PDK rescue, single lab\",\n      \"pmids\": [\"27626669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM4A drives prostate tumorigenesis by interacting with ETS transcription factor ETV1; ETV1 recruits KDM4A to the YAP1 promoter, reducing H3K9me3 and increasing YAP1 expression. YAP1 largely rescues growth inhibitory effects of KDM4A depletion, establishing a JMJD2A/ETV1/YAP1 axis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, mouse xenograft, siRNA, overexpression, rescue experiment\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, in vivo mouse model, genetic rescue; single lab\",\n      \"pmids\": [\"26731476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM4A associates with RNA Polymerase I at active ribosomal DNA genes and is required for serum-induced activation of rDNA transcription. PI3K/SGK1 signaling controls KDM4A cytoplasmic-to-nuclear localization and thereby its occupancy on rDNA.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, subcellular fractionation, siRNA, reporter assay, kinase inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with Pol I, ChIP at rDNA, localization experiment linked to rDNA transcription function, single lab\",\n      \"pmids\": [\"26729372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPS2/KDM4A pioneering activity is required for promoter-specific recruitment of PPARγ in adipocytes; GPS2 inhibits RNF8 ubiquitin ligase activity, stabilizing KDM4A, which demethylates H3K9 to prime PPARγ-responsive genes including ATGL and HSL. Genome-wide profiling confirms the GPS2/KDM4A requirement for this specific transcriptional program.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, siRNA, ubiquitination assay, lipolysis assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genome-wide ChIP-seq, functional rescue; single lab\",\n      \"pmids\": [\"24953653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM4A demethylase activity has a high KM(app) for O₂ of ~173 μM (recombinant enzyme), indicating its H3K9me3 demethylase activity responds sensitively to physiological reductions in oxygen concentration; cellular KDM4A activity against H3K9me3 shows a graded response to decreasing O₂ concentrations consistent with biochemical data.\",\n      \"method\": \"Kinetic analysis of recombinant enzyme, immunofluorescence in cells under graded hypoxia\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinetic analysis plus cellular activity assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"28051298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM4A demethylates H3K9me3 at the HIF-1α locus; depletion or inactivation of KDM4A causes H3K9me3 accumulation at the HIF-1α gene, reducing HIF-1α mRNA and protein, and decreasing hypoxic transcriptional response, invasion, and migration.\",\n      \"method\": \"ChIP, siRNA, RT-PCR, western blot, invasion/migration assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing H3K9me3 accumulation at locus, multiple functional readouts, single lab\",\n      \"pmids\": [\"28894274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KSHV K-bZIP acts as a viral SUMO-2/3-specific E3 ligase that SUMOylates KDM4A at lysine 471 via a SIM-dependent mechanism; SUMOylation stabilizes KDM4A chromatin association and is required for viral gene transactivation and virion production, as well as for KDM4A-dependent cell proliferation.\",\n      \"method\": \"In vitro and in vivo SUMOylation assay, site-directed mutagenesis (K471), co-immunoprecipitation, RNA-seq, virion production assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo SUMOylation, K471 mutant, RNA-seq comparison; single lab\",\n      \"pmids\": [\"28212444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Combined deficiency for Jmjd2a and Jmjd2c (but not individual knockouts) causes early embryonic lethality and impaired ESC self-renewal with spontaneous primitive endoderm differentiation; both demethylases localize to H3K4me3-positive promoters and have redundant roles in preventing H3K9me3 and H3K36me3 accumulation. Catalytic activity is required for ESC maintenance.\",\n      \"method\": \"Conditional triple-KO mouse ESCs, ChIP-seq, RNA-seq, differentiation assays, catalytic mutant rescue\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic models (single/double/triple KO), ChIP-seq, catalytic mutant, multiple phenotypic readouts\",\n      \"pmids\": [\"27266524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Jmjd2/Kdm4 demethylases are required for MLL-AF9 AML in vivo and in vitro; their activity maintains expression of Il3ra (CD123) by removing H3K9me3 from its promoter. Ectopic Il3ra re-expression rescues AML cell survival in Jmjd2/Kdm4 triple-knockout cells, establishing Il3ra as a critical downstream target.