{"gene":"KDM5A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2010,"finding":"KDM5A is an H3K4 demethylase that physically interacts with the Notch transcriptional repressor RBP-J and is required for RBP-J-mediated gene silencing; this interaction is conserved in Drosophila and is crucial for Notch-induced growth and tumorigenesis responses.","method":"Co-immunoprecipitation, ChIP, functional knockdown/rescue in mammalian cells and Drosophila","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal protein interaction data, ChIP, genetic validation in two organisms, multiple orthogonal methods","pmids":["20231316"],"is_preprint":false},{"year":2010,"finding":"Hypoxia inhibits KDM5A (JARID1A) H3K4 demethylase catalytic activity in an oxygen-tension-dependent manner (oxygen is required as a co-substrate), resulting in global and gene-specific increases in H3K4me3; knockdown of JARID1A largely abolishes the hypoxia-induced H3K4me3 increase, identifying KDM5A as the major H3K4 demethylase in Beas-2B cells.","method":"In vitro histone demethylation assay, siRNA knockdown, ChIP, Western blot","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic activity assay combined with cell-based knockdown and ChIP, single lab with multiple orthogonal methods","pmids":["20406991"],"is_preprint":false},{"year":2011,"finding":"KDM5A (JARID1a) forms a complex with CLOCK-BMAL1, is recruited to the Per2 promoter, inhibits HDAC1 function to increase histone acetylation, and thereby enhances CLOCK-BMAL1 transcriptional activity in a demethylase-independent manner; depletion of JARID1a reduces Per promoter histone acetylation and shortens circadian period.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, luciferase reporter assays, Drosophila lid mutant analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, functional knockdown with defined molecular phenotype, replicated in Drosophila","pmids":["21960634"],"is_preprint":false},{"year":2011,"finding":"KDM5A (JARID1A) binds to the progesterone receptor (PR) gene upstream regulatory region in a ligand-independent manner and suppresses PR promoter activity through its H3K4 demethylase activity; enzymatically inactive mutant KDM5A fails to suppress PR transcription.","method":"ChIP, promoter-reporter assay, overexpression of wild-type vs. catalytic mutant KDM5A, siRNA knockdown","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — active-site mutagenesis combined with ChIP and reporter assay, single lab","pmids":["21348942"],"is_preprint":false},{"year":2012,"finding":"KDM5A (Jarid1a) is recruited by the retinoblastoma tumor suppressor to target gene promoters in senescent cells, where it demethylates H3K4 to contribute to silencing of RB target genes; this links KDM5A to a tumor-suppressor network controlling cellular senescence.","method":"Quantitative mass spectrometry, ChIP-seq, shRNA knockdown, functional senescence assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genome-wide and functional methods, replicated across multiple cell models","pmids":["22615382"],"is_preprint":false},{"year":2012,"finding":"KDM5A co-occupies a large fraction of E2F4 target genes and cooperates with E2F4 to promote H3K4me3 removal and deep repression of cell cycle genes during ES cell differentiation; KDM5A is recruited to transcription start sites independently of E2F4 but p130 (DREAM complex component) occupies common KDM5A/E2F4 targets in terminally differentiated cells.","method":"Genome-wide ChIP-seq (location analysis), KDM5A knockout ES cells, quantitative gene-expression analysis","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq plus knockout model with specific cellular phenotype, single lab but multiple orthogonal methods","pmids":["23093672"],"is_preprint":false},{"year":2012,"finding":"KDM5A (Jarid1a) forms a distinct repressive protein complex with the histone methyltransferase G9a/KMT1C; the coordinate action of G9a-mediated H3K9me2 deposition and KDM5A-mediated H3K4me3 removal is required for maintenance of gene silencing at the embryonic globin locus during development.","method":"Co-immunoprecipitation, ChIP, sequential ChIP, knockdown of G9a and Jarid1a in erythroid cells","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing complex membership, ChIP showing coordinate histone mark changes, genetic epistasis via dual knockdowns","pmids":["23112189"],"is_preprint":false},{"year":2014,"finding":"KDM5A is physically and functionally associated with two histone deacetylase complexes: the SIN3B-containing HDAC complex and the NuRD complex; KDM5A depletion co-regulates hundreds of genes with CHD4 (NuRD catalytic subunit), and the C. elegans homologs of KDM5 and CHD4 function in the same pathway during vulva development.","method":"Immunoaffinity purification, sucrose-density gradient sedimentation, sequential co-immunoprecipitation, ChIP, RNAi in C. elegans","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple biochemical methods confirming stable complex, ChIP, genetic epistasis in C. elegans","pmids":["25190814"],"is_preprint":false},{"year":2015,"finding":"The PHD1 domain of KDM5A preferentially binds unmethylated H3K4 (the product of KDM5A-mediated demethylation), and this binding allosterically stimulates the catalytic jumonji C domain to remove methyl marks from H3K4me3 on peptide and nucleosome substrates, creating a positive-feedback mechanism for spreading demethylation.","method":"NMR-based structural studies, biochemical binding assays, in vitro demethylase activity assays with peptide and nucleosome substrates","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure combined with in vitro enzymatic reconstitution on multiple substrates, mechanistic mutagenesis","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 transcriptional repressor of metabolic regulatory genes, and activation of mitochondrial biogenesis (via Pgc-1α, a target of KDM5A) is sufficient to override the differentiation block independently of cell cycle exit.","method":"Kdm5a knockout mouse cells, Rb1 knockout comparison, mitochondrial oxygen consumption assays, ChIP, gene-expression profiling, PGC-1α overexpression rescue","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model, rescue experiments, ChIP showing direct repression, metabolic phenotyping with multiple orthogonal methods","pmids":["26314709"],"is_preprint":false},{"year":2016,"finding":"KDM5A (Kdm5a) associates with the NF-κB subunit p50 and binds the Socs1 promoter in resting NK cells, leading to H3K4me3 demethylation and repressive chromatin at the Socs1 locus; Kdm5a-deficient mice show impaired NK cell activation with decreased IFN-γ production and increased SOCS1 expression, establishing a role for KDM5A in priming innate immune responses.","method":"Kdm5a−/− mouse model, Co-immunoprecipitation (KDM5A-p50 interaction), ChIP (H3K4me3 at Socs1 promoter), cytokine assays, infection model","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined immunological phenotype, Co-IP of binding partner, ChIP of histone modification at specific locus","pmids":["27050510"],"is_preprint":false},{"year":2016,"finding":"KDM5A inhibits BMP2-induced osteogenic differentiation of mesenchymal stem cells by binding to the Runx2 promoter and demethylating H3K4me3, thereby reducing Runx2 expression; this mechanism is elevated in osteoporosis and its inhibition rescues BMP2-induced bone formation.","method":"ChIP assay, KDM5A overexpression/shRNA in MSCs, OVX mouse model, alkaline phosphatase and mineralization assays","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter occupancy and H3K4me3 reduction, functional knockdown/overexpression, single lab","pmids":["27512956"],"is_preprint":false},{"year":2017,"finding":"KDM5A is recruited to DNA double-strand break sites where it demethylates H3K4me3; this demethylation is required for ZMYND8-NuRD complex binding to damaged chromatin and for transcriptional silencing and homologous recombination repair at DSBs.","method":"Laser microirradiation/live-cell imaging, ChIP at DSB sites, KDM5A knockdown, HR repair assay, Co-IP (ZMYND8-NuRD)","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization to damage sites, ChIP of histone marks at DSBs, HR repair functional assay, Co-IP, multiple orthogonal methods in single study","pmids":["28572115"],"is_preprint":false},{"year":2018,"finding":"The catalytic domain of KDM5A contains an active-site cysteine (Cys481) near the αKG/Fe(II) binding pocket that is absent in other histone demethylase families; structure-based irreversible inhibitors form a covalent bond with Cys481, and co-crystal structures of the KDM5A catalytic domain with these inhibitors confirmed the binding mode.","method":"X-ray crystallography (co-crystal structures), in vitro demethylase inhibition assays, dialysis-reversal experiments confirming covalent vs. non-covalent inhibition","journal":"Journal of