{"gene":"KDM5A","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2010,"finding":"KDM5A is an integral component of the Notch/RBP-J repressor complex; KDM5A physically interacts with RBP-J and dynamically erases H3K4 methylation at RBP-J target sites upon Notch signaling inhibition, with this interaction conserved in Drosophila and required for Notch-induced growth responses.","method":"Co-immunoprecipitation, ChIP, genetic conservation analysis (Drosophila), loss-of-function studies","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, ortholog validation in Drosophila, functional rescue; replicated across species","pmids":["20231316"],"is_preprint":false},{"year":2011,"finding":"KDM5A (JARID1a) forms a complex with CLOCK-BMAL1 and is recruited to the Per2 promoter; it enhances CLOCK-BMAL1 transcription by inhibiting HDAC1 function in a demethylase-independent manner, and its depletion dampens circadian gene expression and shortens circadian period.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, Drosophila genetic loss-of-function","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ChIP, KD phenotype, ortholog validated in Drosophila; multiple orthogonal methods in one study","pmids":["21960634"],"is_preprint":false},{"year":2010,"finding":"KDM5A (JARID1A) is the major H3K4 demethylase in bronchial epithelial cells; hypoxia inhibits KDM5A enzymatic activity (requiring molecular oxygen as cofactor) without altering its mRNA or protein levels, leading to global and gene-specific increases in H3K4me3.","method":"In vitro histone demethylation assay with nuclear extracts, siRNA knockdown, ChIP","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro demethylase activity assay combined with KD and ChIP; multiple orthogonal methods","pmids":["20406991"],"is_preprint":false},{"year":2012,"finding":"KDM5A (Jarid1a) cooperates with the retinoblastoma tumor suppressor to silence H3K4-methylated target genes during cellular senescence; Jarid1a/b-mediated H3K4 demethylation contributes to retinoblastoma-dependent gene silencing.","method":"Quantitative mass spectrometry, ChIP-seq, functional knockdown studies in primary human cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq, MS, functional KD with defined phenotype; multiple orthogonal methods","pmids":["22615382"],"is_preprint":false},{"year":2012,"finding":"KDM5A cooperates with E2F4 to repress cell cycle genes during differentiation; KDM5A co-occupies E2F4 target genes genome-wide and its knockout leads to derepression of these loci; in terminally differentiated cells, common targets are bound by p130/DREAM complex.","method":"ChIP-seq (global location analysis), KDM5A knockout in ES cells, co-occupancy analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq plus KO with defined transcriptional phenotype; multiple orthogonal methods","pmids":["23093672"],"is_preprint":false},{"year":2012,"finding":"KDM5A (Jarid1a) physically associates with the H3K9 methyltransferase G9a/KMT1C in a corepressor complex distinct from the G9a-Mediator coactivator complex; coordinate action of G9a and Jarid1a (concurrent H3K9me2 deposition and H3K4me3 removal) maintains silencing of the embryonic globin gene.","method":"Co-immunoprecipitation, ChIP, functional knockdown, reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, functional studies; multiple orthogonal methods","pmids":["23112189"],"is_preprint":false},{"year":2014,"finding":"KDM5A is physically and functionally associated with both the SIN3B-containing HDAC complex and the NuRD complex; KDM5A depletion co-regulates hundreds of developmentally regulated genes with NuRD catalytic subunit CHD4, and the C. elegans homologs function in the same genetic pathway during vulva development.","method":"Immunoaffinity purification, sucrose density gradient, sequential immunoprecipitation, ChIP, genetic epistasis in C. elegans","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, sucrose gradient, sequential IP, ChIP, genetic epistasis; multiple orthogonal methods","pmids":["25190814"],"is_preprint":false},{"year":2015,"finding":"KDM5A PHD1 domain preferentially binds unmethylated H3K4 (the product of KDM5A demethylation); binding of unmodified H3 to PHD1 allosterically stimulates the catalytic domain to demethylate H3K4me3 on peptide and nucleosome substrates, establishing a positive-feedback mechanism.","method":"Biochemical binding assays, NMR structural studies, in vitro demethylation assays on peptide and nucleosome substrates, mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — NMR structure, in vitro reconstitution, mutagenesis; strong mechanistic study with multiple orthogonal methods in single paper","pmids":["25686748"],"is_preprint":false},{"year":2015,"finding":"Loss of Kdm5a restores differentiation in pRb-deficient cells by increasing mitochondrial respiration; KDM5A is a direct repressor of metabolic regulatory genes and its deletion activates Pgc-1α target genes, linking H3K4 demethylation to mitochondrial biogenesis and differentiation.","method":"KO mouse model, RNA-seq, ChIP, metabolic (oxygen consumption) assays, gain-of-function rescue","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — KO with defined phenotype, ChIP, metabolic assays, rescue experiments; multiple orthogonal methods","pmids":["26314709"],"is_preprint":false},{"year":2016,"finding":"KDM5A associates with the NF-κB subunit p50 and binds to the Socs1 promoter in resting NK cells, decreasing H3K4me3 and maintaining a repressive chromatin configuration at Socs1; loss of Kdm5a increases Socs1 expression, impairs STAT4 phosphorylation and nuclear localization, and reduces NK cell IFN-γ production.","method":"Co-immunoprecipitation, ChIP, Kdm5a knockout mice, NK cell activation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ChIP, KO with defined immune phenotype; multiple orthogonal methods","pmids":["27050510"],"is_preprint":false},{"year":2017,"finding":"KDM5A demethylates H3K4me3 near DNA double-strand break (DSB) sites; this demethylation is required for ZMYND8-NuRD complex binding to damaged chromatin, transcriptional silencing at DSBs, and homologous recombination repair.","method":"ChIP near DSBs, siRNA knockdown, DSB repair assays (HR reporter), transcriptional silencing assays at defined DSBs","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — ChIP at defined DSBs, HR reporter assay, KD with defined repair phenotype; multiple orthogonal methods","pmids":["28572115"],"is_preprint":false},{"year":2018,"finding":"KDM5A catalytic domain structure was determined by X-ray crystallography in complex with inhibitors N70 and N71; a noncatalytic cysteine (Cys481) unique to KDM5 family near the active site allows covalent modification by acrylamide-containing inhibitors that inhibit in an αKG-competitive but irreversible manner.","method":"X-ray crystallography (co-crystal structures), enzyme inhibition assays, dialysis/reversibility assays","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation (inhibition kinetics, covalent modification); single rigorous paper with orthogonal methods","pmids":["30392349"],"is_preprint":false},{"year":2019,"finding":"KDM5A sustains ASCL1 expression and neuroendocrine differentiation in SCLC by repressing NOTCH2 and Notch target genes; CRISPR KO of KDM5A in a mouse SCLC model decreased tumorigenesis and metastasis while increasing Notch signaling.","method":"CRISPR/Cas9 KO (in vitro and in vivo mouse model), gene expression analysis, ChIP","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO with defined in vivo tumor phenotype plus mechanistic gene expression data; multiple orthogonal approaches","pmids":["31727771"],"is_preprint":false},{"year":2021,"finding":"KDM5A contains a noncanonical poly(ADP-ribose) (PAR)-binding coiled-coil region unique among KDM5 family members; loss of this PAR-binding region or PARP inhibitor treatment blocks KDM5A-PAR interactions and its DNA repair functions. The histone variant macroH2A1.2 is also specifically required upstream of KDM5A for its recruitment to DNA damage sites and homology-directed repair.","method":"Domain mutagenesis, PAR-binding assays, PARP inhibitor treatment, macroH2A1.2 KD, HR reporter assays, ChIP at DSBs","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — mutagenesis, functional repair assays, KD, ChIP; multiple orthogonal methods identifying two upstream regulators","pmids":["34003252"],"is_preprint":false},{"year":2020,"finding":"The KDM5A PHD1 domain binds the H3 tail with preference for lower methylation states of H3K4 (me0 > me1 > me2 > me3); NMR solution structures of apo and H3-bound PHD1 show conformational changes accommodating H3 in a helical conformation, and post-translational modifications at the distal H3 epitope (residues 