\",\n      \"method\": \"Conditional triple-KO mice, ChIP, lentiviral re-expression rescue, in vivo AML model\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic models, ChIP, genetic rescue, multiple orthogonal assays\",\n      \"pmids\": [\"27257215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4A-mediated H3K9me3 demethylation at broad H3K4me3 domains in oocytes is essential for normal pre-implantation development and zygotic genome activation; loss of KDM4A causes aberrant H3K9me3 spreading over bdH3K4me3 domains, resulting in insufficient transcriptional activation of genes and endogenous retroviral elements. Catalytic activity of KDM4A is essential for this function.\",\n      \"method\": \"Conditional oocyte KO, ChIP-seq, RNA-seq, catalytic mutant, embryo development assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, genome-wide ChIP-seq, catalytic mutant, multiple phenotypic readouts in vivo\",\n      \"pmids\": [\"32231309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4A inhibition promotes formation of liquid-like HP1γ puncta on heterochromatin, stalls DNA replication forks, and activates tumor-cell-intrinsic cGAS-STING signaling through replication-stress-induced cytosolic DNA accumulation, enabling antitumor immunity.\",\n      \"method\": \"KDM4A inhibition (chemical/genetic), live-cell imaging of HP1γ puncta, DNA fiber assay, cGAS-STING pathway assays, CD8+ T cell recruitment assays, in vivo lineage tracing\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"33743195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4A promotes myogenesis by demethylating H3K9me3 at the MyoD, MyoG, and Myf5 gene loci; conditional KDM4A deletion impairs embryonic and postnatal muscle formation; KDM4A-deficient myoblasts show inhibited differentiation, reduced proliferation, increased p21, and decreased Cyclin D1.\",\n      \"method\": \"Conditional knockout mouse, ChIP, western blot, differentiation assay, satellite cell isolation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model, ChIP for direct target loci, multiple functional readouts; single lab\",\n      \"pmids\": [\"34011940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4A regulates SLC7A11 transcription by demethylating H3K9me3 in the SLC7A11 promoter; KDM4A knockdown increases H3K9me3 at the SLC7A11 promoter, decreases SLC7A11 expression, and promotes ferroptotic cell death in osteosarcoma cells.\",\n      \"method\": \"ChIP assay, siRNA, western blot, ferroptosis assays (iron, MDA, GSH), in vivo xenograft\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter regulation, multiple functional readouts, single lab\",\n      \"pmids\": [\"33689883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Drosophila KDM4A (dKDM4A) localizes predominantly to heterochromatin and regulates heterochromatin position-effect variegation and organization of repetitive DNA; its enzymatic activity is dispensable for PEV but required for relocation of heterochromatic DSBs outside the domain and for demethylation of H3K56me3 following DNA damage to facilitate repair.\",\n      \"method\": \"Immunofluorescence, PEV assay, FISH, DNA damage assays, enzymatic mutant, Drosophila genetics\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization by imaging, enzymatic mutant for functional dissection, genetic assays; Drosophila ortholog study\",\n      \"pmids\": [\"28743002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HP1a targets dKDM4A to a subset of heterochromatic genes in Drosophila to regulate H3K36me3 levels; HP1a binding is required for dKDM4A-mediated H3K36me3 demethylation specifically at this gene subset, shown by ChIP-chip in wild-type vs. dkdm4a mutant embryos.\",\n      \"method\": \"ChIP-chip, dkdm4a mutant embryos, genetic epistasis with HP1a\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-chip with genetic mutant, Drosophila ortholog study; single lab\",\n      \"pmids\": [\"22761891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM4A promotes adipogenic and inhibits osteogenic differentiation by directly binding the promoters of Sfrp4 and C/ebpα, removing H3K9me3, and reducing DNA methylation; overexpression inactivates canonical Wnt signaling via Sfrp4 upregulation. Silencing Sfrp4 rescues the osteogenesis block, placing Sfrp4 downstream of KDM4A in this pathway.