Medicinal Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, covalency confirmed biochemically, structure-activity relationship established","pmids":["30392349"],"is_preprint":false},{"year":2018,"finding":"KDM5A is required for repression of astrocytogenesis in neural progenitor cells; KDM5A occupies the Gfap promoter and its loss increases H3K4 methylation at this locus, promoting astrocyte differentiation; KDM5A protein expression is translationally regulated downstream of eIF4E phosphorylation.","method":"KDM5A knockdown/overexpression in NPCs, ChIP (KDM5A and H3K4me3 at Gfap promoter), GFAP reporter assay, eIF4E phosphorylation analysis","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing direct promoter occupancy and H3K4me3 changes, functional overexpression/knockdown with phenotypic readout, single lab","pmids":["29212818"],"is_preprint":false},{"year":2019,"finding":"KDM5A promotes SCLC's neuroendocrine differentiation and proliferation by repressing NOTCH2 and Notch target genes, thereby sustaining ASCL1 expression; KDM5A sgRNA in a CRISPR-based mouse SCLC model decreased tumorigenesis and metastasis, and resulting tumors showed higher NOTCH activity.","method":"CRISPR/Cas9 mouse SCLC model (sgRNA co-delivery), KDM5A knockdown in SCLC cell lines, gene-expression analysis, in vivo tumor formation assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo CRISPR genetic loss-of-function with defined pathway phenotype, cell-line knockdown corroboration, multiple orthogonal methods","pmids":["31727771"],"is_preprint":false},{"year":2019,"finding":"KDM5A binds directly to the MPC-1 promoter and transcriptionally suppresses MPC-1 expression through H3K4 demethylation, thereby redirecting mitochondrial pyruvate metabolism and promoting pancreatic cancer cell proliferation and invasion.","method":"ChIP assay (KDM5A binding at MPC-1 promoter and H3K4me3 levels), KDM5A overexpression/knockdown, in vitro metabolic assays, xenograft mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing direct promoter binding and H3K4 demethylation, functional assays and in vivo model, single lab","pmids":["31641207"],"is_preprint":false},{"year":2019,"finding":"KDM5A is transactivated by C/EBPβ during adipogenesis; KDM5A then demethylates H3K4me3 at the Wnt6 promoter to repress Wnt6 expression, and KDM5A physically interacts with C/EBPβ to cooperatively inhibit Wnt/β-catenin signaling and promote preadipocyte differentiation.","method":"ChIP, co-immunoprecipitation (KDM5A-C/EBPβ interaction), siRNA knockdown, RT-qPCR, immunoblotting","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of physical interaction, ChIP of H3K4me3 at target promoter, functional rescue experiments, single lab","pmids":["31061100"],"is_preprint":false},{"year":2020,"finding":"The PHD1 domain of KDM5A preferentially binds H3K4me0 over methylated states; NMR solution structure of apo and H3-bound PHD1 reveals conformational changes in PHD1 to accommodate H3 in a helical conformation, and post-translational modifications at distal H3 tail positions (residues 14–18) modulate KDM5A-dependent demethylation activity.","method":"NMR solution structure determination, fluorescence polarization binding assays, in vitro demethylase activity assays with modified H3 peptides","journal":"ACS Chemical Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional validation by binding and enzymatic assays, single lab but multiple orthogonal methods","pmids":["33621062"],"is_preprint":false},{"year":2020,"finding":"KDM5A acts as an H3K4me3 demethylase at the miR-495 promoter in prostate cancer cells, repressing miR-495 transcription, which in turn de-represses YTHDF2, leading to m6A-dependent degradation of MOB3B mRNA and promoting cancer progression.","method":"ChIP assay (KDM5A at miR-495 promoter, H3K4me3 levels), dual luciferase reporter, PAR-CLIP, Me-RIP, knockdown/overexpression, xenograft mouse model","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter occupancy, multiple orthogonal assays (PAR-CLIP, Me-RIP, reporter), single lab","pmids":["33087165"],"is_preprint":false},{"year":2021,"finding":"KDM5A is recruited to DNA damage sites via two mechanisms: (1) a noncanonical poly(ADP-ribose) (PAR)-binding coiled-coil domain unique to KDM5A that mediates PAR/PARP interactions, and (2) the histone variant macroH2A1.2; loss of either the PAR-binding region or macroH2A1.2 blocks KDM5A-mediated DNA repair (homology-directed repair) and transcriptional silencing at DSBs.","method":"Live-cell imaging (laser microirradiation), Co-IP (KDM5A-PAR interaction), PARP inhibitor treatment, macroH2A1.2 knockdown, HR repair assay","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments, Co-IP identifying novel binding mode, functional HR repair assay, two independent upstream regulators identified with multiple orthogonal methods","pmids":["34003252"],"is_preprint":false},{"year":2019,"finding":"HDAC1 negatively regulates RBPJ occupancy on mitotic chromatin in a KDM5A-dependent manner; KDM5A knockdown or HDAC1 inactivation both increase site-specific RBPJ binding on mitotic chromatin, and KDM5A is required for this increased RBPJ occupancy.","method":"HDAC1 knockdown/inactivation, KDM5A knockdown, mitotic chromatin ChIP","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic relationship established by dual knockdowns with ChIP readout, single lab","pmids":["30916347"],"is_preprint":false},{"year":2014,"finding":"Decreased JARID1A (KDM5A) occupancy at the PR-A promoter at the onset of human labour correlates with increased H3K4me3 and increased PR-A expression, providing a mechanism for epigenetically regulated progesterone withdrawal that precipitates parturition.","method":"Chromatin immunoprecipitation (ChIP) in human myometrial tissue samples, bisulfite sequencing","journal":"Molecular Human Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP in primary human tissue at specific promoters correlated with functional gene expression changes, single study","pmids":["24442343"],"is_preprint":false},{"year":2020,"finding":"KDM5A recognizes H3Q5 as a critical determinant for substrate recognition; protein-protein interactions between KDM5A and the distal histone H3 tail (residues 14–18) are required for efficient demethylation; post-translational modifications at this distal epitope modulate KDM5A activity.","method":"Alanine scanning mutagenesis of H3 tail, in vitro demethylase activity assays","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with systematic mutagenesis, single lab","pmids":["31985200"],"is_preprint":false},{"year":2020,"finding":"The PHD1 domain of KDM5A is tolerant of mutations at H3Q5, including aromatic substitutions, and binds Q5-serotonylated H3 with high affinity, expanding the known histone modification states recognized by this reader domain.","method":"PI-SAMDI high-throughput binding assay, fluorescence polarization binding assay, panel of 361 H3 mutant ligands","journal":"ACS Chemical Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — high-throughput binding profiling validated by orthogonal fluorescence polarization, single lab","pmids":["33314922"],"is_preprint":false},{"year":2022,"finding":"Fbxo22 targets KDM5A for ubiquitin-mediated proteasomal degradation; reduced KDM5A levels result in increased H3K4me3 at the p16 promoter, upregulating p16 and reducing DNA damage and metastasis in triple-negative breast cancer.","method":"Ubiquitination assay, Co-immunoprecipitation, ChIP (H3K4me3), KDM5A overexpression/knockdown, in vivo xenograft","journal":"Cell Biology and Toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay identifying KDM5A as substrate, Co-IP, ChIP at specific promoter, single lab","pmids":["36112263"],"is_preprint":false},{"year":2023,"finding":"KDM5A physically interacts with the MLL1 and MLL2 histone methyltransferases and their scaffold protein WDR5, acting as a transcriptional activator at mesenchymal gene promoters by inhibiting HDAC activity and increasing H3K18ac, while acting as a classical repressor at the E-cadherin promoter through H3K4me3 demethylation.","method":"ChIP (co-occupancy of KDM5A with MLLs), Co-immunoprecipitation (KDM5A-MLL1/2/WDR5 interaction), H3K18ac ChIP, histone demethylase assay","journal":"Biochimica et Biophysica Acta. Gene Regulatory Mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirming physical interaction with functionally antagonistic partners, ChIP showing co-occupancy, single lab","pmids":["37722486"],"is_preprint":false},{"year":2023,"finding":"KDM5A (JARID1A) directly interacts with the haematopoietic transcription factor GATA1 through its second PHD domain (PHD2) in erythroid cells.","method":"Co-immunoprecipitation, pulldown assay mapping PHD2 as the interaction domain","journal":"Royal Society Open Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct physical interaction mapped to specific domain by pulldown and Co-IP, single