{"gene":"KDM3A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"Jmjd1a (KDM3A) demethylates H3K9me2 at the promoter regions of Tcl1, Tcfcp2l1, and Zfp57 in mouse embryonic stem cells, positively regulating the expression of these pluripotency-associated genes. Jmjd1a depletion leads to ES cell differentiation accompanied by reduction of ES cell-specific gene expression.","method":"RNAi knockdown, ChIP assay, gene expression analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal ChIP and knockdown with defined phenotypic readout, replicated across multiple target genes","pmids":["17938240"],"is_preprint":false},{"year":2008,"finding":"HIF-1α binds to specific hypoxia-response elements (HREs) in the JMJD1A gene promoter and directly induces JMJD1A expression under hypoxia. JMJD1A protein retains H3K9 demethylase activity under hypoxic conditions.","method":"ChIP assay identifying HIF-1α binding to JMJD1A promoter HRE; siRNA knockdown of HIF-1 abolishing hypoxia-induced JMJD1A upregulation; in vitro demethylase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct ChIP demonstrating HIF-1α binding to JMJD1A promoter, HIF-1 siRNA epistasis, replicated across two labs (PMID 18984585, 18538129)","pmids":["18984585","18538129"],"is_preprint":false},{"year":2009,"finding":"Nickel ions inhibit KDM3A demethylase activity by replacing the catalytic Fe(II) at the active site. Without iron, ~1 molecule of Ni(II) inhibits 1 molecule of KDM3A (IC50 ~2.5 µM). Nickel-bound KDM3A cannot be reactivated by excess iron. Nickel also inhibits KDM3A in intact cells.","method":"In vitro demethylase activity assay with varying Ni/Fe concentrations; X-ray absorption spectroscopy on ABH2 showing Ni binds same site as Fe; cell-based inhibition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with stoichiometric analysis plus structural (XAS) validation, consistent with cell-based data","pmids":["20042601"],"is_preprint":false},{"year":2012,"finding":"KDM3A is recruited to the SLC2A3 (GLUT3) locus in a HIF-1-dependent manner and demethylates H3K9me2 at this locus, facilitating chromatin looping and upregulating GLUT3 expression under hypoxia. Knockdown of both HIF-1α and KDM3A suppresses hypoxia-induced glycolytic gene expression.","method":"ChIP-seq, ChIP assay, 3C (chromatin conformation capture), RNAi knockdown, DNA microarray","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, 3C, RNAi) in a single study demonstrating direct recruitment and functional demethylation","pmids":["22645302"],"is_preprint":false},{"year":2013,"finding":"Jmjd1a directly binds to the Sry gene locus and regulates H3K9me2 marks there, positively controlling Sry expression. Loss of Jmjd1a leads to male-to-female sex reversal in mice due to insufficient Sry expression.","method":"Jmjd1a knockout mouse model, ChIP assay at Sry locus, gene expression analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with defined sex-reversal phenotype plus ChIP confirming direct H3K9me2 regulation at Sry locus","pmids":["24009392"],"is_preprint":false},{"year":2013,"finding":"KDM3A forms a complex with KSHV LANA protein in the nucleus. This complex demethylates H3K9me2 at LANA recruitment sites on the KSHV episome, maintaining H3K9 hypomethylation at immediate-early and latent gene promoters and supporting viral gene expression and replication. H3K9 methylation inhibits LANA binding to the H3 tail.","method":"Co-immunoprecipitation from nuclear extracts, pulldown with purified proteins, ChIP with KSHV tiling arrays, KDM3A knockdown","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP with purified proteins plus ChIP-chip and functional knockdown in a single study","pmids":["23576503"],"is_preprint":false},{"year":2013,"finding":"KDM3A demethylates H3K9me2 at the promoter of HOXA1 and activates its transcription, promoting G1/S cell cycle progression. KDM3A siRNA reduces HOXA1 and CCND1 expression, resulting in G1 arrest in cancer cells.","method":"ChIP assay showing KDM3A binding and H3K9me2 demethylation at HOXA1 promoter; siRNA knockdown with cell cycle analysis","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP binding and demethylation at HOXA1 promoter plus siRNA phenotype, single lab","pmids":["22020899"],"is_preprint":false},{"year":2013,"finding":"JMJD1A binds to the MALAT1 gene promoter and demethylates histone H3K9, thereby upregulating MALAT1 expression, which in turn promotes neuroblastoma cell migration and invasion. N-Myc activates JMJD1A expression by binding the JMJD1A promoter.","method":"ChIP assay, RT-PCR, Affymetrix microarray, cell migration/invasion assays, JMJD1A inhibitor treatment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at MALAT1 promoter showing H3K9 demethylation, functional cell assays, single lab","pmids":["24742640"],"is_preprint":false},{"year":2014,"finding":"KDM3A is a positive regulator of estrogen receptor (ER) activity in breast cancer. KDM3A depletion abrogates ER recruitment to cis-regulatory elements at target gene promoters and inhibits estrogen-induced gene expression. Catalytic demethylase activity of KDM3A is required for ER-target gene expression and cell growth.","method":"RNAi knockdown, ChIP assay, global gene expression analysis, catalytic mutant rescue experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating ER recruitment dependence on KDM3A, catalytic mutant establishing enzymatic