\",\n      \"method\": \"ChIP, overexpression/knockdown, catalytic mutant, siRNA rescue, differentiation assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct promoter binding, catalytic mutant controls, genetic rescue; single lab\",\n      \"pmids\": [\"31515577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4A depletion leads to global H3K9me3 and H3K27me3 accumulation at KDM4A-targeted loci in AML cells and downregulates a KDM4A-PAF1-controlled transcriptional program essential for leukemogenesis; KDM4A interacts with the PAF1 complex (distinct from KDM4C-dependent targets).\",\n      \"method\": \"ChIP-seq, RNA-seq, siRNA/shRNA, co-immunoprecipitation, apoptosis assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq, Co-IP, loss-of-function with defined transcriptional phenotype; single lab\",\n      \"pmids\": [\"34083515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"QM/MM computational analysis shows KDM4A catalysis generates a reactive Fe(IV)-oxo intermediate; substrate binding mode, correlated protein-histone motions, and molecular orbital control synergistically determine reactivity. K241A substitution (consistent with experimental studies) abolishes activity by altering substrate orientation; Ser288 and Thr289 contribute through correlated motions.\",\n      \"method\": \"Molecular dynamics + QM/MM calculations with in silico mutagenesis validated against experimental activity data\",\n      \"journal\": \"Chemical science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — computational study validated only against published experimental data, no new experimental results\",\n      \"pmids\": [\"34094257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hypoxia-like conditions promote SUMO1 modification of KDM4A at lysine K471 (K471 is the primary SUMOylation site, confirmed by mutation), which enhances KDM4A chromatin association, reduces H3K9me3 at the SLC7A11 promoter, and upregulates SLC7A11/GPX4 to confer ferroptosis resistance in cervical cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (K471), ChIP, western blot, ferroptosis assays\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K471 mutation, ChIP validation, multiple functional assays; single lab\",\n      \"pmids\": [\"38727079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM4A inhibition (KDM4A-silencing or compound C-4) induces TRAIL and DR5 expression by switching promoter-bound histone-modifying complexes: dissociating KDM4A and NCoR-HDAC complex and recruiting histone acetylase CBP at the CHOP gene promoter, thereby de-repressing TRAIL and DR5 transcription.\",\n      \"method\": \"ChIP, siRNA, small-molecule inhibitor, co-immunoprecipitation, apoptosis assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing complex switching, Co-IP, functional apoptosis readout; single lab\",\n      \"pmids\": [\"27612013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM4A and KDM4C co-occupy promoters with NF-κB p65 (ChIP-seq/motif analysis) and co-target Wdr5, a MLL complex member; their depletion in B cells potentiates activation and upregulates cell cycle inhibitors Cdkn2c and Cdkn3 via WDR5-dependent H3K4 methylation.\",\n      \"method\": \"ChIP-seq, de novo motif analysis, siRNA, co-immunoprecipitation, B cell activation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq, Co-IP, functional B cell assays; single lab\",\n      \"pmids\": [\"29718303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitination and protein stability; USP1 inhibition reduces KDM4A levels and suppresses c-Myc expression (a downstream effector of the USP1-KDM4A/androgen receptor axis) in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA, western blot, proliferation assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue; single lab\",\n      \"pmids\": [\"32133742\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM4A is a JmjC-domain, Fe(II)- and 2-oxoglutarate-dependent dioxygenase that removes di- and tri-methyl marks from histone H3K9 and H3K36 (and H1.4K26), thereby modulating chromatin accessibility, DNA replication timing, transcription factor recruitment (AR, ERα, E2F1, ETV1, PPARγ), and DNA damage repair; its abundance is tightly cell-cycle-regulated through proteasomal degradation mediated by at least two SCF complexes (SCF-FbxL4 and SCF-FBXO22) and by RNF8/RNF168-dependent ubiquitination, while its chromatin occupancy and activity are further tuned by SUMO modification at K471, HP1 interaction, and oxygen availability; through these mechanisms KDM4A controls gene