lab","pmids":["32218938"],"is_preprint":false},{"year":2023,"finding":"RepID recruits the CRL4A E3 ubiquitin ligase complex together with KDM5A (JARID1A) to the DAB2 promoter to repress it during megakaryocyte proliferation; dissociation of this complex during MK differentiation leads to euchromatinization of the DAB2 promoter.","method":"Co-immunoprecipitation, proximity ligation assay (CRL4A-KDM5A interaction), ChIP-qPCR (KDM5A/CRL4A at DAB2 promoter), subcellular fractionation","journal":"Cell Communication and Signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and proximity ligation confirming ternary complex, ChIP at specific locus, single lab","pmids":["37612584"],"is_preprint":false},{"year":2024,"finding":"KDM5A suppresses HIV-1 Tat/LTR-mediated transcription in latently infected cells by demethylating H3K4me3 at the HIV-1 5' LTR promoter; KDM5 inhibition (JQKD82) increases H3K4me3 at the LTR and reactivates latent HIV-1.","method":"KDM5A/B deletion in HIV-1 latent cells, KDM5 inhibitor treatment, H3K4me3 ChIP at HIV-1 LTR, viral reactivation assay, patient PBMC ex vivo assay","journal":"Antiviral Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion combined with ChIP at specific locus and functional reactivation assay, confirmed in primary patient cells","pmids":["38925368"],"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 are necessary for KDM5A catalytic activity on nucleosome substrates.","method":"In vitro demethylase activity assays on nucleosome substrates, cross-linking mass spectrometry (binding interface mapping), IDR deletion mutagenesis","journal":"Journal of Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro activity on nucleosomes combined with structural mass spectrometry and mutagenesis, single lab with multiple orthogonal methods","pmids":["40545232"],"is_preprint":false},{"year":2024,"finding":"KDM5A loss-of-function in knock-out mice causes ASD-related phenotypes including vocalization deficits, repetitive behaviors, sociability deficits, and abnormal dendritic morphogenesis, establishing KDM5A as a functional ASD gene; loss of KDM5A results in dysregulation of the hippocampal transcriptome.","method":"Forward genetics screen in mice, Kdm5a−/− knockout mouse model, behavioral testing battery, dendritic morphology analysis, RNA-seq","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — validated KO mouse model with multiple defined behavioral and cellular phenotypes, human genetic data (WES/microarray cohort) corroborating findings","pmids":["33350388"],"is_preprint":false},{"year":2022,"finding":"Mitochondrial dysfunction induced by amyloid-beta in neural progenitors causes KDM5A protein degradation; since KDM5A also binds and activates neuronal differentiation genes, its loss inhibits adult hippocampal neurogenesis, placing KDM5A as a mediator of retrograde mitochondrial signaling to the nucleus.","method":"Neural progenitor Aβ treatment model, proteomic analysis, KDM5A ChIP at neuronal gene promoters, functional differentiation assays, Kdm5a knockout comparison","journal":"Experimental & Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing KDM5A occupancy at neuronal gene promoters, mechanistic proteomic identification, functional differentiation phenotype, single lab","pmids":["36056186"],"is_preprint":false},{"year":2024,"finding":"KDM5A deficiency suppresses expression of KRAB-ZNF genes (independently of its catalytic activity, since pan-KDM5 catalytic inhibitor CPI-455 does not recapitulate this effect), leading to de-repression of endogenous retroviruses (ERVs), increased dsRNA levels and activation of immune response genes; KDM5A co-immunoprecipitates with the NuRD complex.","method":"KDM5A/B knockout cell lines, RNA-seq, ATAC-seq, H3K4me3 ChIP-seq, KDM5 catalytic inhibitor (CPI-455), dTAG-inducible KDM5A degradation, Co-IP (KDM5A-NuRD)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genomics approaches, dTAG acute degradation, Co-IP; preprint status lowers confidence","pmids":["39386707"],"is_preprint":true}],"current_model":"KDM5A is a JmjC-domain H3K4me2/3 demethylase whose catalytic activity requires molecular oxygen and is allosterically stimulated by its PHD1 reader domain binding the unmethylated H3K4 product; it represses transcription by demethylating H3K4me3 at target gene promoters within multi-protein complexes that include RBP-J (Notch repressor), the NuRD chromatin remodeling complex, G9a, SIN3B, p50 (NF-κB), and CLOCK-BMAL1—where it can also activate transcription by inhibiting HDAC1 in a demethylase-independent manner—and it is recruited to DNA double-strand breaks via a PAR-binding coiled-coil domain and macroH2A1.2 to demethylate H3K4me3 and enable ZMYND8-NuRD-dependent repair; its activity is regulated by FBXO22- and FBXO39-mediated ubiquitination and USP7-mediated deubiquitination, and its multivalent engagement of nucleosomes through an intrinsically disordered arginine-rich region contacting the H2A/H2B acidic patch and DNA is necessary for activity on nucleosome substrates."},"narrative":{"mechanistic_narrative":"KDM5A is a JmjC-domain histone demethylase that removes H3K4me2/3 marks to repress transcription at target gene promoters across diverse developmental, metabolic, immune, and circadian programs [PMID:23093672, PMID:26314709]. Its catalysis is iron- and oxygen-dependent, such that hypoxia inhibits the enzyme and elevates global and gene-specific H3K4me3 [PMID:20406991], and proceeds through a cysteine (Cys481) adjacent to the αKG/Fe(II) pocket that is targetable by covalent inhibitors [PMID:30392349]. Substrate engagement is multilayered: the PHD1 reader domain preferentially binds the unmethylated H3K4 product and allosterically stimulates the catalytic domain, generating positive feedback that spreads demethylation [PMID:25686748, PMID:33621062], while an intrinsically disordered arginine-rich region contacts the H2A/H2B acidic patch and nucleosomal DNA to enable activity on nucleosome substrates [PMID:40545232]. KDM5A operates within multiprotein repressive assemblies—the NuRD and SIN3B HDAC complexes [PMID:25190814], a G9a co-repressor complex coordinating H3K9me2 deposition with H3K4me3 removal [PMID:23112189], and the Notch repressor RBP-J [PMID:20231316]—and is recruited to specific loci by sequence-specific factors including E2F4/p130 and the retinoblastoma tumor suppressor [PMID:23093672, PMID:22615382], NF-κB p50 [PMID:27050510], C/EBPβ [PMID:31061100], and GATA1 [PMID:32218938]. Beyond classical repression, KDM5A can activate transcription in a demethylase-independent manner by inhibiting HDAC1, as at CLOCK-BMAL1-driven circadian promoters [PMID:21960634]. KDM5A is also recruited to DNA double-strand breaks via a noncanonical PAR-binding coiled-coil domain and the histone variant macroH2A1.2, where its H3K4me3 demethylation licenses ZMYND8-NuRD binding and homology-directed repair [PMID:28572115, PMID:34003252]. Its abundance is controlled by FBXO22-mediated ubiquitin-proteasomal degradation [PMID:36112263]. Loss-of-function in mice produces autism-related behavioral and dendritic phenotypes, establishing KDM5A as a functional ASD gene [PMID:33350388].","teleology":[{"year":2010,"claim":"Established KDM5A as a bona fide H3K4 demethylase whose enzymatic activity depends on molecular oxygen, explaining how its repressive output is environmentally tunable.","evidence":"In vitro demethylation assays plus siRNA knockdown and ChIP under varied oxygen tension in Beas-2B cells","pmids":["20406991"],"confidence":"High","gaps":["Did not define the genome-wide set of physiological target promoters","Oxygen sensitivity threshold relative to cellular hypoxic ranges not fully mapped"]},{"year":2010,"claim":"Connected KDM5A's demethylase function to a defined repressive pathway by showing it partners with the Notch effector RBP-J for gene silencing, conserved from Drosophila to mammals.","evidence":"Reciprocal Co-IP, ChIP, and knockdown/rescue in mammalian cells and Drosophila","pmids":["20231316"],"confidence":"High","gaps":["Whether demethylase activity is required at all RBP-J target loci not resolved","Structural basis of the KDM5A-RBP-J interaction unknown"]},{"year":2011,"claim":"Revealed a demethylase-independent activating mode in which KDM5A inhibits HDAC1 within the CLOCK-BMAL1 complex, showing the enzyme is not exclusively repressive.","evidence":"Co-IP, ChIP, luciferase reporters, and Drosophila lid mutant analysis","pmids":["21960634"],"confidence":"High","gaps":["Molecular mechanism by which KDM5A inhibits HDAC1 not defined","Generality of this activating mode beyond circadian promoters unclear at the time"]},{"year":2012,"claim":"Placed KDM5A within tumor-suppressor and cell-cycle repression networks by showing recruitment by RB and cooperation with E2F4/p130 to deeply silence cell-cycle genes during differentiation and senescence.","evidence":"Mass spectrometry, ChIP-seq, knockout ES cells, and senescence