requirement, multiple cell line validations","pmids":["25488809"],"is_preprint":false},{"year":2014,"finding":"ACK1 tyrosine kinase phosphorylates KDM3A at tyrosine 1114 (Y1114) in a heregulin-dependent manner. This phosphorylation enhances KDM3A demethylase activity, decreasing H3K9me2 marks and increasing transcription of the ER co-regulated gene HOXA1 even in the presence of tamoxifen.","method":"In vitro kinase assay, phospho-site mapping, ChIP assay, ACK1 knockdown/inhibitor treatment, mutational analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro phosphorylation assay at defined site plus ChIP and functional inhibitor epistasis in a single study","pmids":["25148682"],"is_preprint":false},{"year":2014,"finding":"Kdm3a localizes to cytoplasmic structures in maturing spermatids (acrosome, manchette) in addition to its nuclear role. Kdm3a protein stability, subcellular distribution, and demethylase activity are dependent on Hsp90, identifying it as an Hsp90 client. Loss of Kdm3a demethylase activity causes abnormal acrosome, manchette, and absence of implantation fossa, affecting cytoskeletal components β-actin and γ-tubulin fractionation.","method":"Electron microscopy, cellular fractionation, Hsp90 inhibitor treatment, two Kdm3a mouse models (demethylase activity mutant), immunolocalization","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — two mouse models with defined ultrastructural phenotypes, fractionation, Hsp90 inhibition, multiple orthogonal methods","pmids":["24554764"],"is_preprint":false},{"year":2015,"finding":"JMJD1A is phosphorylated at serine 265 (S265) by protein kinase A (PKA) downstream of β-adrenergic signaling. This phosphorylation promotes JMJD1A interaction with the SWI/SNF nucleosome remodelling complex and DNA-bound PPARγ, facilitating long-range chromatin interactions and rapid target gene activation (Adrb1, Ucp1) in brown adipocytes. The S265 phosphorylation-dependent chromatin scaffold function is independent of demethylase activity, while H3K9me2 demethylation is a separate function required for sustained gene activation.","method":"PKA phosphorylation assay, Co-IP of JMJD1A with SWI/SNF and PPARγ, ChIP, chromatin conformation capture, S265A mutant rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro phosphorylation, Co-IP of complex, ChIP, chromatin looping, mutant dissection of two functional roles, multiple orthogonal methods","pmids":["25948511"],"is_preprint":false},{"year":2015,"finding":"JMJD1A promotes c-Myc transcriptional activation by enhancing androgen receptor (AR) recruitment to the c-Myc gene enhancer and inducing H3K9 demethylation, increasing AR-dependent c-Myc mRNA. In parallel, JMJD1A (including catalytically inactive mutant) binds HUWE1 E3 ubiquitin ligase, attenuating HUWE1-dependent ubiquitination and degradation of c-Myc protein.","method":"ChIP assay, Co-IP (JMJD1A-HUWE1), ubiquitination assay, catalytic mutant analysis, knockdown/rescue experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP, ubiquitination assay, catalytic mutant dissecting two distinct mechanisms in one study","pmids":["26279298"],"is_preprint":false},{"year":2015,"finding":"JMJD1A demethylates H3K9me2 at the PPARγ gene promoter in hepatic stellate cells, maintaining PPARγ expression and restraining fibrosis. JMJD1A knockdown reinforces H3K9me2 at the PPARγ promoter and increases fibrosis markers; overexpression of wild-type but not catalytically inactive JMJD1A rescues the phenotype.","method":"ChIP assay, siRNA/shRNA knockdown, wild-type vs. catalytic mutant overexpression, in vivo mouse liver fibrosis model","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus catalytic mutant rescue in vitro and in vivo with defined fibrotic phenotype","pmids":["25609425"],"is_preprint":false},{"year":2016,"finding":"KDM3A maintains expression of KLF2 and IRF4 in multiple myeloma cells through H3K9 demethylation at their loci. KDM3A, KLF2, and IRF4 form a survival axis where KLF2 directly activates IRF4 and IRF4 reciprocally upregulates KLF2. KDM3A/KLF2/IRF4 knockdown also decreases ITGB7 expression, reducing MM cell adhesion to bone marrow stromal cells and homing.","method":"ChIP assay showing H3K9 demethylation at KLF2/IRF4 loci, siRNA knockdown (in vitro and in vivo xenograft), luciferase reporter assay for KLF2→IRF4 axis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, functional KO in vitro and in vivo, epistasis among three pathway members, multiple orthogonal methods","pmids":["26728187"],"is_preprint":false},{"year":2016,"finding":"KDM3A demethylates non-histone substrate p53 at monomethylated K372 (p53-K372me1), suppressing p53's pro-apoptotic function. KDM3A also demethylates H3K9 to promote pro-invasive gene transcription. Depletion of KDM3A can reactivate mutant p53 to induce pro-apoptotic gene expression.","method":"Co-IP, in vitro demethylation assay on p53-K372me1 peptide, ChIP, RNAi knockdown, gene expression analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro demethylation assay on p53 substrate plus Co-IP and ChIP, single lab","pmids":["27270439"],"is_preprint":false},{"year":2016,"finding":"Normal ECM mechanosensing triggers downregulation and nuclear exit of JMJD1A in carcinoma cells, resulting in epigenetic growth restriction. JMJD1A positively regulates transcription of multiple target genes including YAP/TAZ in a matrix-stiffness-dependent