14–18) modulate KDM5A demethylation activity.","method":"NMR spectroscopy (solution structure), fluorescence polarization binding assays, demethylation activity assays, mutagenesis","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with functional validation by demethylation assays and mutagenesis","pmids":["33621062"],"is_preprint":false},{"year":2020,"finding":"KDM5A extended substrate recognition of H3 tail involves H3Q5 as critical for demethylation and a distal epitope at positions 14–18 whose deletion increases KMapp ~8-fold; post-translational modifications on the distal epitope modulate KDM5A-dependent demethylation.","method":"Alanine scanning mutagenesis, in vitro demethylation activity assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with quantitative in vitro demethylase assays; rigorous biochemical characterization","pmids":["31985200"],"is_preprint":false},{"year":2019,"finding":"KDM5A acts as a transcriptional repressor of MPC-1 by binding directly to its promoter and demethylating H3K4, suppressing mitochondrial pyruvate metabolism in pancreatic cancer cells; KDM5A expression is inversely correlated with MPC-1 in patient samples.","method":"ChIP assay, overexpression and knockdown experiments, in vitro and in vivo tumor growth assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirming promoter binding, functional KD/OE; single lab with moderate methods","pmids":["31641207"],"is_preprint":false},{"year":2019,"finding":"KDM5A promotes preadipocyte differentiation by repressing Wnt6 transcription; C/EBPβ binds the KDM5A promoter to transactivate its expression, and KDM5A interacts with C/EBPβ and cooperates with it to reduce H3K4me3 at the Wnt6 promoter, inhibiting Wnt/β-catenin signaling.","method":"ChIP, immunoprecipitation, RT-qPCR, siRNA knockdown in 3T3-L1 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ChIP, functional rescue; single lab but multiple orthogonal methods","pmids":["31061100"],"is_preprint":false},{"year":2022,"finding":"Fbxo22 reduces KDM5A protein levels via ubiquitination; KDM5A promotes H3K4me3 demethylation at the p16 promoter to downregulate p16 expression, and Fbxo22-mediated KDM5A degradation rescues p16 expression to suppress TNBC tumorigenesis.","method":"Immunoprecipitation/ubiquitination assay, ChIP, knockdown/overexpression, in vitro and in vivo tumor assays","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assay, ChIP, functional KO/OE; single lab","pmids":["36112263"],"is_preprint":false},{"year":2023,"finding":"KDM5A physically interacts with MLL1, MLL2, and WDR5 (normally its functional antagonists); when bound at mesenchymal gene promoters KDM5A acts as a transcriptional activator by inhibiting HDAC activity and increasing H3K18ac, while at E-cadherin promoter it acts as a classical repressor by demethylating H3K4me3.","method":"ChIP, co-immunoprecipitation, HDAC activity assays, gene expression analysis","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP; single lab with two orthogonal methods","pmids":["37722486"],"is_preprint":false},{"year":2019,"finding":"HDAC1 negatively regulates RBPJ occupancy on mitotic chromatin in a KDM5A-dependent manner; KDM5A knockdown or inactivation reduces HDAC1-dependent regulation of RBPJ mitotic chromatin binding, and KDM5A presence at these sites is essential for increased RBPJ occupancy.","method":"ChIP on mitotic chromatin, siRNA knockdown, HDAC1 inhibitor treatment","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP on mitotic chromatin with KD; single lab but mechanistically defined","pmids":["30916347"],"is_preprint":false},{"year":2020,"finding":"KDM5A mutations cause autism spectrum disorder (ASD) with lack of speech; Kdm5a knockout mice display repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis, with dysregulation of the hippocampal transcriptome.","method":"Forward genetics screen, Kdm5a knockout mouse model, behavioral assays, RNA-seq, dendritic morphology analysis, human WES/microarray","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with multiple behavioral and cellular phenotypes, human genetic validation; strong evidence across multiple methods and species","pmids":["33350388"],"is_preprint":false},{"year":2016,"finding":"KDM5A controls BMP2-induced osteogenic differentiation of bone marrow mesenchymal stem cells by decreasing H3K4me3 levels at the Runx2 promoter in a demethylase activity-dependent manner; elevated KDM5A in osteoporotic MSCs impairs BMP2-induced osteogenesis.","method":"ChIP, shRNA knockdown, KDM5A inhibitor, overexpression, OVX mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirming promoter occupancy, functional rescue; single lab but multiple methods","pmids":["27512956"],"is_preprint":false},{"year":2006,"finding":"KDM5A (JARID1A) is identified as a fusion partner of NUP98 in pediatric AML through the t(11;21) translocation, generating a NUP98-JARID1A fusion oncoprotein implicated in transcriptional regulation.","method":"3' RACE, RT-PCR, FISH, karyotyping","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 — molecular characterization of fusion gene by multiple techniques; single study","pmids":["16419055"],"is_preprint":false},{"year":2023,"finding":"RepID recruits CRL4A-JARID1A (KDM5A) to the DAB2 promoter during proliferation, maintaining H3K4 demethylation and repressive chromatin; during megakaryocytic differentiation, RepID, CRL4A, and JARID1A dissociate from chromatin, allowing euchromatinization and DAB2 expression.","method":"Immunoprecipitation, proximity ligation assay, ChIP-qPCR, subcellular fractionation","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ChIP-qPCR, PLA; single lab with multiple methods","pmids":["37612584"],"is_preprint":false},{"year":2020,"finding":"KDM5A acts as an H3K4me3 demethylase at the miR-495 promoter in prostate cancer cells, inhibiting miR-495 transcription; reduced miR-495 elevates YTHDF2, which degrades MOB3B mRNA via m6A recognition, promoting cancer progression.","method":"ChIP assay, dual luciferase reporter, PAR-CLIP, me-RIP, xenograft mouse model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirming promoter binding plus functional cascade validation; single lab","pmids":["33087165"],"is_preprint":false},{"year":2020,"finding":"KDM5A in neural progenitors binds to and activates neuronal genes involved in early differentiation; mitochondrial damage causes characteristic KDM5A protein degradation in neural progenitors, inhibiting neuronal differentiation and adult hippocampal neurogenesis.","method":"Proteomics, KDM5A overexpression/knockdown in neural progenitors, neurogenesis assays, KO mouse","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — proteomic identification, functional KD/OE with defined differentiation phenotype; single lab","pmids":["36056186"],"is_preprint":false},{"year":2011,"finding":"KDM5A (JARID1A) binds in a ligand-independent manner to a progesterone receptor gene upstream regulatory region and represses progesterone receptor promoter activity through its demethylase activity; JARID1A depletion elevates H3K4me3 in this region and increases progesterone receptor expression.","method":"ChIP, overexpression of wild-type vs. catalytically inactive JARID1A mutant, siRNA knockdown, reporter assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, catalytic mutant comparison, KD with defined phenotype; single lab, multiple methods","pmids":["21348942"],"is_preprint":false},{"year":2025,"finding":"KDM5A contains an intrinsically disordered region (IDR) with bifunctional arginine-rich motifs that bind both the histone H2A/H2B acidic patch and nucleosomal DNA; these multivalent interactions with the nucleosome are necessary for KDM5A catalytic activity on nucleosome substrates.","method":"Cross-linking mass spectrometry, binding assays, mutagenesis, in vitro demethylation assays on nucleosomes","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — cross-linking MS, mutagenesis, in vitro reconstitution on nucleosomes; rigorous biochemical study","pmids":["40545232"],"is_preprint":false},{"year":2026,"finding":"KDM5A is methylated by SMYD2 at K1063; this methylation decreases KDM5A histone demethylase activity and alters its protein interactome; a K1063 mutant unable to be methylated demethylates H3K4me3 more robustly at additional genomic loci and affects cell proliferation pathways.","method":"In vitro methylation assay, site-directed mutagenesis, genome-wide ChIP-seq, protein interactome (MS), cell growth assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic modification identified, mutagenesis, genome-wide ChIP-seq, interactome; multiple orthogonal methods","pmids":["41962864"],"is_preprint":false},{"year":2020,"finding":"The direct physical contact between GATA1 and the second PHD domain of KDM5A (JARID1A) was identified in erythroid cells, along with an interaction with SCL, linking KDM5A to the haematopoietic transcription factor machinery.","method":"Co-immunoprecipitation, pull-down assays with defined PHD domain constructs","journal":"Royal Society open science","confidence":"Medium","confidence_rationale":"Tier 3 — direct pulldown with domain-level resolution; single lab, single method","pmids":["32218938"],"is_preprint":false},{"year":2024,"finding":"KDM5A suppresses HIV-1 Tat/LTR-mediated viral transcription in latent cells by maintaining H3K4me3 demethylation at the HIV-1 5' LTR promoter; deletion or inhibition of KDM5A reactivates HIV-1 lytic replication in latently infected T cells and microglia.","method":"KDM5A KO/inhibitor (JQKD82), ChIP for H3K4me3 at HIV-1 LTR, latency reactivation assays, PBMCs from HIV-1 patients","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP at viral promoter, KO and pharmacological inhibition, patient-derived cell validation; single lab","pmids":["38925368"],"is_preprint":false},{"year":2024,"finding":"KDM5A deficiency in endothelial cells exacerbates aging; mechanistically, loss of KDM5A increases H3K4me3 enrichment at the FABP4 promoter, driving active FABP4 transcription and fatty acid metabolism disorders; endothelial-specific KDM5A-deficient mice show shortened lifespan and multiple senescent phenotypes.","method":"Endothelial-specific KO mouse model, ChIP for H3K4me3 at FABP4 promoter, metabolic assays, lifespan analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — tissue-specific KO with lifespan/metabolic phenotype plus ChIP at target promoter; single lab","pmids":["41236095"],"is_preprint":false},{"year":2024,"finding":"KDM5A suppresses expression of the antigen-presentation pathway genes (e.g., HLA-A, HLA-B) in epithelial ovarian cancer; KDM5A inhibition restores antigen-presentation gene expression and promotes CD8+ T cell-mediated antitumor immunity in syngeneic mouse models.","method":"KDM5A knockdown, gene expression analysis, in vivo syngeneic tumor model with CD8+ T cell assessment","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined immune phenotype in vivo; single lab","pmids":["35726891"],"is_preprint":false},{"year":2024,"finding":"KDM5A and KDM5B suppress transcription of endogenous retroviral elements (ERVs) via maintenance of KRAB-ZNF gene expression; loss of KDM5A (by gene inactivation or acute dTAG degradation) elevates ERV expression, increases dsRNA levels, and activates immune response genes. This regulation requires KDM5A protein rather than its demethylase activity, and KDM5A co-immunoprecipitates with the NuRD complex.","method":"KO and dTAG acute degradation, RNA-seq, ATAC-seq, H3K4me3 ChIP-seq, pan-KDM5 inhibitor treatment, Co-immunoprecipitation of KDM5A-NuRD","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omic KO analysis plus dTAG and Co-IP; preprint, single lab","pmids":["39386707"],"is_preprint":true},{"year":2025,"finding":"KDM5A maintains H3K4 hypomethylation at the Il4 promoter in CD4+ T cells, facilitating STAT6/GATA3 recruitment for IL-4 transcription; TCR signaling stabilizes KDM5A via USP7-mediated deubiquitination, and KDM5A deficiency abolishes TCR-induced IL-4 production.","method":"CD4+ T cell-specific Kdm5a KO mice, ChIP-qPCR at Il4 promoter, ubiquitination assays, USP7 knockdown","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type-specific KO, ChIP, ubiquitination assay; single lab with multiple methods","pmids":["41188062"],"is_preprint":false}],"current_model":"KDM5A is a JmjC-domain H3K4me3/me2/me1 demethylase whose catalytic activity is allosterically regulated through a positive-feedback loop involving its PHD1 reader domain binding unmethylated H3K4 product, and is further modulated by SMYD2-mediated methylation at K1063; it functions in multiple chromatin complexes (NuRD, SIN3B, HDAC1, RBP-J/Notch repressor, CLOCK-BMAL1, G9a corepressor) to silence developmentally regulated and cell-cycle genes via H3K4 demethylation, and is recruited to DNA double-strand break sites through PAR-binding and macroH2A1.2 to promote ZMYND8-NuRD-dependent transcriptional silencing and homologous recombination repair."},"narrative":{"teleology":[{"year":2006,"claim":"KDM5A was first linked to human disease through identification of the NUP98-JARID1A fusion in pediatric AML, establishing that its chromatin-regulatory domains could be co-opted in oncogenic fusions.","evidence":"3' RACE, RT-PCR, FISH, and karyotyping in a pediatric AML case with t(11;21)","pmids":["16419055"],"confidence":"Medium","gaps":["Fusion protein mechanism not characterized","No functional assays for the fusion oncoprotein performed"]},{"year":2010,"claim":"Two studies established KDM5A as an oxygen-dependent H3K4me3 demethylase whose enzymatic activity is integrated into the Notch/RBP-J transcriptional repressor complex, demonstrating that KDM5A links signal-responsive transcription factor complexes to histone demethylation.","evidence":"In vitro demethylase assays under hypoxia, Co-IP/ChIP of KDM5A-RBP-J, Drosophila conservation analysis","pmids":["20406991","20231316"],"confidence":"High","gaps":["Structural basis for KDM5A-RBP-J interaction unknown","How oxygen sensing integrates with signaling-dependent recruitment not resolved"]},{"year":2011,"claim":"Discovery that KDM5A functions within the CLOCK-BMAL1 complex to regulate circadian gene expression independently of its demethylase activity — by inhibiting HDAC1 — revealed an unexpected catalysis-independent chromatin regulatory role.","evidence":"Co-IP, ChIP at Per2 promoter, siRNA knockdown in mammalian cells, Drosophila genetic validation","pmids":["21960634"],"confidence":"High","gaps":["Mechanism by which KDM5A inhibits HDAC1 activity not defined at molecular level","Whether demethylase-independent function extends to other loci unclear"]},{"year":2012,"claim":"Multiple studies converged to show that KDM5A operates as a corepressor in diverse developmental and cell-cycle contexts — silencing RB-target genes during senescence, E2F4-target cell-cycle genes during differentiation, and embryonic globin genes in concert with G9a — establishing it as a broadly used transcriptional silencer.","evidence":"ChIP-seq in ES cells and primary human cells, KO/KD with transcriptomic phenotypes, Co-IP of KDM5A-G9a complex","pmids":["22615382","23093672","23112189"],"confidence":"High","gaps":["Whether KDM5A directly contacts RB or E2F4 proteins not demonstrated","How KDM5A is selectively recruited to different gene sets not resolved"]},{"year":2014,"claim":"Biochemical purification established that KDM5A is a stable subunit of both SIN3B-HDAC and NuRD complexes and co-regulates hundreds of developmental genes with NuRD, with genetic epistasis in C. elegans confirming functional conservation of this partnership.","evidence":"Immunoaffinity purification, sucrose gradient, sequential IP, ChIP, C. elegans epistasis","pmids":["25190814"],"confidence":"High","gaps":["Which KDM5A domain mediates NuRD versus SIN3B interaction not mapped","Whether KDM5A exists simultaneously in both complexes or is partitioned unclear"]},{"year":2015,"claim":"The positive-feedback allosteric mechanism was uncovered: PHD1 binds unmethylated H3K4 (the demethylation product) and stimulates JmjC catalytic activity, explaining how KDM5A can spread demethylation across nucleosomes; separately, KDM5A was linked to mitochondrial metabolism through repression of PGC-1α target genes.","evidence":"NMR structure of PHD1, in vitro demethylation on nucleosomes with mutagenesis; Kdm5a KO mouse with metabolic and RNA-seq phenotyping","pmids":["25686748","26314709"],"confidence":"High","gaps":["Full-length structural context of PHD1-catalytic domain communication not determined","Whether allosteric mechanism operates equivalently on all methylation states unknown"]},{"year":2017,"claim":"KDM5A was shown to demethylate H3K4me3 at DNA double-strand breaks, a prerequisite for ZMYND8-NuRD binding, transcriptional silencing at damage sites, and homologous recombination, thus revealing a direct role in the DNA damage response.","evidence":"ChIP at defined DSBs, HR reporter assay, siRNA knockdown","pmids":["28572115"],"confidence":"High","gaps":["How KDM5A is initially recruited to DSBs not determined in this study","Whether catalytic activity versus scaffolding is sufficient for repair not separated"]},{"year":2018,"claim":"X-ray crystallography of the KDM5A catalytic domain revealed a druggable active site with a unique noncatalytic cysteine (Cys481) amenable to covalent inhibition, providing the first high-resolution structural view of the enzyme.","evidence":"Co-crystal structures with inhibitors N70/N71, enzyme kinetics, dialysis/reversibility