assays","pmids":["22615382","23093672"],"confidence":"High","gaps":["How RB/E2F4 physically recruit KDM5A to start sites not mechanistically dissected","Relative contribution of demethylase versus scaffold function in repression unresolved"]},{"year":2012,"claim":"Defined KDM5A as a member of dedicated co-repressor complexes, coordinating H3K4me3 removal with G9a-mediated H3K9me2 deposition for stable gene silencing.","evidence":"Co-IP, sequential ChIP, and dual knockdowns in erythroid cells","pmids":["23112189"],"confidence":"High","gaps":["Order of events between H3K4 demethylation and H3K9 methylation not established","Whether the G9a complex is distinct from NuRD/SIN3B assemblies unclear"]},{"year":2014,"claim":"Demonstrated stable association of KDM5A with the NuRD and SIN3B HDAC complexes, linking H3K4 demethylation to deacetylation in conserved repressive machinery.","evidence":"Immunoaffinity purification, density-gradient sedimentation, sequential Co-IP, and C. elegans genetic epistasis","pmids":["25190814"],"confidence":"High","gaps":["Subunit-level architecture of KDM5A within NuRD not resolved","Whether complex membership is dynamic across cell types unknown"]},{"year":2015,"claim":"Uncovered the allosteric logic of the enzyme: the PHD1 reader binds the unmethylated H3K4 product to stimulate the catalytic domain, creating a feed-forward mechanism for demethylation spreading.","evidence":"NMR structural studies with in vitro demethylase assays on peptide and nucleosome substrates","pmids":["25686748"],"confidence":"High","gaps":["Whether this feedback operates on chromatin in cells not directly shown","Quantitative contribution of spreading to genome-wide repression unknown"]},{"year":2015,"claim":"Linked KDM5A repression to metabolism by showing it directly silences mitochondrial biogenesis genes including Pgc-1α, with loss restoring respiration and overriding a differentiation block.","evidence":"Kdm5a knockout mouse cells, ChIP, metabolic phenotyping, and PGC-1α rescue","pmids":["26314709"],"confidence":"High","gaps":["How KDM5A is targeted to metabolic gene promoters not defined","Reciprocal regulation between mitochondrial state and KDM5A not addressed here"]},{"year":2017,"claim":"Extended KDM5A function to genome maintenance by showing it is recruited to double-strand breaks to demethylate H3K4me3, enabling ZMYND8-NuRD recruitment, transcriptional silencing, and homologous recombination.","evidence":"Laser microirradiation, ChIP at DSBs, HR repair assay, and Co-IP","pmids":["28572115"],"confidence":"High","gaps":["At this stage the recruitment mechanism to breaks was not identified","Timing relative to other DSB chromatin events unclear"]},{"year":2018,"claim":"Solved the structural basis for selective inhibition, identifying active-site Cys481 unique to KDM5A and establishing covalent inhibitors as chemical tools.","evidence":"Co-crystal X-ray structures, demethylase inhibition assays, and dialysis-reversal covalency tests","pmids":["30392349"],"confidence":"High","gaps":["Selectivity over KDM5 paralogs sharing the cysteine not fully resolved","In-cell engagement of Cys481 by these inhibitors not quantified"]},{"year":2019,"claim":"Established KDM5A as a driver in small-cell lung cancer by repressing NOTCH2 to sustain ASCL1-driven neuroendocrine differentiation, with in vivo CRISPR loss reducing tumorigenesis.","evidence":"CRISPR mouse SCLC model, cell-line knockdown, and in vivo tumor assays","pmids":["31727771"],"confidence":"High","gaps":["Whether catalytic activity is essential for the NOTCH2 repression not isolated","Direct versus indirect repression of NOTCH2 not fully distinguished"]},{"year":2016,"claim":"Showed KDM5A primes innate immunity by partnering with NF-κB p50 to demethylate H3K4me3 and silence Socs1, with knockout impairing NK cell activation.","evidence":"Kdm5a-/- mouse, Co-IP, ChIP at Socs1, cytokine and infection assays","pmids":["27050510"],"confidence":"High","gaps":["Whether p50 directly recruits KDM5A to Socs1 not structurally confirmed","Breadth of immune target loci beyond Socs1 not defined"]},{"year":2020,"claim":"Refined substrate recognition rules, showing PHD1 reads H3K4me0 with conformational adaptation and that distal H3 tail residues and modifications (including Q5 serotonylation) tune demethylase activity.","evidence":"NMR solution structures, fluorescence polarization, alanine scanning, and high-throughput binding profiling with modified H3 peptides","pmids":["33621062","31985200","33314922"],"confidence":"Medium","gaps":["Physiological relevance of H3Q5 serotonylation sensing in cells not established","Crosstalk between distal tail modifications and recruitment factors unknown"]},{"year":2021,"claim":"Identified the DSB recruitment mechanism: a noncanonical PAR-binding coiled-coil domain unique to KDM5A together with macroH2A1.2 directs the enzyme to damage sites for repair.","evidence":"Live-cell laser microirradiation, PAR Co-IP, PARP inhibition, macroH2A1.2 knockdown, and HR repair assay","pmids":["34003252"],"confidence":"High","gaps":["Whether PAR binding and macroH2A1.2 act sequentially or in parallel not resolved","Structural definition of the PAR-binding coiled-coil not provided"]},{"year":2022,"claim":"Defined post-translational control of KDM5A abundance through FBXO22-mediated ubiquitin-proteasomal degradation, linking turnover to p16 derepression and reduced metastasis.","evidence":"Ubiquitination assay, Co-IP, ChIP at p16, and xenograft model","pmids":["36112263"],"confidence":"Medium","gaps":["Signals controlling FBXO22-KDM5A engagement not defined","Degron within KDM5A not mapped"]},{"year":2024,"claim":"Established KDM5A as a functional autism gene by showing loss-of-function mice exhibit core ASD-related behavioral and dendritic phenotypes with hippocampal transcriptome dysregulation.","evidence":"Forward genetics screen, Kdm5a-/- mouse behavioral battery, dendritic morphology, and RNA-seq with human cohort corroboration","pmids":["33350388"],"confidence":"High","gaps":["Causal target genes driving the neurodevelopmental phenotype not pinpointed","Whether catalytic versus scaffold function underlies the phenotype unresolved"]},{"year":2025,"claim":"Resolved how KDM5A acts on physiological substrates, showing an intrinsically disordered arginine-rich region binds the nucleosome acidic patch and DNA to enable demethylation of nucleosomes rather than peptides.","evidence":"In vitro nucleosome demethylase assays, crosslinking mass spectrometry, and IDR deletion mutagenesis","pmids":["40545232"],"confidence":"High","gaps":["In-cell requirement of the IDR contacts not demonstrated","Integration of IDR-nucleosome binding with PHD1 allostery not modeled"]},{"year":null,"claim":"It remains unresolved when KDM5A acts as a catalytic demethylase versus a non-catalytic scaffold, and how its many recruitment factors, complexes, and post-translational controls are coordinated to select context-specific targets in vivo.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model distinguishing demethylase-dependent from scaffold functions across contexts","Mechanisms selecting among RBP-J, E2F4, p50, C/EBPβ, GATA1, and other recruiters at given loci unknown","Whether catalytic inhibitors phenocopy genetic loss for non-catalytic roles unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,8,12]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[1,13]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[8,18,24]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,9,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[30]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,12]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[5,9]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,7,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,10]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[12,20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[2]}],"complexes":["NuRD complex","SIN3B HDAC complex","G9a co-repressor complex","CLOCK-BMAL1 complex"],"partners":["RBPJ","CHD4","G9A","E2F4","ZMYND8","MACROH2A1.2","GATA1","C/EBPΒ"],"other_free_text":[]}},"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. 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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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H3K4 demethylase that physically interacts with the Notch transcriptional repressor RBP-J and is required for RBP-J-mediated gene silencing; this interaction is conserved in Drosophila and is crucial for Notch-induced growth and tumorigenesis responses.