manner.","method":"JMJD1A knockdown and localization studies, cell growth assays on different ECM stiffness, gene expression profiling","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct nuclear exit localization tied to functional growth consequence, single lab study","pmids":["27488962"],"is_preprint":false},{"year":2016,"finding":"KDM3A directly demethylates H3K9me2 at the MCAM promoter and also regulates MCAM expression indirectly via the Ets1 transcription factor, promoting Ewing Sarcoma cell migration and metastasis.","method":"ChIP assay at MCAM promoter, RNAi knockdown, in vitro migration assay, in vivo experimental metastasis model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct H3K9me2 demethylation at MCAM promoter plus functional in vitro and in vivo metastasis assays","pmids":["28319067"],"is_preprint":false},{"year":2013,"finding":"Control of H3K9 methylation state by JMJD1A homodimerization: JMJD1A forms a homodimer through its catalytic domains, placing two active sites in proximity. This enables substrate channeling—efficient conversion of H3K9me2 to unmethylated H3K9 by reducing release of the monomethylated intermediate. Inactivating one active site in the dimer significantly reduces demethylation rate without changing affinity for the intermediate.","method":"In vitro demethylation assay, size-exclusion chromatography/native gel demonstrating homodimerization, heterodimer (WT + inactive mutant) enzymatic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with active site mutagenesis and substrate kinetics demonstrating substrate channeling mechanism","pmids":["24214985"],"is_preprint":false},{"year":2017,"finding":"JMJD1A (KDM3A) promotes alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF). JMJD1A interacts with HNRNPF and promotes its recruitment to a cryptic exon 3b on AR pre-mRNA. Knockdown of JMJD1A or HNRNPF inhibits AR-V7 splicing but not full-length AR in a minigene reporter assay.","method":"Co-IP (JMJD1A-HNRNPF), RIP (RNA immunoprecipitation), minigene reporter assay, siRNA knockdown","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, RIP, functional minigene assay, multiple orthogonal methods in one study","pmids":["29712835"],"is_preprint":false},{"year":2017,"finding":"KDM3A is recruited to the promoter of glycolytic gene PGK1, demethylates H3K9me2, and cooperates with HIF1α to induce glycolytic gene expression. A catalytically inactive JMJD1A mutant (H1120Y) fails to demethylate H3K9me2 at the PGK1 promoter and fails to cooperate with HIF1α, establishing that demethylase activity is required for HIF1α coactivation.","method":"ChIP assay at PGK1 promoter, catalytic mutant (H1120Y) analysis, siRNA knockdown, cell proliferation/colony formation assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP with direct H3K9me2 demethylation readout plus catalytic mutant demonstrating enzymatic requirement","pmids":["28263974"],"is_preprint":false},{"year":2017,"finding":"KDM3A promotes tumorigenesis in the PI3K-activated liver by recruiting c-Jun to AP-1 binding sites of target genes (Cd44, Mmp7, Pdgfrb) and facilitating Brg1 (SWI/SNF component) binding, in a Kdm3a-dependent manner, without affecting c-Jun expression. Loss of Kdm3a attenuates tumor formation in Pik3ca transgenic mice.","method":"ChIP assay showing KDM3A, c-Jun, and Brg1 binding at AP-1 sites, Kdm3a knockout in Pik3ca transgenic mice, transcriptome analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct recruitment of c-Jun and Brg1/SWI/SNF by KDM3A, in vivo tumor model epistasis","pmids":["28692045"],"is_preprint":false},{"year":2017,"finding":"KDM3A coordinates cilia stability by regulating actin gene expression (nuclear function) and by directly binding to the actin cytoskeleton (non-nuclear function), creating an 'actin gate' involving ARP2/3 activity that controls IFT protein recruitment into cilia. Loss of KDM3A causes abnormally wide range of cilia lengths, delayed disassembly, and accumulation of IFT proteins. Promoting actin filament formation rescues KDM3A mutant ciliary defects.","method":"KDM3A knockout mouse model (phenocopying ciliopathy), actin cytoskeleton binding assay, IFT protein accumulation imaging, ARP2/3 inhibitor rescue, actin depolymerization mimicry experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with defined cilia phenotype, direct binding to cytoskeleton, rescue experiments, multiple orthogonal methods","pmids":["28246120"],"is_preprint":false},{"year":2018,"finding":"KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2-mediated KDM3A phosphorylation induced by IL-6 alters histone H3K9 methylation as the predominant epigenetic event in JAK2-STAT3 pathway activation.","method":"In vitro kinase assay (JAK2 phosphorylating KDM3A), Co-IP, ChIP showing H3K9 methylation changes, cell-based IL-6 stimulation experiments","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro JAK2 kinase assay plus Co-IP and ChIP demonstrating functional consequence, single lab","pmids":["30377265"],"is_preprint":false},{"year":2018,"finding":"JMJD1A coordinates acute and chronic cold adaptation through two mechanisms requiring S265 phosphorylation by PKA: (1) phosphorylation-dependent but demethylation-independent acute Ucp1 induction in BAT via long-range chromatin interactions; (2) phosphorylation plus H3K9me2 demethylation for chronic Ucp1 expression in beige subcutaneous