assays","pmids":["30392349"],"confidence":"High","gaps":["No full-length structure available","How PHD1-catalytic domain coupling occurs structurally remains unresolved"]},{"year":2020,"claim":"Detailed biochemical characterization of substrate recognition showed that KDM5A requires H3Q5 and a distal H3 epitope (residues 14–18) for efficient catalysis, and NMR structures of apo versus H3-bound PHD1 revealed conformational changes, deepening the mechanistic understanding of allosteric regulation.","evidence":"Systematic alanine scanning, quantitative demethylase assays, NMR solution structures, fluorescence polarization","pmids":["31985200","33621062"],"confidence":"High","gaps":["How chromatin modifications at the distal epitope integrate with allosteric activation in vivo unknown","No cryo-EM or full-length structure capturing PHD1-JmjC communication"]},{"year":2020,"claim":"Human genetic and mouse knockout studies demonstrated that KDM5A mutations cause autism spectrum disorder, linking the demethylase to neurodevelopmental function through regulation of dendritic morphogenesis and hippocampal gene expression.","evidence":"Forward genetics, WES in human ASD families, Kdm5a KO mouse behavioral/cellular/transcriptomic phenotyping","pmids":["33350388"],"confidence":"High","gaps":["Specific neuronal target genes mediating behavioral phenotype not fully defined","Whether catalytic activity or scaffolding roles drive the ASD phenotype not separated"]},{"year":2021,"claim":"The recruitment mechanism of KDM5A to DNA damage sites was resolved: a noncanonical PAR-binding coiled-coil region unique to KDM5A mediates PARP-dependent recruitment, and the histone variant macroH2A1.2 acts upstream, connecting KDM5A's DSB function to PARylation signaling.","evidence":"Domain mutagenesis, PAR-binding assays, PARP inhibitor treatment, macroH2A1.2 KD, HR reporter","pmids":["34003252"],"confidence":"High","gaps":["Whether PAR binding and macroH2A1.2 act in the same linear pathway or parallel pathways not fully resolved","Structural basis of the PAR-binding coiled-coil not determined"]},{"year":2025,"claim":"An intrinsically disordered region in KDM5A was found to engage the nucleosome acidic patch and DNA through bifunctional arginine-rich motifs, revealing a previously unrecognized mechanism for nucleosome-level substrate recognition essential for catalytic activity.","evidence":"Cross-linking mass spectrometry, mutagenesis, in vitro demethylation on nucleosome substrates","pmids":["40545232"],"confidence":"High","gaps":["How IDR-nucleosome contacts integrate with PHD1 allosteric activation not determined","In vivo relevance of IDR-nucleosome interaction not tested"]},{"year":2026,"claim":"SMYD2-mediated methylation of KDM5A at K1063 was identified as a post-translational regulatory mechanism that attenuates demethylase activity and reshapes the KDM5A interactome, establishing a new layer of regulation beyond substrate-level allostery.","evidence":"In vitro methylation assay, K1063 mutagenesis, genome-wide ChIP-seq, interactome MS, proliferation assays","pmids":["41962864"],"confidence":"High","gaps":["Whether K1063 methylation is dynamically regulated in physiological contexts unknown","The specific interactors gained or lost upon methylation not fully characterized"]},{"year":null,"claim":"A full-length structural model integrating PHD1 allostery, the IDR-nucleosome interface, and catalytic domain communication is still lacking, and the rules governing how KDM5A switches between demethylase-dependent repression and demethylase-independent activation remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cryo-EM or full-length structure of KDM5A on a nucleosome substrate","Molecular basis of demethylase-independent transcriptional activation not resolved","How KDM5A is partitioned among distinct chromatin complexes in a cell-type-specific manner is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,7,11,14,15,28,29]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[7,14,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,5,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,4,6,10,11]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[10,13,20,28]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,3,4,7,10,14,15,28,29]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,4,5,8,9]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[10,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,12,9]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,33,35]}],"complexes":["NuRD","SIN3B-HDAC","RBP-J/Notch repressor","CLOCK-BMAL1"],"partners":["CHD4","RBPJ","HDAC1","G9A","ZMYND8","SMYD2","GATA1","WDR5"],"other_free_text":[]},"mechanistic_narrative":"KDM5A is a JmjC-domain histone demethylase that removes mono-, di-, and trimethylation from H3K4, functioning as a transcriptional repressor at developmentally regulated, cell-cycle, and metabolic genes through its association with chromatin-remodeling complexes including NuRD, SIN3B-HDAC, and the Notch/RBP-J repressor [PMID:25190814, PMID:20231316, PMID:23093672]. Its catalytic activity is allosterically stimulated by a positive-feedback mechanism in which the PHD1 domain binds the unmethylated H3K4 product, and is further modulated by SMYD2-mediated methylation at K1063, while an intrinsically disordered region engages the nucleosome acidic patch and DNA for efficient substrate demethylation [PMID:25686748, PMID:41962864, PMID:40545232]. Beyond canonical repression, KDM5A exhibits demethylase-independent functions, including inhibition of HDAC1 activity within the CLOCK-BMAL1 complex to regulate circadian transcription, and it is recruited to DNA double-strand breaks via PAR-binding and macroH2A1.2 to promote ZMYND8-NuRD-dependent transcriptional silencing and homologous recombination repair [PMID:21960634, PMID:28572115, PMID:34003252]. Loss-of-function mutations in KDM5A cause autism spectrum disorder with speech deficits, as demonstrated by human genetics and Kdm5a knockout mice exhibiting repetitive behaviors, sociability deficits, and abnormal dendritic morphogenesis [PMID:33350388]."},"prefetch_data":{"uniprot":{"accession":"P29375","full_name":"Lysine-specific demethylase 5A","aliases":["Histone demethylase JARID1A","Jumonji/ARID domain-containing protein 1A","Retinoblastoma-binding protein 2","RBBP-2","[histone H3]-trimethyl-L-lysine(4) demethylase 5A"],"length_aa":1690,"mass_kda":192.1,"function":"Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Regulates specific gene transcription through DNA-binding on 5'-CCGCCC-3' motif (PubMed:18270511). May stimulate transcription mediated by nuclear receptors. Involved in transcriptional regulation of Hox proteins during cell differentiation (PubMed:19430464). May participate in transcriptional repression of cytokines such as CXCL12. Plays a role in the regulation of the circadian rhythm and in maintaining the normal periodicity of the circadian clock. In a histone demethylase-independent manner, acts as a coactivator of the CLOCK-BMAL1-mediated transcriptional activation of PER1/2 and other clock-controlled genes and increases histone acetylation at PER1/2 promoters by inhibiting the activity of HDAC1 (By similarity). Seems to act as a transcriptional corepressor for some genes such as MT1F and to favor the proliferation of cancer cells (PubMed:27427228)","subcellular_location":"Nucleus, nucleolus; Nucleus","url":"https://www.uniprot.org/uniprotkb/P29375/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM5A","classification":"Not Classified","n_dependent_lines":84,"n_total_lines":1208,"dependency_fraction":0.0695364238410596},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GATAD1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KDM5A","total_profiled":1310},"omim":[{"mim_id":"620820","title":"EL HAYEK-CHAHROUR NEURODEVELOPMENTAL SYNDROME; NEDEHC","url":"https://www.omim.org/entry/620820"},{"mim_id":"610588","title":"DENDRIN; DDN","url":"https://www.omim.org/entry/610588"},{"mim_id":"610016","title":"MICRO RNA 132; MIR132","url":"https://www.omim.org/entry/610016"},{"mim_id":"609132","title":"LYSINE DEMETHYLASE 1A; KDM1A","url":"https://www.omim.org/entry/609132"},{"mim_id":"606834","title":"LYSINE-SPECIFIC METHYLTRANSFERASE 2B; KMT2B","url":"https://www.omim.org/entry/606834"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":42.9}],"url":"https://www.proteinatlas.org/search/KDM5A"},"hgnc":{"alias_symbol":[],"prev_symbol":["RBBP2","JARID1A"]},"alphafold":{"accession":"P29375","domains":[{"cath_id":"2.60.120.650","chopping":"48-73_357-585","consensus_level":"high","plddt":88.6827,"start":48,"end":585},{"cath_id":"1.10.150.60","chopping":"105-175","consensus_level":"medium","plddt":83.9145,"start":105,"end":175},{"cath_id":"2.10.110,2.10.110","chopping":"657-727","consensus_level":"medium","plddt":92.9652,"start":657,"end":727},{"cath_id":"-","chopping":"759-804_821-901","consensus_level":"medium","plddt":82.7858,"start":759,"end":901},{"cath_id":"-","chopping":"914-1038","consensus_level":"medium","plddt":82.6766,"start":914,"end":1038},{"cath_id":"-","chopping":"1069-1083_1124-1192_1208-1299_1436-1484","consensus_level":"medium","plddt":83.4893,"start":1069,"end":1484},{"cath_id":"3.30.40.10","chopping":"1626-1655","consensus_level":"medium","plddt":87.6247,"start":1626,"end":1655}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P29375","model_url":"https://alphafold.ebi.ac.uk/files/AF-P29375-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P29375-F1-predicted_aligned_error_v6.png","plddt_mean":70.