expression programs in development, differentiation, and oncogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM4A (JMJD2A/JHDM3A) is a JmjC-domain, Fe(II)- and 2-oxoglutarate-dependent histone demethylase that removes di- and tri-methyl marks from histone H3K9 and H3K36 (and H1.4K26), and through this catalysis controls chromatin accessibility, replication, and transcriptional programs across development, differentiation, and oncogenesis [#0, #8, #15]. Crystal structures of its catalytic core (JmjN+JmjC+zinc finger) bound to methylated H3K9 and H3K36 peptides define a lysyl-binding pocket whose main-chain contacts and bent substrate conformations dictate methylation-state and sequence selectivity, including exclusion of H3K27 [#2, #3, #4]. By erasing H3K9me3, KDM4A antagonizes HP1-nucleated heterochromatin, and its overexpression accelerates S-phase, alters replication timing, and drives site-specific rereplication and copy-number gain in an enzymatic-activity-dependent manner that is opposed by Suv39h1/HP1\\u03b3 [#1, #10, #15]; KDM4A inhibition conversely stabilizes liquid-like HP1\\u03b3 puncta, stalls replication forks, and triggers cGAS-STING-dependent antitumor immunity [#31]. KDM4A is recruited to specific loci by transcription factors and corepressor/coactivator complexes\\u2014pRb/HDAC and N-CoR for E2F- and ASCL2-target repression, and AR, E2F1, ETV1, PPAR\\u03b3 (via GPS2), and the PAF1 complex for target activation\\u2014linking demethylation to androgen signaling, metabolic gene control, leukemogenesis, and tumorigenesis [#5, #6, #7, #21, #22, #24, #37]. KDM4A redundantly with KDM4C maintains ESC self-renewal and is required for oocyte zygotic genome activation, myogenesis, and adipo-/osteogenic lineage choice through demethylation of defined target loci [#28, #30, #32, #36]. Its abundance is tightly controlled by ubiquitin-proteasome turnover via SCF(FbxL4) and SCF(FBXO22) and by RNF8/RNF168, the latter degradation permitting 53BP1 recruitment at DNA damage sites, while USP1 deubiquitination, SUMOylation at K471, and oxygen availability further tune its chromatin occupancy and activity [#11, #12, #13, #25, #39, #42].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the founding enzymatic identity\\u2014that KDM4A is a histone demethylase\\u2014answering whether trimethyl-lysine marks are reversible and defining its H3K9me3/H3K36me3 substrates.\",\n      \"evidence\": \"In vitro demethylase assays with catalytic-mutant controls, cellular over/knockdown, and C. elegans genetics\",\n      \"pmids\": [\"16603238\", \"16732292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve atomic basis of substrate selection\", \"In vivo locus-specific targeting not yet mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected demethylase activity to chromatin state by showing KDM4A antagonizes HP1 recruitment and de-represses active genes, establishing functional consequences of erasing H3K9me3.\",\n      \"evidence\": \"Reciprocal siRNA/overexpression with immunofluorescence and RT-PCR readouts\",\n      \"pmids\": [\"16732292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of locus selection unaddressed\", \"Direct HP1 binding vs indirect competition not distinguished here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the structural mechanism of methylation-state and sequence selectivity, explaining why KDM4A acts on H3K9 and H3K36 but not H3K27.\",\n      \"evidence\": \"X-ray co-crystal structures of catalytic core with tri-/di-/monomethyl peptides plus mutagenesis and activity assays\",\n      \"pmids\": [\"16677698\", \"17589501\", \"17567753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length enzyme/reader-domain architecture not resolved\", \"Dynamics of catalysis not captured by static structures\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified KDM4A as a transcriptional corepressor that engages pRb/HDAC and N-CoR via its tandem Tudor domain, showing it functions beyond bulk demethylation in targeted gene repression.\",\n      \"evidence\": \"Co-IP, GST pulldown, ChIP, reporter assays, and domain deletion mapping\",\n      \"pmids\": [\"15927959\", \"16024779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interactions without independent structural validation\", \"Whether repression requires demethylase activity unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked KDM4A to nuclear-receptor signaling by showing catalytic-activity-dependent coactivation of androgen receptor target genes.