WAT via a PRDM16-PPARγ-P-JMJD1A complex.","method":"S265A phospho-mutant mouse model, ChIP, chromatin conformation capture, Co-IP of JMJD1A-PRDM16-PPARγ complex, cold exposure experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-mutant mouse model, Co-IP of complex, ChIP, chromatin looping, multiple orthogonal methods dissecting two mechanistic arms","pmids":["29674659"],"is_preprint":false},{"year":2019,"finding":"KDM3A binds PGC-1α and demethylates monomethylated K224 of PGC-1α (a non-histone substrate) under normoxic conditions. Hypoxia inhibits KDM3A (which has high KM for oxygen), causing accumulation of PGC-1α K224 monomethylation that decreases PGC-1α activity for NRF1/NRF2-dependent transcription of TFAM, TFB1M, TFB2M, reducing mitochondrial biogenesis. PGC-1α K224R mutant significantly increases mitochondrial biogenesis and tumor cell apoptosis.","method":"Co-IP (KDM3A-PGC-1α), in vitro demethylation assay on PGC-1α K224me1, oxygen-dependent activity assay, PGC-1α K224R mutant in cells and brain tumor xenograft model","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of non-histone demethylation, Co-IP, oxygen-KM measurement, K224R mutant rescue, in vivo tumor model","pmids":["31629659"],"is_preprint":false},{"year":2019,"finding":"PHF5A acetylation at K29 (by p300 in response to nutrient stress) strengthens U2 snRNP interactions and induces alternative splicing that stabilizes KDM3A mRNA, increasing KDM3A protein expression. This PHF5A acetylation → KDM3A upregulation axis promotes colorectal cancer stress resistance.","method":"Proteomics identifying PHF5A hyperacetylation, Co-IP (PHF5A-U2 snRNP components), splicing reporter assay, RNA-seq, KDM3A rescue experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, RNA-seq, splicing reporter, and rescue experiments establishing post-transcriptional regulation of KDM3A","pmids":["31054974"],"is_preprint":false},{"year":2019,"finding":"KDM3A binds to the DCLK1 promoter and activates DCLK1 expression. KDM3A knockdown reduces DCLK1 levels in pancreatic cancer cells; overexpression of KDM3A in normal pancreatic ductal cells enables tumor and metastasis formation in vivo.","method":"ChIP identifying KDM3A binding sites at DCLK1 promoter, siRNA knockdown, KDM3A overexpression in HPNE cells, orthotopic xenograft model","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at DCLK1 promoter plus in vivo functional transformation assay","pmids":["31442435"],"is_preprint":false},{"year":2019,"finding":"KDM3A demethylates H3K9me2 at enhancers of hippo pathway target genes and promotes H3K27ac deposition there. KDM3A associates with p300 and is required for p300 recruitment to enhancers. KDM3A depletion causes H3K9me2 accumulation mainly at TEAD1-binding enhancers, reducing TEAD1 binding and impairing transcription. KDM3A also upregulates YAP1 expression.","method":"ChIP-seq (H3K9me2, H3K27ac, H3K4me3), Co-IP (KDM3A-p300), siRNA knockdown, YAP1 rescue experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq with multiple histone marks, Co-IP demonstrating p300 interaction, functional rescue, multiple orthogonal methods","pmids":["30649550"],"is_preprint":false},{"year":2019,"finding":"KDM3A and KDM4C regulate heterochromatin reorganization during MSC senescence by transcriptionally activating condensin components NCAPD2 and NCAPG2 through H3K9 demethylation. Kdm3a-/- mouse MSCs exhibit defective chromosome organization and exacerbated DNA damage response, associated with accelerated bone aging.","method":"KDM3A/KDM4C knockdown and Kdm3a-/- mouse model, ChIP assay at condensin gene promoters, DNA damage response assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined phenotype plus ChIP, single lab","pmids":["31704649"],"is_preprint":false},{"year":2020,"finding":"JMJD1A protein stability is regulated by the E3 ubiquitin ligase STUB1, which mediates JMJD1A degradation. The acetyltransferase p300 acetylates JMJD1A at lysine 421 (K421), recruiting BRD4 to block STUB1-mediated degradation and promoting JMJD1A recruitment to AR target sites. Additionally, HUWE1 induces K27-/K29-linked noncanonical ubiquitination of JMJD1A at lysine-918.","method":"Co-IP (JMJD1A-STUB1, JMJD1A-p300, JMJD1A-BRD4), ubiquitination assay, acetylation mapping (K421), ChIP, CRPC clinical specimen correlation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IPs, defined acetylation site (K421) and ubiquitination site (K918), functional consequence on AR activity, multiple orthogonal methods","pmids":["32522824","32238799"],"is_preprint":false},{"year":2020,"finding":"KDM3A regulates alternative splicing of cell-cycle genes following DNA damage. KDM3A undergoes PKA-mediated phosphorylation at S265 upon DNA damage, which is required for proper cell-cycle regulation. KDM3A regulates SAT1 alternative splicing through a demethylase-independent mechanism requiring its interaction with ARID1A (SWI/SNF subunit) and SRSF3 splicing factor; KDM3A is essential for SRSF3 binding to SAT1 pre-mRNA.","method":"RNA-seq, Co-IP (KDM3A-ARID1A, KDM3A-SRSF3), phosphorylation assay at S265, catalytic mutant analysis, RIP (SRSF3 on SAT1 pre-mRNA)","journal":"RNA","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of splicing complex, RIP, phosphorylation assay, catalytic mutant dissecting enzymatic vs. scaffold functions, multiple methods","pmids":["34321328"],"is_preprint":false},{"year":2021,"finding":"KDM3A