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM5A","jax_strain_url":"https://www.jax.org/strain/search?query=KDM5A"},"sequence":{"accession":"P29375","fasta_url":"https://rest.uniprot.org/uniprotkb/P29375.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P29375/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P29375"}},"corpus_meta":[{"pmid":"21960634","id":"PMC_21960634","title":"Histone 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upon Notch signaling inhibition, with this interaction conserved in Drosophila and required for Notch-induced growth responses.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, genetic conservation analysis (Drosophila), loss-of-function studies\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, ortholog validation in Drosophila, functional rescue; replicated across species\",\n      \"pmids\": [\"20231316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM5A (JARID1a) forms a complex with CLOCK-BMAL1 and is recruited to the Per2 promoter; it enhances CLOCK-BMAL1 transcription by inhibiting HDAC1 function in a demethylase-independent manner, and its depletion dampens circadian gene expression and shortens circadian period.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, Drosophila genetic loss-of-function\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, KD phenotype, ortholog validated in Drosophila; multiple orthogonal methods in one study\",\n      \"pmids\": [\"21960634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KDM5A (JARID1A) is the major H3K4 demethylase in bronchial epithelial cells; hypoxia inhibits KDM5A enzymatic activity (requiring molecular oxygen as cofactor) without altering its mRNA or protein levels, leading to global and gene-specific increases in H3K4me3.\",\n      \"method\": \"In vitro histone demethylation assay with nuclear extracts, siRNA knockdown, ChIP\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro demethylase activity assay combined with KD and ChIP; multiple orthogonal methods\",\n      \"pmids\": [\"20406991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM5A (Jarid1a) cooperates with the retinoblastoma tumor suppressor to silence H3K4-methylated target genes during cellular senescence; Jarid1a/b-mediated H3K4 demethylation contributes to retinoblastoma-dependent gene silencing.\",\n      \"method\": \"Quantitative mass spectrometry, ChIP-seq, functional knockdown studies in primary human cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq, MS, functional KD with defined phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"22615382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM5A cooperates with E2F4 to repress cell cycle genes during differentiation; KDM5A co-occupies E2F4 target genes genome-wide and its knockout leads to derepression of these loci; in terminally differentiated cells, common targets are bound by p130/DREAM complex.\",\n      \"method\": \"ChIP-seq (global location analysis), KDM5A knockout in ES cells, co-occupancy analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq plus KO with defined transcriptional phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"23093672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM5A (Jarid1a) physically associates with the H3K9 methyltransferase G9a/KMT1C in a corepressor complex distinct from the G9a-Mediator coactivator complex; coordinate action of G9a and Jarid1a (concurrent H3K9me2 deposition and H3K4me3 removal) maintains silencing of the embryonic globin gene.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, functional knockdown, reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, functional studies; multiple orthogonal methods\",\n      \"pmids\": [\"23112189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM5A is physically and functionally associated with both the SIN3B-containing HDAC complex and the NuRD complex; KDM5A depletion co-regulates hundreds of developmentally regulated genes with NuRD catalytic subunit CHD4, and the C. elegans homologs function in the same genetic pathway during vulva development.\",\n      \"method\": \"Immunoaffinity purification, sucrose density gradient, sequential immunoprecipitation, ChIP, genetic epistasis in C. elegans\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, sucrose gradient, sequential IP, ChIP, genetic epistasis; multiple orthogonal methods\",\n      \"pmids\": [\"25190814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KDM5A PHD1 domain preferentially binds unmethylated H3K4 (the product of KDM5A demethylation); binding of unmodified H3 to PHD1 allosterically stimulates the catalytic domain to demethylate H3K4me3 on peptide and nucleosome substrates, establishing a positive-feedback mechanism.\",\n      \"method\": \"Biochemical binding assays, NMR structural studies, in vitro demethylation assays on peptide and nucleosome substrates, mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure, in vitro reconstitution, mutagenesis; strong mechanistic study with multiple orthogonal methods in single paper\",\n      \"pmids\": [\"25686748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of Kdm5a restores differentiation in pRb-deficient cells by increasing mitochondrial respiration; KDM5A is a direct repressor of metabolic regulatory genes and its deletion activates Pgc-1α target genes, linking H3K4 demethylation to mitochondrial biogenesis and differentiation.\",\n      \"method\": \"KO mouse model, RNA-seq, ChIP, metabolic (oxygen consumption) assays, gain-of-function rescue\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined phenotype, ChIP, metabolic assays, rescue experiments; multiple orthogonal methods\",\n      \"pmids\": [\"26314709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM5A associates with the NF-κB subunit p50 and binds to the Socs1 promoter in resting NK cells, decreasing H3K4me3 and maintaining a repressive chromatin configuration at Socs1; loss of Kdm5a increases Socs1 expression, impairs STAT4 phosphorylation and nuclear localization, and reduces NK cell IFN-γ production.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, Kdm5a knockout mice, NK cell activation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, KO with defined immune phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"27050510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM5A demethylates H3K4me3 near DNA double-strand break (DSB) sites; this demethylation is required for ZMYND8-NuRD complex binding to damaged chromatin, transcriptional silencing at DSBs, and homologous recombination repair.\",\n      \"method\": \"ChIP near DSBs, siRNA knockdown, DSB repair assays (HR reporter), transcriptional silencing assays at defined DSBs\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP at defined DSBs, HR reporter assay, KD with defined repair phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"28572115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM5A catalytic domain structure was determined by X-ray crystallography in complex with inhibitors N70 and N71; a noncatalytic cysteine (Cys481) unique to KDM5 family near the active site allows covalent modification by acrylamide-containing inhibitors that inhibit in an αKG-competitive but irreversible manner.\",\n      \"method\": \"X-ray crystallography (co-crystal structures), enzyme inhibition assays, dialysis/reversibility assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation (inhibition kinetics, covalent modification); single rigorous paper with orthogonal methods\",\n      \"pmids\": [\"30392349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM5A sustains ASCL1 expression and neuroendocrine differentiation in SCLC by repressing NOTCH2 and Notch target genes; CRISPR KO of KDM5A in a mouse SCLC model decreased tumorigenesis and metastasis while increasing Notch signaling.