\",\n      \"evidence\": \"Co-IP, domain mapping, catalytic-mutant reporter assays, and siRNA in LNCaP cells\",\n      \"pmids\": [\"17555712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct histone substrate at AR target promoters not defined here\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined HP1 as a regulator of KDM4A targeting and activity, showing HP1 binding stimulates H3K36 demethylation at specific heterochromatic genes.\",\n      \"evidence\": \"AP-MS, in vitro demethylase assays, domain mapping, and ChIP in Drosophila\",\n      \"pmids\": [\"19061644\", \"22761891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of HP1 stimulation in mammalian KDM4A not fully established\", \"Ortholog-based mechanism\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Expanded the substrate repertoire to linker histone H1.4K26, showing KDM4A reverses G9a-deposited marks beyond core histones.\",\n      \"evidence\": \"In vitro methylation/demethylation assays with cellular over/knockdown\",\n      \"pmids\": [\"19144645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequence of H1.4K26 demethylation not defined\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established cell-cycle-coupled proteasomal turnover of KDM4A via SCF(FbxL4) and SCF(FBXO22), linking enzyme abundance to S-phase progression and histone-mark homeostasis.\",\n      \"evidence\": \"Co-IP, domain mapping, ubiquitin-rescue, BrdU incorporation, and histone-mark westerns\",\n      \"pmids\": [\"21757720\", \"21768309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron and signal controlling F-box recognition undefined\", \"Single-lab Co-IP-based ligase assignments\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed KDM4A in the DNA damage response, showing its tandem Tudor binds H4K20me2 and that RNF8/RNF168-dependent degradation is required to clear KDM4A and permit 53BP1 recruitment.\",\n      \"evidence\": \"Binding/ubiquitination assays, laser micro-irradiation imaging, and siRNA epistasis\",\n      \"pmids\": [\"22373579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether demethylase activity contributes to repair distinct from chromatin occlusion unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated an in vivo developmental/disease role in cardiac hypertrophy, with KDM4A activating FHL1 via H3K9me3 removal in a demethylase-dependent manner.\",\n      \"evidence\": \"Conditional KO and transgenic mice, ChIP, reporter assays, and catalytic mutant\",\n      \"pmids\": [\"21555854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals recruiting KDM4A to FHL1 under stress not fully defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed KDM4A overexpression drives site-specific rereplication and copy-number gain, mechanistically linking demethylase-driven chromatin opening to genomic instability.\",\n      \"evidence\": \"FISH, BrdU, ChIP, enzymatic mutant, and genetic suppression by Suv39h1/HP1\\u03b3\",\n      \"pmids\": [\"23871696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How specific amplicon loci are selected unresolved\", \"Relevance to spontaneous tumor amplification not directly tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected KDM4A to p53/oncogenic programs, showing interaction with p53 at p21 and repression of CHD5 to suppress Ras-induced senescence.\",\n      \"evidence\": \"Pulldown, Co-IP, ChIP, senescence and transformation assays\",\n      \"pmids\": [\"22134899\", \"23168260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct catalytic mechanism at these loci versus scaffolding unclear\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reframed KDM4A-p53 interplay as ubiquitin-mediated, showing SCF(Fbxo22)-KDM4A degrades methylated p53 to drive p16 induction and SASP in late senescence.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, catalytic mutant, and Fbxo22-KO mice\",\n      \"pmids\": [\"26868148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How methylation state of p53 is read by the complex not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened KDM4A's transcription-factor partnerships and outputs, identifying E2F1, ETV1, and Pol I associations governing metabolism, prostate tumorigenesis, and rDNA transcription.\",\n      \"evidence\": \"Co-IP, ChIP, metabolic flux/reporter assays, xenografts, and fractionation with kinase inhibition\",\n      \"pmids\": [\"27626669\", \"26731476\", \"26729372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether each axis requires demethylase activity at the implicated promoter not uniformly tested\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established essential, partly KDM4C-redundant developmental and leukemic roles, showing requirement for ESC self-renewal and MLL-AF9 AML via Il3ra maintenance.