and KDM3B form a complex (demonstrated by IP-MS) that performs H3K9 demethylation cooperatively. OCT4 and SOX2 co-operate with the KDM3A/KDM3B-containing complex to maintain H3K9 hypomethylation at pluripotency gene loci and sustain the pluripotency gene regulatory network in porcine iPSCs.","method":"IP-mass spectrometry (KDM3A-KDM3B complex), ChIP-seq (H3K9me2/me3), co-depletion of KDM3A and KDM3B, gene expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS demonstrating complex plus ChIP-seq and co-depletion phenotype, single lab","pmids":["34042215"],"is_preprint":false},{"year":2021,"finding":"MDFI and MDFIC proteins interact with JMJD1A. JMJD1A influences transcription of several genes co-regulated by MDFI or MDFIC, including the HIC1 tumor suppressor gene which is co-stimulated by JMJD1A and MDFIC. Catalytically inactive JMJD1A mutant does not cooperate with ETV1 to induce MMP1, establishing demethylase requirement for this co-activation.","method":"Co-IP (JMJD1A-MDFI/MDFIC), RNA-seq, luciferase reporter with JMJD1A catalytic mutant, gene expression analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and reporter assay with catalytic mutant, single lab","pmids":["32457453"],"is_preprint":false},{"year":2016,"finding":"KDM3A promotes anoikis in epithelial cells following matrix detachment by transcriptionally activating BNIP3 and BNIP3L via H3K9 demethylation. Integrin signaling in attached cells maintains low KDM3A expression; upon detachment, reduced integrin signaling increases KDM3A expression. KDM3A knockdown substantially reduces apoptosis following detachment; KDM3A ectopic expression induces cell death in attached cells.","method":"RNAi screen identifying KDM3A, ChIP assay at BNIP3/BNIP3L promoters, ectopic KDM3A expression, mouse breast cancer metastasis model","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — large-scale RNAi discovery plus ChIP validation, gain-of-function, and in vivo metastasis model","pmids":["27472901"],"is_preprint":false},{"year":2016,"finding":"In hypoxic myeloma cells, the HIF-1α→KDM3A→MALAT1 axis promotes antiapoptotic phenotype independent of IRF4. KDM3A expression is HIF-1α-dependent, and KDM3A knockdown induces myeloma cell apoptosis under chronic hypoxia, while knockdown increases H3K9 methylation at MALAT1 locus.","method":"siRNA knockdown, ChIP at MALAT1 locus, gene expression analysis, apoptosis assays under chronic hypoxia","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and siRNA epistasis, single lab","pmids":["29444873"],"is_preprint":false},{"year":2017,"finding":"JMJD1A promotes Snail transcriptional activation by directly binding to the Snail gene promoter and demethylating H3K9me1 and H3K9me2 at its specific promoter region, thereby promoting prostate cancer progression.","method":"ChIP assay at Snail promoter, Co-IP (JMJD1A-Snail gene complex), siRNA knockdown, ectopic expression, xenograft model","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at defined promoter plus functional in vivo data, single lab","pmids":["32019811"],"is_preprint":false},{"year":2018,"finding":"JMJD1A promotes β-catenin expression, interacts with β-catenin to enhance its transactivation, and demethylates H3K9me2 at c-Myc and MMP9 gene promoters to activate Wnt/β-catenin target genes. A catalytic mutant (H1120Y) fails to demethylate H3K9me2 at these promoters and fails to promote CRC progression, establishing demethylase activity requirement.","method":"ChIP assay at c-Myc and MMP9 promoters, Co-IP (JMJD1A-β-catenin), H1120Y catalytic mutant analysis, xenograft tumor model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP with H3K9me2 readout, catalytic mutant establishing enzymatic requirement, in vivo model","pmids":["29802196"],"is_preprint":false},{"year":2023,"finding":"JMJD1A is a major iron-dependent epigenetic enzyme for adipocyte differentiation, demethylating H3K9me2 at Pparg and other adipogenesis gene loci. Iron supply through lysosome-mediated ferritinophagy is crucial for JMJD1A activity during early adipocyte differentiation; iron deficiency suppresses H3K9me2 demethylation and blocks terminal differentiation.","method":"JMJD1A knockdown, ChIP-seq (H3K9me2), iron chelation/ferritinophagy inhibition, mass spectrometry of histone marks, integrated genome-wide analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq, iron manipulation, knockdown with defined differentiation phenotype, mass spectrometry validation, multiple orthogonal methods","pmids":["37158274"],"is_preprint":false},{"year":2024,"finding":"JMJD1A mediates β-adrenergic-induced H3K9 demethylation at Pgc1a/b enhancers in subcutaneous white adipose tissue (scWAT), promoting PGC-1α/β-dependent mitochondrial biogenesis and beige adipocyte formation. Disruption of JMJD1A demethylase activity in mice impairs Pgc1a/b activation in scWAT and causes obesity, insulin resistance, and metabolic disorders, whereas JMJD1A demethylase activity is dispensable for BAT thermogenesis during acute cold stress.","method":"JMJD1A demethylase-activity mutant knock-in mice, ChIP at Pgc1a/b enhancers, β-adrenergic stimulation, metabolic phenotyping","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — demethylase-specific mutant mouse model, ChIP at target enhancers, metabolic phenotyping dissecting tissue-specific roles","pmids":["38544573"],"is_preprint":false},{"year":2006,"finding":"TSGA/Jmjd1a (KDM3A) is a nuclear protein that contains functional transcription repression domains and interacts with the ETS transcription factor ER71 both in vitro and in vivo via its N-terminus (TSGA) and ER71's C-terminus. TSGA impairs ER71-mediated transcriptional activation from the MMP-1 promoter.","method":"GST pulldown, co-immunoprecipitation, reporter gene assay, immunostaining","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vitro pulldown and Co-IP defining interaction domain, reporter assay for functional consequence, single lab","pmids":["16619273"],"is_preprint":false},{"year":2017,"finding":"KDM3A regulates H3K9me2 at the proximal promoter regions of AGTR1 and ROCK2 to control their transcription, mediating the Rho/ROCK and AngII/AGTR1 signaling pathways in vascular smooth muscle cells. KDM3A overexpression accelerates while knockdown reduces neointima formation after carotid artery balloon injury in diabetic rats.","method":"ChIP assay at AGTR1 and ROCK2 promoters, adenoviral KDM3A overexpression and lentiviral siRNA knockdown in vivo and in vitro, rat carotid artery injury model","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at defined promoters plus in vivo vascular model, single lab","pmids":["28135625"],"is_preprint":false},{"year":2019,"finding":"KDM3A activates the JMJD1A-mediated demethylation of H3K9me2 at Erk2 and Klf2 promoters in bone marrow MSCs, elevating their expression and promoting osteogenic differentiation.","method":"ChIP assay at Erk2 and Klf2 promoters, miR-199a-3p targeting of KDM3A (dual-luciferase), overexpression and knockdown in MSCs","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at defined promoters plus functional differentiation assay, single lab","pmids":["33410908"],"is_preprint":false},{"year":2018,"finding":"JMJD1A and JMJD1B preferentially target H3K9 demethylation in gene-dense euchromatic regions of chromosomes, establishing global H3K9 hypomethylation in euchromatin. G9a-mediated H3K9 overmethylation is the direct cause of cell death and perturbed gene expression in JMJD1A/JMJD1B-depleted ESCs, established by epistasis using G9a heterozygous mutation or chemical inhibitor rescue.","method":"Double knockout ESCs and embryos, ChIP-seq (H3K9me1/me2), G9a heterozygous rescue, G9a inhibitor rescue","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — double KO model with defined lethality, ChIP-seq, clear genetic epistasis with G9a","pmids":["29526734"],"is_preprint":false},{"year":2017,"finding":"The GLP/G9a H3K9 methyltransferase complex catalyzes H3K9 methylation at the Sry locus. Heterozygous GLP mutation or chemical GLP/G9a inhibitor rescues sex-reversal in Jmjd1a-deficient mice by restoring Sry expression, demonstrating that Jmjd1a/KDM3A and GLP/G9a form a methylation-demethylation balance at the Sry locus.","method":"Genetic epistasis (Jmjd1a KO × Glp heterozygous mice), GLP/G9a chemical inhibitor treatment in Jmjd1a-deficient embryos, ChIP assay at Sry locus","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis rescue plus chemical epistasis and ChIP, clearly demonstrates opposing enzyme balance at defined locus","pmids":["28949961"],"is_preprint":false},{"year":2017,"finding":"Vitamin C specifically induces rapid, reversible demethylation of H3K9me2 (but not other histone methylation marks) in naïve embryonic stem cells via Kdm3a and Kdm3b. Kdm3a and Kdm3b are required for vitamin C-induced H3K9me2 demethylation at chromosomal domains, gene promoters, and repeat elements. This H3K9me2 demethylation is independent of Tet-mediated DNA demethylation at specific loci.","method":"Western blot, immunofluorescence, mass spectrometry of histone marks, ChIP-seq, Kdm3a/Kdm3b knockdown, epistasis with Tet enzyme inhibition","journal":"Epigenetics & chromatin","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal quantification methods, ChIP-seq, KDM3A/B knockdown epistasis establishing specificity","pmids":["28706564"],"is_preprint":false},{"year":2022,"finding":"KDM3A binds to the ETS1 promoter and removes H3K9me2 to promote ETS1 transcription, protecting against myocardial I/R injury. KDM3A knockout exacerbates cardiac dysfunction, mitochondrial apoptosis, ROS, and inflammation both in vivo and in vitro.","method":"ChIP-PCR at ETS1 promoter, KDM3A knockout/overexpression (in vitro and rat in vivo I/R model), H3K9me2 demethylation assay","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-PCR at defined promoter plus in vivo KO model, single lab","pmids":["35338235"],"is_preprint":false},{"year":2021,"finding":"KDM3A activates DCLK1 expression by demethylating H3K9me2 at its promoter; DCLK1 in turn suppresses FXYD3 expression. Let-7i targets and downregulates KDM3A mRNA, reversing this axis in lung cancer cells.","method":"ChIP assay at DCLK1 promoter, dual-luciferase reporter (let-7i targeting KDM3A 3'UTR), siRNA knockdown, xenograft model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at DCLK1 promoter, reporter assay, single lab","pmids":["33350586"],"is_preprint":false},{"year":2023,"finding":"NUPR1 promotes TFEB transcription in hypoxic glioma cells by binding to KDM3A, which reduces H3K9me2 levels at the TFEB promoter, thereby augmenting autophagy and TMZ resistance.","method":"Co-IP (NUPR1-KDM3A interaction), ChIP at TFEB promoter (KDM3A binding and H3K9me2 levels), siRNA knockdown, xenograft