\",\n      \"method\": \"CRISPR/Cas9 KO (in vitro and in vivo mouse model), gene expression analysis, ChIP\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with defined in vivo tumor phenotype plus mechanistic gene expression data; multiple orthogonal approaches\",\n      \"pmids\": [\"31727771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM5A contains a noncanonical poly(ADP-ribose) (PAR)-binding coiled-coil region unique among KDM5 family members; loss of this PAR-binding region or PARP inhibitor treatment blocks KDM5A-PAR interactions and its DNA repair functions. The histone variant macroH2A1.2 is also specifically required upstream of KDM5A for its recruitment to DNA damage sites and homology-directed repair.\",\n      \"method\": \"Domain mutagenesis, PAR-binding assays, PARP inhibitor treatment, macroH2A1.2 KD, HR reporter assays, ChIP at DSBs\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis, functional repair assays, KD, ChIP; multiple orthogonal methods identifying two upstream regulators\",\n      \"pmids\": [\"34003252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The KDM5A PHD1 domain binds the H3 tail with preference for lower methylation states of H3K4 (me0 > me1 > me2 > me3); NMR solution structures of apo and H3-bound PHD1 show conformational changes accommodating H3 in a helical conformation, and post-translational modifications at the distal H3 epitope (residues 14–18) modulate KDM5A demethylation activity.\",\n      \"method\": \"NMR spectroscopy (solution structure), fluorescence polarization binding assays, demethylation activity assays, mutagenesis\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with functional validation by demethylation assays and mutagenesis\",\n      \"pmids\": [\"33621062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM5A extended substrate recognition of H3 tail involves H3Q5 as critical for demethylation and a distal epitope at positions 14–18 whose deletion increases KMapp ~8-fold; post-translational modifications on the distal epitope modulate KDM5A-dependent demethylation.\",\n      \"method\": \"Alanine scanning mutagenesis, in vitro demethylation activity assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with quantitative in vitro demethylase assays; rigorous biochemical characterization\",\n      \"pmids\": [\"31985200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM5A acts as a transcriptional repressor of MPC-1 by binding directly to its promoter and demethylating H3K4, suppressing mitochondrial pyruvate metabolism in pancreatic cancer cells; KDM5A expression is inversely correlated with MPC-1 in patient samples.\",\n      \"method\": \"ChIP assay, overexpression and knockdown experiments, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirming promoter binding, functional KD/OE; single lab with moderate methods\",\n      \"pmids\": [\"31641207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM5A promotes preadipocyte differentiation by repressing Wnt6 transcription; C/EBPβ binds the KDM5A promoter to transactivate its expression, and KDM5A interacts with C/EBPβ and cooperates with it to reduce H3K4me3 at the Wnt6 promoter, inhibiting Wnt/β-catenin signaling.\",\n      \"method\": \"ChIP, immunoprecipitation, RT-qPCR, siRNA knockdown in 3T3-L1 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, functional rescue; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31061100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Fbxo22 reduces KDM5A protein levels via ubiquitination; KDM5A promotes H3K4me3 demethylation at the p16 promoter to downregulate p16 expression, and Fbxo22-mediated KDM5A degradation rescues p16 expression to suppress TNBC tumorigenesis.\",\n      \"method\": \"Immunoprecipitation/ubiquitination assay, ChIP, knockdown/overexpression, in vitro and in vivo tumor assays\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay, ChIP, functional KO/OE; single lab\",\n      \"pmids\": [\"36112263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM5A physically interacts with MLL1, MLL2, and WDR5 (normally its functional antagonists); when bound at mesenchymal gene promoters KDM5A acts as a transcriptional activator by inhibiting HDAC activity and increasing H3K18ac, while at E-cadherin promoter it acts as a classical repressor by demethylating H3K4me3.\",\n      \"method\": \"ChIP, co-immunoprecipitation, HDAC activity assays, gene expression analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP; single lab with two orthogonal methods\",\n      \"pmids\": [\"37722486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC1 negatively regulates RBPJ occupancy on mitotic chromatin in a KDM5A-dependent manner; KDM5A knockdown or inactivation reduces HDAC1-dependent regulation of RBPJ mitotic chromatin binding, and KDM5A presence at these sites is essential for increased RBPJ occupancy.\",\n      \"method\": \"ChIP on mitotic chromatin, siRNA knockdown, HDAC1 inhibitor treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP on mitotic chromatin with KD; single lab but mechanistically defined\",\n      \"pmids\": [\"30916347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM5A mutations cause autism spectrum disorder (ASD) with lack of speech; Kdm5a knockout mice display repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis, with dysregulation of the hippocampal transcriptome.\",\n      \"method\": \"Forward genetics screen, Kdm5a knockout mouse model, behavioral assays, RNA-seq, dendritic morphology analysis, human WES/microarray\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple behavioral and cellular phenotypes, human genetic validation; strong evidence across multiple methods and species\",\n      \"pmids\": [\"33350388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM5A controls BMP2-induced osteogenic differentiation of bone marrow mesenchymal stem cells by decreasing H3K4me3 levels at the Runx2 promoter in a demethylase activity-dependent manner; elevated KDM5A in osteoporotic MSCs impairs BMP2-induced osteogenesis.\",\n      \"method\": \"ChIP, shRNA knockdown, KDM5A inhibitor, overexpression, OVX mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirming promoter occupancy, functional rescue; single lab but multiple methods\",\n      \"pmids\": [\"27512956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KDM5A (JARID1A) is identified as a fusion partner of NUP98 in pediatric AML through the t(11;21) translocation, generating a NUP98-JARID1A fusion oncoprotein implicated in transcriptional regulation.\",\n      \"method\": \"3' RACE, RT-PCR, FISH, karyotyping\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular characterization of fusion gene by multiple techniques; single study\",\n      \"pmids\": [\"16419055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RepID recruits CRL4A-JARID1A (KDM5A) to the DAB2 promoter during proliferation, maintaining H3K4 demethylation and repressive chromatin; during megakaryocytic differentiation, RepID, CRL4A, and JARID1A dissociate from chromatin, allowing euchromatinization and DAB2 expression.\",\n      \"method\": \"Immunoprecipitation, proximity ligation assay, ChIP-qPCR, subcellular fractionation\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP-qPCR, PLA; single lab with multiple methods\",\n      \"pmids\": [\"37612584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM5A acts as an H3K4me3 demethylase at the miR-495 promoter in prostate cancer cells, inhibiting miR-495 transcription; reduced miR-495 elevates YTHDF2, which degrades MOB3B mRNA via m6A recognition, promoting cancer progression.\",\n      \"method\": \"ChIP assay, dual luciferase reporter, PAR-CLIP, me-RIP, xenograft mouse model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirming promoter binding plus functional cascade validation; single lab\",\n      \"pmids\": [\"33087165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM5A in neural progenitors binds to and activates neuronal genes involved in early differentiation; mitochondrial damage causes characteristic KDM5A protein degradation in neural progenitors, inhibiting neuronal differentiation and adult hippocampal neurogenesis.\",\n      \"method\": \"Proteomics, KDM5A overexpression/knockdown in neural progenitors, neurogenesis assays, KO mouse\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomic identification, functional KD/OE with defined differentiation phenotype; single lab\",\n      \"pmids\": [\"36056186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM5A (JARID1A) binds in a ligand-independent manner to a progesterone receptor gene upstream regulatory region and represses progesterone receptor promoter activity through its demethylase activity; JARID1A depletion elevates H3K4me3 in this region and increases progesterone receptor expression.