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, functional knockdown/rescue in mammalian cells and Drosophila\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal protein interaction data, ChIP, genetic validation in two organisms, multiple orthogonal methods\",\n      \"pmids\": [\"20231316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hypoxia inhibits KDM5A (JARID1A) H3K4 demethylase catalytic activity in an oxygen-tension-dependent manner (oxygen is required as a co-substrate), resulting in global and gene-specific increases in H3K4me3; knockdown of JARID1A largely abolishes the hypoxia-induced H3K4me3 increase, identifying KDM5A as the major H3K4 demethylase in Beas-2B cells.\",\n      \"method\": \"In vitro histone demethylation assay, siRNA knockdown, ChIP, Western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic activity assay combined with cell-based knockdown and ChIP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20406991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM5A (JARID1a) forms a complex with CLOCK-BMAL1, is recruited to the Per2 promoter, inhibits HDAC1 function to increase histone acetylation, and thereby enhances CLOCK-BMAL1 transcriptional activity in a demethylase-independent manner; depletion of JARID1a reduces Per promoter histone acetylation and shortens circadian period.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, luciferase reporter assays, Drosophila lid mutant analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, functional knockdown with defined molecular phenotype, replicated in Drosophila\",\n      \"pmids\": [\"21960634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM5A (JARID1A) binds to the progesterone receptor (PR) gene upstream regulatory region in a ligand-independent manner and suppresses PR promoter activity through its H3K4 demethylase activity; enzymatically inactive mutant KDM5A fails to suppress PR transcription.\",\n      \"method\": \"ChIP, promoter-reporter assay, overexpression of wild-type vs. catalytic mutant KDM5A, siRNA knockdown\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — active-site mutagenesis combined with ChIP and reporter assay, single lab\",\n      \"pmids\": [\"21348942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM5A (Jarid1a) is recruited by the retinoblastoma tumor suppressor to target gene promoters in senescent cells, where it demethylates H3K4 to contribute to silencing of RB target genes; this links KDM5A to a tumor-suppressor network controlling cellular senescence.\",\n      \"method\": \"Quantitative mass spectrometry, ChIP-seq, shRNA knockdown, functional senescence assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genome-wide and functional methods, replicated across multiple cell models\",\n      \"pmids\": [\"22615382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM5A co-occupies a large fraction of E2F4 target genes and cooperates with E2F4 to promote H3K4me3 removal and deep repression of cell cycle genes during ES cell differentiation; KDM5A is recruited to transcription start sites independently of E2F4 but p130 (DREAM complex component) occupies common KDM5A/E2F4 targets in terminally differentiated cells.\",\n      \"method\": \"Genome-wide ChIP-seq (location analysis), KDM5A knockout ES cells, quantitative gene-expression analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq plus knockout model with specific cellular phenotype, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23093672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM5A (Jarid1a) forms a distinct repressive protein complex with the histone methyltransferase G9a/KMT1C; the coordinate action of G9a-mediated H3K9me2 deposition and KDM5A-mediated H3K4me3 removal is required for maintenance of gene silencing at the embryonic globin locus during development.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, sequential ChIP, knockdown of G9a and Jarid1a in erythroid cells\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing complex membership, ChIP showing coordinate histone mark changes, genetic epistasis via dual knockdowns\",\n      \"pmids\": [\"23112189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM5A is physically and functionally associated with two histone deacetylase complexes: the SIN3B-containing HDAC complex and the NuRD complex; KDM5A depletion co-regulates hundreds of genes with CHD4 (NuRD catalytic subunit), and the C. elegans homologs of KDM5 and CHD4 function in the same pathway during vulva development.\",\n      \"method\": \"Immunoaffinity purification, sucrose-density gradient sedimentation, sequential co-immunoprecipitation, ChIP, RNAi in C. elegans\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple biochemical methods confirming stable complex, ChIP, genetic epistasis in C. elegans\",\n      \"pmids\": [\"25190814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The PHD1 domain of KDM5A preferentially binds unmethylated H3K4 (the product of KDM5A-mediated demethylation), and this binding allosterically stimulates the catalytic jumonji C domain to remove methyl marks from H3K4me3 on peptide and nucleosome substrates, creating a positive-feedback mechanism for spreading demethylation.\",\n      \"method\": \"NMR-based structural studies, biochemical binding assays, in vitro demethylase activity assays with peptide and nucleosome substrates\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure combined with in vitro enzymatic reconstitution on multiple substrates, mechanistic mutagenesis\",\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 transcriptional repressor of metabolic regulatory genes, and activation of mitochondrial biogenesis (via Pgc-1α, a target of KDM5A) is sufficient to override the differentiation block independently of cell cycle exit.\",\n      \"method\": \"Kdm5a knockout mouse cells, Rb1 knockout comparison, mitochondrial oxygen consumption assays, ChIP, gene-expression profiling, PGC-1α overexpression rescue\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model, rescue experiments, ChIP showing direct repression, metabolic phenotyping with multiple orthogonal methods\",\n      \"pmids\": [\"26314709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM5A (Kdm5a) associates with the NF-κB subunit p50 and binds the Socs1 promoter in resting NK cells, leading to H3K4me3 demethylation and repressive chromatin at the Socs1 locus; Kdm5a-deficient mice show impaired NK cell activation with decreased IFN-γ production and increased SOCS1 expression, establishing a role for KDM5A in priming innate immune responses.\",\n      \"method\": \"Kdm5a−/− mouse model, Co-immunoprecipitation (KDM5A-p50 interaction), ChIP (H3K4me3 at Socs1 promoter), cytokine assays, infection model\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined immunological phenotype, Co-IP of binding partner, ChIP of histone modification at specific locus\",\n      \"pmids\": [\"27050510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM5A inhibits BMP2-induced osteogenic differentiation of mesenchymal stem cells by binding to the Runx2 promoter and demethylating H3K4me3, thereby reducing Runx2 expression; this mechanism is elevated in osteoporosis and its inhibition rescues BMP2-induced bone formation.\",\n      \"method\": \"ChIP assay, KDM5A overexpression/shRNA in MSCs, OVX mouse model, alkaline phosphatase and mineralization assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter occupancy and H3K4me3 reduction, functional knockdown/overexpression, single lab\",\n      \"pmids\": [\"27512956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM5A is recruited to DNA double-strand break sites where it demethylates H3K4me3; this demethylation is required for ZMYND8-NuRD complex binding to damaged chromatin and for transcriptional silencing and homologous recombination repair at DSBs.\",\n      \"method\": \"Laser microirradiation/live-cell imaging, ChIP at DSB sites, KDM5A knockdown, HR repair assay, Co-IP (ZMYND8-NuRD)\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization to damage sites, ChIP of histone marks at DSBs, HR repair functional assay, Co-IP, multiple orthogonal methods in single study\",\n      \"pmids\": [\"28572115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The catalytic domain of KDM5A contains an active-site cysteine (Cys481) near the αKG/Fe(II) binding pocket that is absent in other histone demethylase families; structure-based irreversible inhibitors form a covalent bond with Cys481, and co-crystal structures of the KDM5A catalytic domain with these inhibitors confirmed the binding mode.\",\n      \"method\": \"X-ray crystallography (co-crystal structures), in vitro demethylase inhibition assays, dialysis-reversal experiments confirming covalent vs. non-covalent inhibition\",\n      \"journal\": \"Journal of Medicinal Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, covalency confirmed biochemically, structure-activity relationship established\",\n      \"pmids\": [\"30392349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM5A is required for repression of astrocytogenesis in neural progenitor cells; KDM5A occupies the Gfap promoter and its loss increases H3K4 methylation at this locus, promoting astrocyte differentiation; KDM5A protein expression is translationally regulated downstream of eIF4E phosphorylation.