model","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP at defined promoter, single lab","pmids":["37305393"],"is_preprint":false}],"current_model":"KDM3A (JMJD1A/JHDM2A/JMJD1) is a JmjC-domain Fe(II)/2-oxoglutarate-dependent dioxygenase that catalyzes removal of mono- and di-methyl marks from histone H3K9 (H3K9me1/me2), as well as monomethyl marks from non-histone substrates including PGC-1α K224 and p53 K372; its catalytic activity is oxygen-sensitive (high KM for O2) and is inhibited by nickel ions displacing the active-site iron; it is transcriptionally induced by HIF-1α binding to promoter HREs under hypoxia; it operates as a signal-sensing scaffold that is phosphorylated at S265 by PKA downstream of β-adrenergic signaling, enabling demethylase-independent recruitment of SWI/SNF and PPARγ for rapid chromatin looping, and is phosphorylated at Y1114 by ACK1 tyrosine kinase to enhance its demethylase activity; protein stability is regulated by STUB1-mediated ubiquitin-proteasomal degradation, counteracted by p300-dependent K421 acetylation that recruits BRD4, and by HUWE1-mediated noncanonical K918 ubiquitination; KDM3A forms homodimers that enable substrate channeling for efficient H3K9me2→H3K9me0 conversion, forms a complex with KDM3B in pluripotent cells co-operating with OCT4/SOX2, interacts with splicing factors HNRNPF and SRSF3 (via ARID1A/SWI/SNF) to regulate alternative splicing independently of demethylase activity, and coordinates actin dynamics with intraflagellar transport to regulate cilia stability through both transcriptional (actin gene expression) and direct cytoskeletal binding functions."},"narrative":{"mechanistic_narrative":"KDM3A (JMJD1A/JHDM2A) is an iron(II)/2-oxoglutarate-dependent JmjC dioxygenase that removes mono- and di-methyl marks from histone H3K9, acting as a transcriptional coactivator that converts repressive H3K9me1/me2 into permissive chromatin at the promoters and enhancers of developmental, metabolic, and oncogenic gene programs [PMID:17938240, PMID:29526734]. Its catalytic mechanism depends on a metal center: nickel ions inhibit activity by displacing the active-site iron [PMID:20042601], and iron availability supplied by lysosomal ferritinophagy limits its demethylase output during adipogenesis [PMID:37158274]. Catalysis is rendered efficient by homodimerization, which juxtaposes two active sites to channel the monomethyl intermediate to the fully demethylated product [PMID:24214985]. KDM3A operates in dynamic opposition to the GLP/G9a H3K9 methyltransferase, and this methylation–demethylation balance governs euchromatic H3K9 hypomethylation, pluripotency gene expression, and a developmental switch exemplified by Sry-dependent male sex determination, where loss of KDM3A causes male-to-female sex reversal in mice [PMID:29526734, PMID:28949961, PMID:24009392]. Beyond chromatin, KDM3A demethylates non-histone substrates: it removes monomethylation from p53-K372 to suppress apoptosis [PMID:27270439] and from PGC-1α-K224, an oxygen-sensitive reaction whose loss under hypoxia restrains mitochondrial biogenesis [PMID:31629659]. KDM3A is a hub for signal-responsive transcription, being transcriptionally induced by HIF-1α under hypoxia to drive glycolytic genes [PMID:18984585, PMID:18538129, PMID:22645302, PMID:28263974], and post-translationally tuned by phosphorylation — PKA at S265 downstream of β-adrenergic signaling enables a demethylase-independent scaffold function that recruits SWI/SNF and PPARγ to drive chromatin looping in adipocyte thermogenesis [PMID:25948511, PMID:29674659], while ACK1 (Y1114) and JAK2 tyrosine phosphorylation enhance its coactivator output [PMID:25148682, PMID:30377265]. Protein abundance is set by STUB1-mediated degradation, antagonized by p300-dependent K421 acetylation that recruits BRD4, and by HUWE1-mediated noncanonical K918 ubiquitination [PMID:32522824, PMID:32238799]. KDM3A also acts through demethylase-independent routes, scaffolding splicing factors HNRNPF and SRSF3 (via ARID1A/SWI/SNF) to control alternative splicing [PMID:29712835, PMID:34321328] and coordinating actin dynamics with intraflagellar transport to maintain cilia stability [PMID:28246120]. Across many cancers KDM3A behaves as a pro-tumorigenic coactivator for receptor- and oncogene-driven programs including ER, AR, c-Myc, Wnt/β-catenin, and Hippo/YAP-TEAD [PMID:25488809, PMID:26279298, PMID:29802196, PMID:30649550].","teleology":[{"year":2007,"claim":"Established KDM3A as an H3K9me2 demethylase that activates transcription, answering whether this JmjC protein had a defined chromatin-modifying function with biological consequence.","evidence":"RNAi knockdown and ChIP at pluripotency gene promoters in mouse ES cells with differentiation readout","pmids":["17938240"],"confidence":"High","gaps":["Did not resolve substrate specificity between me1 and me2","No structural basis for catalysis","Genome-wide target scope unknown"]},{"year":2008,"claim":"Placed KDM3A downstream of hypoxia signaling by showing HIF-1α directly induces its expression, linking the demethylase to oxygen sensing.","evidence":"ChIP of HIF-1α at JMJD1A promoter HREs, HIF-1 siRNA epistasis, in vitro demethylase assay (replicated across two labs)","pmids":["18984585","18538129"],"confidence":"High","gaps":["Did not define which target genes KDM3A regulates under hypoxia","Direct enzymatic role at hypoxic loci not yet