\",\n      \"method\": \"ChIP, overexpression of wild-type vs. catalytically inactive JARID1A mutant, siRNA knockdown, reporter assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, catalytic mutant comparison, KD with defined phenotype; single lab, multiple methods\",\n      \"pmids\": [\"21348942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM5A contains an intrinsically disordered region (IDR) with bifunctional arginine-rich motifs that bind both the histone H2A/H2B acidic patch and nucleosomal DNA; these multivalent interactions with the nucleosome are necessary for KDM5A catalytic activity on nucleosome substrates.\",\n      \"method\": \"Cross-linking mass spectrometry, binding assays, mutagenesis, in vitro demethylation assays on nucleosomes\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cross-linking MS, mutagenesis, in vitro reconstitution on nucleosomes; rigorous biochemical study\",\n      \"pmids\": [\"40545232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KDM5A is methylated by SMYD2 at K1063; this methylation decreases KDM5A histone demethylase activity and alters its protein interactome; a K1063 mutant unable to be methylated demethylates H3K4me3 more robustly at additional genomic loci and affects cell proliferation pathways.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis, genome-wide ChIP-seq, protein interactome (MS), cell growth assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic modification identified, mutagenesis, genome-wide ChIP-seq, interactome; multiple orthogonal methods\",\n      \"pmids\": [\"41962864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The direct physical contact between GATA1 and the second PHD domain of KDM5A (JARID1A) was identified in erythroid cells, along with an interaction with SCL, linking KDM5A to the haematopoietic transcription factor machinery.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assays with defined PHD domain constructs\",\n      \"journal\": \"Royal Society open science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct pulldown with domain-level resolution; single lab, single method\",\n      \"pmids\": [\"32218938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5A suppresses HIV-1 Tat/LTR-mediated viral transcription in latent cells by maintaining H3K4me3 demethylation at the HIV-1 5' LTR promoter; deletion or inhibition of KDM5A reactivates HIV-1 lytic replication in latently infected T cells and microglia.\",\n      \"method\": \"KDM5A KO/inhibitor (JQKD82), ChIP for H3K4me3 at HIV-1 LTR, latency reactivation assays, PBMCs from HIV-1 patients\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP at viral promoter, KO and pharmacological inhibition, patient-derived cell validation; single lab\",\n      \"pmids\": [\"38925368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5A deficiency in endothelial cells exacerbates aging; mechanistically, loss of KDM5A increases H3K4me3 enrichment at the FABP4 promoter, driving active FABP4 transcription and fatty acid metabolism disorders; endothelial-specific KDM5A-deficient mice show shortened lifespan and multiple senescent phenotypes.\",\n      \"method\": \"Endothelial-specific KO mouse model, ChIP for H3K4me3 at FABP4 promoter, metabolic assays, lifespan analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with lifespan/metabolic phenotype plus ChIP at target promoter; single lab\",\n      \"pmids\": [\"41236095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5A suppresses expression of the antigen-presentation pathway genes (e.g., HLA-A, HLA-B) in epithelial ovarian cancer; KDM5A inhibition restores antigen-presentation gene expression and promotes CD8+ T cell-mediated antitumor immunity in syngeneic mouse models.\",\n      \"method\": \"KDM5A knockdown, gene expression analysis, in vivo syngeneic tumor model with CD8+ T cell assessment\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined immune phenotype in vivo; single lab\",\n      \"pmids\": [\"35726891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5A and KDM5B suppress transcription of endogenous retroviral elements (ERVs) via maintenance of KRAB-ZNF gene expression; loss of KDM5A (by gene inactivation or acute dTAG degradation) elevates ERV expression, increases dsRNA levels, and activates immune response genes. This regulation requires KDM5A protein rather than its demethylase activity, and KDM5A co-immunoprecipitates with the NuRD complex.\",\n      \"method\": \"KO and dTAG acute degradation, RNA-seq, ATAC-seq, H3K4me3 ChIP-seq, pan-KDM5 inhibitor treatment, Co-immunoprecipitation of KDM5A-NuRD\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omic KO analysis plus dTAG and Co-IP; preprint, single lab\",\n      \"pmids\": [\"39386707\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM5A maintains H3K4 hypomethylation at the Il4 promoter in CD4+ T cells, facilitating STAT6/GATA3 recruitment for IL-4 transcription; TCR signaling stabilizes KDM5A via USP7-mediated deubiquitination, and KDM5A deficiency abolishes TCR-induced IL-4 production.\",\n      \"method\": \"CD4+ T cell-specific Kdm5a KO mice, ChIP-qPCR at Il4 promoter, ubiquitination assays, USP7 knockdown\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO, ChIP, ubiquitination assay; single lab with multiple methods\",\n      \"pmids\": [\"41188062\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM5A is a JmjC-domain H3K4me3/me2/me1 demethylase whose catalytic activity is allosterically regulated through a positive-feedback loop involving its PHD1 reader domain binding unmethylated H3K4 product, and is further modulated by SMYD2-mediated methylation at K1063; it functions in multiple chromatin complexes (NuRD, SIN3B, HDAC1, RBP-J/Notch repressor, CLOCK-BMAL1, G9a corepressor) to silence developmentally regulated and cell-cycle genes via H3K4 demethylation, and is recruited to DNA double-strand break sites through PAR-binding and macroH2A1.2 to promote ZMYND8-NuRD-dependent transcriptional silencing and homologous recombination repair.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KDM5A is a JmjC-domain histone demethylase that removes mono-, di-, and trimethylation from H3K4, functioning as a transcriptional repressor at developmentally regulated, cell-cycle, and metabolic genes through its association with chromatin-remodeling complexes including NuRD, SIN3B-HDAC, and the Notch/RBP-J repressor [PMID:25190814, PMID:20231316, PMID:23093672]. Its catalytic activity is allosterically stimulated by a positive-feedback mechanism in which the PHD1 domain binds the unmethylated H3K4 product, and is further modulated by SMYD2-mediated methylation at K1063, while an intrinsically disordered region engages the nucleosome acidic patch and DNA for efficient substrate demethylation [PMID:25686748, PMID:41962864, PMID:40545232]. Beyond canonical repression, KDM5A exhibits demethylase-independent functions, including inhibition of HDAC1 activity within the CLOCK-BMAL1 complex to regulate circadian transcription, and it is recruited to DNA double-strand breaks via PAR-binding and macroH2A1.2 to promote ZMYND8-NuRD-dependent transcriptional silencing and homologous recombination repair [PMID:21960634, PMID:28572115, PMID:34003252]. Loss-of-function mutations in KDM5A cause autism spectrum disorder with speech deficits, as demonstrated by human genetics and Kdm5a knockout mice exhibiting repetitive behaviors, sociability deficits, and abnormal dendritic morphogenesis [PMID:33350388].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"KDM5A was first linked to human disease through identification of the NUP98-JARID1A fusion in pediatric AML, establishing that its chromatin-regulatory domains could be co-opted in oncogenic fusions.\",\n      \"evidence\": \"3' RACE, RT-PCR, FISH, and karyotyping in a pediatric AML case with t(11;21)\",\n      \"pmids\": [\"16419055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fusion protein mechanism not characterized\", \"No functional assays for the fusion oncoprotein performed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Two studies established KDM5A as an oxygen-dependent H3K4me3 demethylase whose enzymatic activity is integrated into the Notch/RBP-J transcriptional repressor complex, demonstrating that KDM5A links signal-responsive transcription factor complexes to histone demethylation.\",\n      \"evidence\": \"In vitro demethylase assays under hypoxia, Co-IP/ChIP of KDM5A-RBP-J, Drosophila conservation analysis\",\n      \"pmids\": [\"20406991\", \"20231316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for KDM5A-RBP-J interaction unknown\", \"How oxygen sensing integrates with signaling-dependent recruitment not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that KDM5A functions within the CLOCK-BMAL1 complex to regulate circadian gene expression independently of its demethylase activity — by inhibiting HDAC1 — revealed an unexpected catalysis-independent chromatin regulatory role.