\",\n      \"method\": \"KDM5A knockdown/overexpression in NPCs, ChIP (KDM5A and H3K4me3 at Gfap promoter), GFAP reporter assay, eIF4E phosphorylation analysis\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing direct promoter occupancy and H3K4me3 changes, functional overexpression/knockdown with phenotypic readout, single lab\",\n      \"pmids\": [\"29212818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM5A promotes SCLC's neuroendocrine differentiation and proliferation by repressing NOTCH2 and Notch target genes, thereby sustaining ASCL1 expression; KDM5A sgRNA in a CRISPR-based mouse SCLC model decreased tumorigenesis and metastasis, and resulting tumors showed higher NOTCH activity.\",\n      \"method\": \"CRISPR/Cas9 mouse SCLC model (sgRNA co-delivery), KDM5A knockdown in SCLC cell lines, gene-expression analysis, in vivo tumor formation assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo CRISPR genetic loss-of-function with defined pathway phenotype, cell-line knockdown corroboration, multiple orthogonal methods\",\n      \"pmids\": [\"31727771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM5A binds directly to the MPC-1 promoter and transcriptionally suppresses MPC-1 expression through H3K4 demethylation, thereby redirecting mitochondrial pyruvate metabolism and promoting pancreatic cancer cell proliferation and invasion.\",\n      \"method\": \"ChIP assay (KDM5A binding at MPC-1 promoter and H3K4me3 levels), KDM5A overexpression/knockdown, in vitro metabolic assays, xenograft mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing direct promoter binding and H3K4 demethylation, functional assays and in vivo model, single lab\",\n      \"pmids\": [\"31641207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM5A is transactivated by C/EBPβ during adipogenesis; KDM5A then demethylates H3K4me3 at the Wnt6 promoter to repress Wnt6 expression, and KDM5A physically interacts with C/EBPβ to cooperatively inhibit Wnt/β-catenin signaling and promote preadipocyte differentiation.\",\n      \"method\": \"ChIP, co-immunoprecipitation (KDM5A-C/EBPβ interaction), siRNA knockdown, RT-qPCR, immunoblotting\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of physical interaction, ChIP of H3K4me3 at target promoter, functional rescue experiments, single lab\",\n      \"pmids\": [\"31061100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The PHD1 domain of KDM5A preferentially binds H3K4me0 over methylated states; NMR solution structure of apo and H3-bound PHD1 reveals conformational changes in PHD1 to accommodate H3 in a helical conformation, and post-translational modifications at distal H3 tail positions (residues 14–18) modulate KDM5A-dependent demethylation activity.\",\n      \"method\": \"NMR solution structure determination, fluorescence polarization binding assays, in vitro demethylase activity assays with modified H3 peptides\",\n      \"journal\": \"ACS Chemical Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional validation by binding and enzymatic assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33621062\"],\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, repressing miR-495 transcription, which in turn de-represses YTHDF2, leading to m6A-dependent degradation of MOB3B mRNA and promoting cancer progression.\",\n      \"method\": \"ChIP assay (KDM5A at miR-495 promoter, H3K4me3 levels), dual luciferase reporter, PAR-CLIP, Me-RIP, knockdown/overexpression, xenograft mouse model\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter occupancy, multiple orthogonal assays (PAR-CLIP, Me-RIP, reporter), single lab\",\n      \"pmids\": [\"33087165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM5A is recruited to DNA damage sites via two mechanisms: (1) a noncanonical poly(ADP-ribose) (PAR)-binding coiled-coil domain unique to KDM5A that mediates PAR/PARP interactions, and (2) the histone variant macroH2A1.2; loss of either the PAR-binding region or macroH2A1.2 blocks KDM5A-mediated DNA repair (homology-directed repair) and transcriptional silencing at DSBs.\",\n      \"method\": \"Live-cell imaging (laser microirradiation), Co-IP (KDM5A-PAR interaction), PARP inhibitor treatment, macroH2A1.2 knockdown, HR repair assay\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments, Co-IP identifying novel binding mode, functional HR repair assay, two independent upstream regulators identified with multiple orthogonal methods\",\n      \"pmids\": [\"34003252\"],\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 HDAC1 inactivation both increase site-specific RBPJ binding on mitotic chromatin, and KDM5A is required for this increased RBPJ occupancy.\",\n      \"method\": \"HDAC1 knockdown/inactivation, KDM5A knockdown, mitotic chromatin ChIP\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic relationship established by dual knockdowns with ChIP readout, single lab\",\n      \"pmids\": [\"30916347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Decreased JARID1A (KDM5A) occupancy at the PR-A promoter at the onset of human labour correlates with increased H3K4me3 and increased PR-A expression, providing a mechanism for epigenetically regulated progesterone withdrawal that precipitates parturition.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) in human myometrial tissue samples, bisulfite sequencing\",\n      \"journal\": \"Molecular Human Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in primary human tissue at specific promoters correlated with functional gene expression changes, single study\",\n      \"pmids\": [\"24442343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM5A recognizes H3Q5 as a critical determinant for substrate recognition; protein-protein interactions between KDM5A and the distal histone H3 tail (residues 14–18) are required for efficient demethylation; post-translational modifications at this distal epitope modulate KDM5A activity.\",\n      \"method\": \"Alanine scanning mutagenesis of H3 tail, in vitro demethylase activity assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with systematic mutagenesis, single lab\",\n      \"pmids\": [\"31985200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The PHD1 domain of KDM5A is tolerant of mutations at H3Q5, including aromatic substitutions, and binds Q5-serotonylated H3 with high affinity, expanding the known histone modification states recognized by this reader domain.\",\n      \"method\": \"PI-SAMDI high-throughput binding assay, fluorescence polarization binding assay, panel of 361 H3 mutant ligands\",\n      \"journal\": \"ACS Chemical Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — high-throughput binding profiling validated by orthogonal fluorescence polarization, single lab\",\n      \"pmids\": [\"33314922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Fbxo22 targets KDM5A for ubiquitin-mediated proteasomal degradation; reduced KDM5A levels result in increased H3K4me3 at the p16 promoter, upregulating p16 and reducing DNA damage and metastasis in triple-negative breast cancer.\",\n      \"method\": \"Ubiquitination assay, Co-immunoprecipitation, ChIP (H3K4me3), KDM5A overexpression/knockdown, in vivo xenograft\",\n      \"journal\": \"Cell Biology and Toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay identifying KDM5A as substrate, Co-IP, ChIP at specific promoter, single lab\",\n      \"pmids\": [\"36112263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM5A physically interacts with the MLL1 and MLL2 histone methyltransferases and their scaffold protein WDR5, acting as a transcriptional activator at mesenchymal gene promoters by inhibiting HDAC activity and increasing H3K18ac, while acting as a classical repressor at the E-cadherin promoter through H3K4me3 demethylation.\",\n      \"method\": \"ChIP (co-occupancy of KDM5A with MLLs), Co-immunoprecipitation (KDM5A-MLL1/2/WDR5 interaction), H3K18ac ChIP, histone demethylase assay\",\n      \"journal\": \"Biochimica et Biophysica Acta. Gene Regulatory Mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirming physical interaction with functionally antagonistic partners, ChIP showing co-occupancy, single lab\",\n      \"pmids\": [\"37722486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM5A (JARID1A) directly interacts with the haematopoietic transcription factor GATA1 through its second PHD domain (PHD2) in erythroid cells.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assay mapping PHD2 as the interaction domain\",\n      \"journal\": \"Royal Society Open Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct physical interaction mapped to specific domain by pulldown and Co-IP, single lab\",\n      \"pmids\": [\"32218938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RepID recruits the CRL4A E3 ubiquitin ligase complex together with KDM5A (JARID1A) to the DAB2 promoter to repress it during megakaryocyte proliferation; dissociation of this complex during MK differentiation leads to euchromatinization of the DAB2 promoter.