\",\n      \"evidence\": \"Conditional double/triple-KO mice/ESCs, ChIP-seq, RNA-seq, and genetic rescue\",\n      \"pmids\": [\"27266524\", \"27257215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degree of paralog redundancy in other tissues not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined oxygen sensitivity of KDM4A catalysis, establishing it as an O2-responsive demethylase that can act on the HIF-1\\u03b1 locus to shape the hypoxic response.\",\n      \"evidence\": \"Kinetic analysis of recombinant enzyme (high KM for O2) plus cellular activity and ChIP under hypoxia\",\n      \"pmids\": [\"28051298\", \"28894274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of KDM4A among O2-sensing enzymes in physiological hypoxia unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified SUMOylation at K471 as a post-translational switch enhancing KDM4A chromatin association, initially via a KSHV SUMO E3 ligase.\",\n      \"evidence\": \"In vitro/in vivo SUMOylation assays, K471 mutant, Co-IP, and RNA-seq\",\n      \"pmids\": [\"28212444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous (non-viral) SUMO machinery acting on K471 defined only later\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated catalytically essential roles in zygotic genome activation and lineage differentiation, showing KDM4A clears H3K9me3 spread over broad H3K4me3 domains and controls myogenic and adipo/osteogenic programs.\",\n      \"evidence\": \"Conditional KO mice, ChIP-seq, RNA-seq, catalytic mutant, and differentiation assays\",\n      \"pmids\": [\"32231309\", \"34011940\", \"31515577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Targeting determinants directing KDM4A to broad domains incompletely defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed therapeutic and ferroptosis-linked consequences of KDM4A loss, showing inhibition stabilizes HP1\\u03b3 condensates to trigger cGAS-STING immunity and that KDM4A controls SLC7A11 to modulate ferroptosis.\",\n      \"evidence\": \"Chemical/genetic inhibition, live-cell imaging, DNA fiber and ferroptosis assays, and in vivo immunity readouts\",\n      \"pmids\": [\"33743195\", \"33689883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mechanistic chains\", \"Direct demethylation versus indirect effects on SLC7A11 not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Closed the loop on K471 regulation by showing hypoxia-driven endogenous SUMO1 modification enhances chromatin binding and confers ferroptosis resistance via SLC7A11/GPX4.\",\n      \"evidence\": \"Co-IP, K471 mutagenesis, ChIP, and ferroptosis assays\",\n      \"pmids\": [\"38727079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Host SUMO E3 ligase for K471 not identified\", \"Single-lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many recruitment cues (transcription factors, HP1, SUMO, oxygen, F-box ligases) are integrated to select specific genomic loci and dictate activation versus repression by a single KDM4A enzyme remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM state to locus targeting\", \"Catalytic versus scaffolding contributions vary by context and are not reconciled\", \"Full-length structure with reader domains and partners not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 8, 9]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 25, 38]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [11, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 7, 21, 22, 24]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 23, 30]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 15, 34]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [20, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 7, 21, 24]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10, 12, 15]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [11, 34]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [28, 30, 32, 36]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [17, 22, 29, 37]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 12, 13, 19, 42]}\n    ],\n    \"complexes\": [\"SCF(FBXO22)\", \"SCF(FbxL4)\", \"N-CoR/HDAC corepressor complex\", \"PAF1 complex\"],\n    \"partners\": [\"HP1 (CBX/HP1\\u03b3)\", \"AR\", \"E2F1\", \"ETV1\", \"TP53\", \"FBXO22\", \"GPS2\", \"USP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}