\",\n      \"evidence\": \"Co-IP, ChIP at Per2 promoter, siRNA knockdown in mammalian cells, Drosophila genetic validation\",\n      \"pmids\": [\"21960634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which KDM5A inhibits HDAC1 activity not defined at molecular level\", \"Whether demethylase-independent function extends to other loci unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Multiple studies converged to show that KDM5A operates as a corepressor in diverse developmental and cell-cycle contexts — silencing RB-target genes during senescence, E2F4-target cell-cycle genes during differentiation, and embryonic globin genes in concert with G9a — establishing it as a broadly used transcriptional silencer.\",\n      \"evidence\": \"ChIP-seq in ES cells and primary human cells, KO/KD with transcriptomic phenotypes, Co-IP of KDM5A-G9a complex\",\n      \"pmids\": [\"22615382\", \"23093672\", \"23112189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KDM5A directly contacts RB or E2F4 proteins not demonstrated\", \"How KDM5A is selectively recruited to different gene sets not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Biochemical purification established that KDM5A is a stable subunit of both SIN3B-HDAC and NuRD complexes and co-regulates hundreds of developmental genes with NuRD, with genetic epistasis in C. elegans confirming functional conservation of this partnership.\",\n      \"evidence\": \"Immunoaffinity purification, sucrose gradient, sequential IP, ChIP, C. elegans epistasis\",\n      \"pmids\": [\"25190814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which KDM5A domain mediates NuRD versus SIN3B interaction not mapped\", \"Whether KDM5A exists simultaneously in both complexes or is partitioned unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The positive-feedback allosteric mechanism was uncovered: PHD1 binds unmethylated H3K4 (the demethylation product) and stimulates JmjC catalytic activity, explaining how KDM5A can spread demethylation across nucleosomes; separately, KDM5A was linked to mitochondrial metabolism through repression of PGC-1α target genes.\",\n      \"evidence\": \"NMR structure of PHD1, in vitro demethylation on nucleosomes with mutagenesis; Kdm5a KO mouse with metabolic and RNA-seq phenotyping\",\n      \"pmids\": [\"25686748\", \"26314709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length structural context of PHD1-catalytic domain communication not determined\", \"Whether allosteric mechanism operates equivalently on all methylation states unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"KDM5A was shown to demethylate H3K4me3 at DNA double-strand breaks, a prerequisite for ZMYND8-NuRD binding, transcriptional silencing at damage sites, and homologous recombination, thus revealing a direct role in the DNA damage response.\",\n      \"evidence\": \"ChIP at defined DSBs, HR reporter assay, siRNA knockdown\",\n      \"pmids\": [\"28572115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How KDM5A is initially recruited to DSBs not determined in this study\", \"Whether catalytic activity versus scaffolding is sufficient for repair not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"X-ray crystallography of the KDM5A catalytic domain revealed a druggable active site with a unique noncatalytic cysteine (Cys481) amenable to covalent inhibition, providing the first high-resolution structural view of the enzyme.\",\n      \"evidence\": \"Co-crystal structures with inhibitors N70/N71, enzyme kinetics, dialysis/reversibility assays\",\n      \"pmids\": [\"30392349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length structure available\", \"How PHD1-catalytic domain coupling occurs structurally remains unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Detailed biochemical characterization of substrate recognition showed that KDM5A requires H3Q5 and a distal H3 epitope (residues 14–18) for efficient catalysis, and NMR structures of apo versus H3-bound PHD1 revealed conformational changes, deepening the mechanistic understanding of allosteric regulation.\",\n      \"evidence\": \"Systematic alanine scanning, quantitative demethylase assays, NMR solution structures, fluorescence polarization\",\n      \"pmids\": [\"31985200\", \"33621062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How chromatin modifications at the distal epitope integrate with allosteric activation in vivo unknown\", \"No cryo-EM or full-length structure capturing PHD1-JmjC communication\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Human genetic and mouse knockout studies demonstrated that KDM5A mutations cause autism spectrum disorder, linking the demethylase to neurodevelopmental function through regulation of dendritic morphogenesis and hippocampal gene expression.\",\n      \"evidence\": \"Forward genetics, WES in human ASD families, Kdm5a KO mouse behavioral/cellular/transcriptomic phenotyping\",\n      \"pmids\": [\"33350388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific neuronal target genes mediating behavioral phenotype not fully defined\", \"Whether catalytic activity or scaffolding roles drive the ASD phenotype not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The recruitment mechanism of KDM5A to DNA damage sites was resolved: a noncanonical PAR-binding coiled-coil region unique to KDM5A mediates PARP-dependent recruitment, and the histone variant macroH2A1.2 acts upstream, connecting KDM5A's DSB function to PARylation signaling.\",\n      \"evidence\": \"Domain mutagenesis, PAR-binding assays, PARP inhibitor treatment, macroH2A1.2 KD, HR reporter\",\n      \"pmids\": [\"34003252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PAR binding and macroH2A1.2 act in the same linear pathway or parallel pathways not fully resolved\", \"Structural basis of the PAR-binding coiled-coil not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An intrinsically disordered region in KDM5A was found to engage the nucleosome acidic patch and DNA through bifunctional arginine-rich motifs, revealing a previously unrecognized mechanism for nucleosome-level substrate recognition essential for catalytic activity.\",\n      \"evidence\": \"Cross-linking mass spectrometry, mutagenesis, in vitro demethylation on nucleosome substrates\",\n      \"pmids\": [\"40545232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IDR-nucleosome contacts integrate with PHD1 allosteric activation not determined\", \"In vivo relevance of IDR-nucleosome interaction not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"SMYD2-mediated methylation of KDM5A at K1063 was identified as a post-translational regulatory mechanism that attenuates demethylase activity and reshapes the KDM5A interactome, establishing a new layer of regulation beyond substrate-level allostery.\",\n      \"evidence\": \"In vitro methylation assay, K1063 mutagenesis, genome-wide ChIP-seq, interactome MS, proliferation assays\",\n      \"pmids\": [\"41962864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether K1063 methylation is dynamically regulated in physiological contexts unknown\", \"The specific interactors gained or lost upon methylation not fully characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full-length structural model integrating PHD1 allostery, the IDR-nucleosome interface, and catalytic domain communication is still lacking, and the rules governing how KDM5A switches between demethylase-dependent repression and demethylase-independent activation remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No cryo-EM or full-length structure of KDM5A on a nucleosome substrate\", \"Molecular basis of demethylase-independent transcriptional activation not resolved\", \"How KDM5A is partitioned among distinct chromatin complexes in a cell-type-specific manner is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 7, 11, 14, 15, 28, 29]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7, 14, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 4, 6, 10, 11]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [10, 13, 20, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 3, 4, 7, 10, 14, 15, 28, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 4, 5, 8, 9]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 12, 9]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 33, 35]}\n    ],\n    \"complexes\": [\n      \"NuRD\",\n      \"SIN3B-HDAC\",\n      \"RBP-J/Notch repressor\",\n      \"CLOCK-BMAL1\"\n    ],\n    \"partners\": [\n      \"CHD4\",\n      \"RBPJ\",\n      \"HDAC1\",\n      \"G9a\",\n      \"ZMYND8\",\n      \"SMYD2\",\n      \"GATA1\",\n      \"WDR5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}