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay (CRL4A-KDM5A interaction), ChIP-qPCR (KDM5A/CRL4A at DAB2 promoter), subcellular fractionation\",\n      \"journal\": \"Cell Communication and Signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and proximity ligation confirming ternary complex, ChIP at specific locus, single lab\",\n      \"pmids\": [\"37612584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5A suppresses HIV-1 Tat/LTR-mediated transcription in latently infected cells by demethylating H3K4me3 at the HIV-1 5' LTR promoter; KDM5 inhibition (JQKD82) increases H3K4me3 at the LTR and reactivates latent HIV-1.\",\n      \"method\": \"KDM5A/B deletion in HIV-1 latent cells, KDM5 inhibitor treatment, H3K4me3 ChIP at HIV-1 LTR, viral reactivation assay, patient PBMC ex vivo assay\",\n      \"journal\": \"Antiviral Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion combined with ChIP at specific locus and functional reactivation assay, confirmed in primary patient cells\",\n      \"pmids\": [\"38925368\"],\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 are necessary for KDM5A catalytic activity on nucleosome substrates.\",\n      \"method\": \"In vitro demethylase activity assays on nucleosome substrates, cross-linking mass spectrometry (binding interface mapping), IDR deletion mutagenesis\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro activity on nucleosomes combined with structural mass spectrometry and mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40545232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5A loss-of-function in knock-out mice causes ASD-related phenotypes including vocalization deficits, repetitive behaviors, sociability deficits, and abnormal dendritic morphogenesis, establishing KDM5A as a functional ASD gene; loss of KDM5A results in dysregulation of the hippocampal transcriptome.\",\n      \"method\": \"Forward genetics screen in mice, Kdm5a−/− knockout mouse model, behavioral testing battery, dendritic morphology analysis, RNA-seq\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — validated KO mouse model with multiple defined behavioral and cellular phenotypes, human genetic data (WES/microarray cohort) corroborating findings\",\n      \"pmids\": [\"33350388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mitochondrial dysfunction induced by amyloid-beta in neural progenitors causes KDM5A protein degradation; since KDM5A also binds and activates neuronal differentiation genes, its loss inhibits adult hippocampal neurogenesis, placing KDM5A as a mediator of retrograde mitochondrial signaling to the nucleus.\",\n      \"method\": \"Neural progenitor Aβ treatment model, proteomic analysis, KDM5A ChIP at neuronal gene promoters, functional differentiation assays, Kdm5a knockout comparison\",\n      \"journal\": \"Experimental & Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing KDM5A occupancy at neuronal gene promoters, mechanistic proteomic identification, functional differentiation phenotype, single lab\",\n      \"pmids\": [\"36056186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5A deficiency suppresses expression of KRAB-ZNF genes (independently of its catalytic activity, since pan-KDM5 catalytic inhibitor CPI-455 does not recapitulate this effect), leading to de-repression of endogenous retroviruses (ERVs), increased dsRNA levels and activation of immune response genes; KDM5A co-immunoprecipitates with the NuRD complex.\",\n      \"method\": \"KDM5A/B knockout cell lines, RNA-seq, ATAC-seq, H3K4me3 ChIP-seq, KDM5 catalytic inhibitor (CPI-455), dTAG-inducible KDM5A degradation, Co-IP (KDM5A-NuRD)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genomics approaches, dTAG acute degradation, Co-IP; preprint status lowers confidence\",\n      \"pmids\": [\"39386707\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KDM5A is a JmjC-domain H3K4me2/3 demethylase whose catalytic activity requires molecular oxygen and is allosterically stimulated by its PHD1 reader domain binding the unmethylated H3K4 product; it represses transcription by demethylating H3K4me3 at target gene promoters within multi-protein complexes that include RBP-J (Notch repressor), the NuRD chromatin remodeling complex, G9a, SIN3B, p50 (NF-κB), and CLOCK-BMAL1—where it can also activate transcription by inhibiting HDAC1 in a demethylase-independent manner—and it is recruited to DNA double-strand breaks via a PAR-binding coiled-coil domain and macroH2A1.2 to demethylate H3K4me3 and enable ZMYND8-NuRD-dependent repair; its activity is regulated by FBXO22- and FBXO39-mediated ubiquitination and USP7-mediated deubiquitination, and its multivalent engagement of nucleosomes through an intrinsically disordered arginine-rich region contacting the H2A/H2B acidic patch and DNA is necessary for activity on nucleosome substrates.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM5A is a JmjC-domain histone demethylase that removes H3K4me2/3 marks to repress transcription at target gene promoters across diverse developmental, metabolic, immune, and circadian programs [#5, #9]. Its catalysis is iron- and oxygen-dependent, such that hypoxia inhibits the enzyme and elevates global and gene-specific H3K4me3 [#1], and proceeds through a cysteine (Cys481) adjacent to the αKG/Fe(II) pocket that is targetable by covalent inhibitors [#13]. Substrate engagement is multilayered: the PHD1 reader domain preferentially binds the unmethylated H3K4 product and allosterically stimulates the catalytic domain, generating positive feedback that spreads demethylation [#8, #18], while an intrinsically disordered arginine-rich region contacts the H2A/H2B acidic patch and nucleosomal DNA to enable activity on nucleosome substrates [#30]. KDM5A operates within multiprotein repressive assemblies—the NuRD and SIN3B HDAC complexes [#7], a G9a co-repressor complex coordinating H3K9me2 deposition with H3K4me3 removal [#6], and the Notch repressor RBP-J [#0]—and is recruited to specific loci by sequence-specific factors including E2F4/p130 and the retinoblastoma tumor suppressor [#5, #4], NF-κB p50 [#10], C/EBPβ [#17], and GATA1 [#27]. Beyond classical repression, KDM5A can activate transcription in a demethylase-independent manner by inhibiting HDAC1, as at CLOCK-BMAL1-driven circadian promoters [#2]. KDM5A is also recruited to DNA double-strand breaks via a noncanonical PAR-binding coiled-coil domain and the histone variant macroH2A1.2, where its H3K4me3 demethylation licenses ZMYND8-NuRD binding and homology-directed repair [#12, #20]. Its abundance is controlled by FBXO22-mediated ubiquitin-proteasomal degradation [#25]. Loss-of-function in mice produces autism-related behavioral and dendritic phenotypes, establishing KDM5A as a functional ASD gene [#31].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established KDM5A as a bona fide H3K4 demethylase whose enzymatic activity depends on molecular oxygen, explaining how its repressive output is environmentally tunable.\",\n      \"evidence\": \"In vitro demethylation assays plus siRNA knockdown and ChIP under varied oxygen tension in Beas-2B cells\",\n      \"pmids\": [\"20406991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the genome-wide set of physiological target promoters\", \"Oxygen sensitivity threshold relative to cellular hypoxic ranges not fully mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected KDM5A's demethylase function to a defined repressive pathway by showing it partners with the Notch effector RBP-J for gene silencing, conserved from Drosophila to mammals.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, and knockdown/rescue in mammalian cells and Drosophila\",\n      \"pmids\": [\"20231316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether demethylase activity is required at all RBP-J target loci not resolved\", \"Structural basis of the KDM5A-RBP-J interaction unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a demethylase-independent activating mode in which KDM5A inhibits HDAC1 within the CLOCK-BMAL1 complex, showing the enzyme is not exclusively repressive.\",\n      \"evidence\": \"Co-IP, ChIP, luciferase reporters, and Drosophila lid mutant analysis\",\n      \"pmids\": [\"21960634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which KDM5A inhibits HDAC1 not defined\", \"Generality of this activating mode beyond circadian promoters unclear at the time\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed KDM5A within tumor-suppressor and cell-cycle repression networks by showing recruitment by RB and cooperation with E2F4/p130 to deeply silence cell-cycle genes during differentiation and senescence.\",\n      \"evidence\": \"Mass spectrometry, ChIP-seq, knockout ES cells, and senescence assays\",\n      \"pmids\": [\"22615382\", \"23093672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RB/E2F4 physically recruit KDM5A to start sites not mechanistically dissected\", \"Relative contribution of demethylase versus scaffold function in repression unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined KDM5A as a member of dedicated co-repressor complexes, coordinating H3K4me3 removal with G9a-mediated H3K9me2 deposition for stable gene silencing.\",\n      \"evidence\": \"Co-IP, sequential ChIP, and dual knockdowns in erythroid cells\",\n      \"pmids\": [\"23112189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of events between H3K4 demethylation and H3K9 methylation not established\", \"Whether the G9a complex is distinct from NuRD/SIN3B assemblies unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated stable association of KDM5A with the NuRD and SIN3B HDAC complexes, linking H3K4 demethylation to deacetylation in conserved repressive machinery.\",\n      \"evidence\": \"Immunoaffinity purification, density-gradient sedimentation, sequential Co-IP, and C. elegans genetic epistasis\",\n      \"pmids\": [\"25190814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit-level architecture of KDM5A within NuRD not resolved\", \"Whether complex membership is dynamic across cell types unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Uncovered the allosteric logic of the enzyme: the PHD1 reader binds the unmethylated H3K4 product to stimulate the catalytic domain, creating a feed-forward mechanism for demethylation spreading.\",\n      \"evidence\": \"NMR structural studies with in vitro demethylase assays on peptide and nucleosome substrates\",\n      \"pmids\": [\"25686748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this feedback operates on chromatin in cells not directly shown\", \"Quantitative contribution of spreading to genome-wide repression unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked KDM5A repression to metabolism by showing it directly silences mitochondrial biogenesis genes including Pgc-1α, with loss restoring respiration and overriding a differentiation block.\",\n      \"evidence\": \"Kdm5a knockout mouse cells, ChIP, metabolic phenotyping, and PGC-1α rescue\",\n      \"pmids\": [\"26314709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How KDM5A is targeted to metabolic gene promoters not defined\", \"Reciprocal regulation between mitochondrial state and KDM5A not addressed here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended KDM5A function to genome maintenance by showing it is recruited to double-strand breaks to demethylate H3K4me3, enabling ZMYND8-NuRD recruitment, transcriptional silencing, and homologous recombination.\",\n      \"evidence\": \"Laser microirradiation, ChIP at DSBs, HR repair assay, and Co-IP\",\n      \"pmids\": [\"28572115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"At this stage the recruitment mechanism to breaks was not identified\", \"Timing relative to other DSB chromatin events unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Solved the structural basis for selective inhibition, identifying active-site Cys481 unique to KDM5A and establishing covalent inhibitors as chemical tools.\",\n      \"evidence\": \"Co-crystal X-ray structures, demethylase inhibition assays, and dialysis-reversal covalency tests\",\n      \"pmids\": [\"30392349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity over KDM5 paralogs sharing the cysteine not fully resolved\", \"In-cell engagement of Cys481 by these inhibitors not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established KDM5A as a driver in small-cell lung cancer by repressing NOTCH2 to sustain ASCL1-driven neuroendocrine differentiation, with in vivo CRISPR loss reducing tumorigenesis.\",\n      \"evidence\": \"CRISPR mouse SCLC model, cell-line knockdown, and in vivo tumor assays\",\n      \"pmids\": [\"31727771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether catalytic activity is essential for the NOTCH2 repression not isolated\", \"Direct versus indirect repression of NOTCH2 not fully distinguished\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed KDM5A primes innate immunity by partnering with NF-κB p50 to demethylate H3K4me3 and silence Socs1, with knockout impairing NK cell activation.\",\n      \"evidence\": \"Kdm5a-/- mouse, Co-IP, ChIP at Socs1, cytokine and infection assays\",\n      \"pmids\": [\"27050510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p50 directly recruits KDM5A to Socs1 not structurally confirmed\", \"Breadth of immune target loci beyond Socs1 not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Refined substrate recognition rules, showing PHD1 reads H3K4me0 with conformational adaptation and that distal H3 tail residues and modifications (including Q5 serotonylation) tune demethylase activity.\",\n      \"evidence\": \"NMR solution structures, fluorescence polarization, alanine scanning, and high-throughput binding profiling with modified H3 peptides\",\n      \"pmids\": [\"33621062\", \"31985200\", \"33314922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of H3Q5 serotonylation sensing in cells not established\", \"Crosstalk between distal tail modifications and recruitment factors unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the DSB recruitment mechanism: a noncanonical PAR-binding coiled-coil domain unique to KDM5A together with macroH2A1.2 directs the enzyme to damage sites for repair.\",\n      \"evidence\": \"Live-cell laser microirradiation, PAR Co-IP, PARP inhibition, macroH2A1.2 knockdown, and HR repair assay\",\n      \"pmids\": [\"34003252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PAR binding and macroH2A1.2 act sequentially or in parallel not resolved\", \"Structural definition of the PAR-binding coiled-coil not provided\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined post-translational control of KDM5A abundance through FBXO22-mediated ubiquitin-proteasomal degradation, linking turnover to p16 derepression and reduced metastasis.\",\n      \"evidence\": \"Ubiquitination assay, Co-IP, ChIP at p16, and xenograft model\",\n      \"pmids\": [\"36112263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals controlling FBXO22-KDM5A engagement not defined\", \"Degron within KDM5A not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established KDM5A as a functional autism gene by showing loss-of-function mice exhibit core ASD-related behavioral and dendritic phenotypes with hippocampal transcriptome dysregulation.\",\n      \"evidence\": \"Forward genetics screen, Kdm5a-/- mouse behavioral battery, dendritic morphology, and RNA-seq with human cohort corroboration\",\n      \"pmids\": [\"33350388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal target genes driving the neurodevelopmental phenotype not pinpointed\", \"Whether catalytic versus scaffold function underlies the phenotype unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved how KDM5A acts on physiological substrates, showing an intrinsically disordered arginine-rich region binds the nucleosome acidic patch and DNA to enable demethylation of nucleosomes rather than peptides.\",\n      \"evidence\": \"In vitro nucleosome demethylase assays, crosslinking mass spectrometry, and IDR deletion mutagenesis\",\n      \"pmids\": [\"40545232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell requirement of the IDR contacts not demonstrated\", \"Integration of IDR-nucleosome binding with PHD1 allostery not modeled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved when KDM5A acts as a catalytic demethylase versus a non-catalytic scaffold, and how its many recruitment factors, complexes, and post-translational controls are coordinated to select context-specific targets in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model distinguishing demethylase-dependent from scaffold functions across contexts\", \"Mechanisms selecting among RBP-J, E2F4, p50, C/EBPβ, GATA1, and other recruiters at given loci unknown\", \"Whether catalytic inhibitors phenocopy genetic loss for non-catalytic roles unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 8, 12]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [8, 18, 24]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 9, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 12]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 7, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 10]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [12, 20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"NuRD complex\", \"SIN3B HDAC complex\", \"G9a co-repressor complex\", \"CLOCK-BMAL1 complex\"],\n    \"partners\": [\"RBPJ\", \"CHD4\", \"G9a\", \"E2F4\", \"ZMYND8\", \"macroH2A1.2\", \"GATA1\", \"C/EBPβ\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}