shown"]},{"year":2009,"claim":"Defined the metal-dependent catalytic mechanism and a mode of inhibition by demonstrating nickel displaces active-site iron, explaining environmental modulation of activity.","evidence":"In vitro stoichiometric Ni/Fe demethylase assays, XAS structural validation, cell-based inhibition","pmids":["20042601"],"confidence":"High","gaps":["Physiological relevance of nickel exposure unaddressed","Did not measure oxygen dependence of catalysis"]},{"year":2012,"claim":"Connected HIF-1α-induced KDM3A to glycolytic gene activation via direct demethylation and chromatin looping, establishing it as a functional hypoxia effector.","evidence":"ChIP-seq, 3C, and RNAi at the GLUT3 locus","pmids":["22645302"],"confidence":"High","gaps":["Mechanism of recruitment to specific loci not defined","Whether looping requires demethylase activity unresolved"]},{"year":2013,"claim":"Demonstrated a developmental switch role by showing KDM3A controls Sry expression, with loss causing sex reversal — establishing a non-redundant in vivo function.","evidence":"Jmjd1a knockout mice with sex-reversal phenotype and ChIP at the Sry locus","pmids":["24009392"],"confidence":"High","gaps":["Opposing methyltransferase not yet identified","Recruitment mechanism to Sry unknown"]},{"year":2013,"claim":"Revealed the catalytic basis for efficient me2-to-me0 conversion through homodimerization-driven substrate channeling.","evidence":"In vitro demethylation kinetics with size-exclusion, native gel, and WT/inactive heterodimer analysis","pmids":["24214985"],"confidence":"High","gaps":["No crystal structure of the dimer","Whether dimerization is regulated in cells unknown"]},{"year":2013,"claim":"Extended KDM3A function to viral chromatin by showing it partners with KSHV LANA to keep viral promoters H3K9-hypomethylated, broadening its coactivator repertoire.","evidence":"Reciprocal Co-IP with purified proteins, ChIP-chip on KSHV episome, knockdown","pmids":["23576503"],"confidence":"High","gaps":["Single-virus context","Generalizability to host loci not addressed here"]},{"year":2014,"claim":"Established KDM3A as a catalytically required coactivator of nuclear hormone receptor signaling (ER) and identified a tyrosine kinase (ACK1) input that boosts its activity, defining signal-to-chromatin coupling in cancer.","evidence":"ChIP, catalytic mutant rescue for ER target genes; in vitro ACK1 kinase assay mapping Y1114 with ChIP/inhibitor epistasis","pmids":["25488809","25148682"],"confidence":"High","gaps":["How Y1114 phosphorylation enhances catalysis mechanistically unclear","Reciprocal regulation of ACK1 not addressed"]},{"year":2014,"claim":"Uncovered cytoplasmic and chaperone-dependent dimensions of KDM3A, showing Hsp90-client status and roles in spermatid cytoskeletal structures beyond chromatin.","evidence":"Two Kdm3a mouse models, EM, fractionation, Hsp90 inhibition, immunolocalization","pmids":["24554764"],"confidence":"High","gaps":["Direct cytoskeletal binding partners not defined here","Separation of nuclear vs cytoplasmic contributions incomplete"]},{"year":2015,"claim":"Discovered the demethylase-independent scaffold function: PKA-driven S265 phosphorylation recruits SWI/SNF and PPARγ to enable rapid chromatin looping, dissociating scaffold from enzymatic roles.","evidence":"PKA phosphorylation assay, Co-IP, ChIP, 3C, S265A mutant rescue in brown adipocytes","pmids":["25948511"],"confidence":"High","gaps":["Structural basis for phospho-dependent complex assembly unknown","Generality beyond adipocytes not yet tested"]},{"year":2015,"claim":"Showed KDM3A stabilizes c-Myc protein via a catalysis-independent interaction with HUWE1, in addition to activating c-Myc transcription, revealing dual oncogenic mechanisms.","evidence":"Co-IP, ubiquitination assay, ChIP, catalytic mutant analysis","pmids":["26279298"],"confidence":"High","gaps":["How KDM3A blocks HUWE1 catalysis not defined","Whether this competes with HUWE1 acting on KDM3A itself unaddressed"]},{"year":2016,"claim":"Identified the first non-histone substrate, p53-K372me1, establishing KDM3A as a protein demethylase that suppresses apoptosis.","evidence":"In vitro demethylation of p53-K372me1 peptide, Co-IP, ChIP, RNAi","pmids":["27270439"],"confidence":"High","gaps":["Specificity determinants for non-histone substrates unknown","Single lab"]},{"year":2016,"claim":"Expanded the oncogenic and mechanosensing repertoire, linking KDM3A levels and nuclear localization to ECM stiffness, anoikis (BNIP3/BNIP3L), and myeloma survival axes.","evidence":"Knockdown/localization on varying ECM, RNAi screen with ChIP at BNIP3/BNIP3L, HIF-1α→KDM3A→MALAT1 epistasis, KLF2/IRF4 ChIP and in vivo models","pmids":["27488962","27472901","29444873","26728187"],"confidence":"High","gaps":["Mechanism coupling mechanosignaling to KDM3A abundance/localization unresolved","Context-dependence of pro- vs anti-survival roles not reconciled"]},{"year":2017,"claim":"Defined demethylase-independent splicing control through HNRNPF recruitment to AR pre-mRNA, broadening KDM3A function into RNA processing.","evidence":"Co-IP, RIP, minigene reporter, siRNA in prostate cancer cells","pmids":["29712835"],"confidence":"High","gaps":["Whether chromatin recruitment couples to splicing not shown","Breadth of splicing targets undefined"]},{"year":2017,"claim":"Established the actin/cilia axis, showing KDM3A controls cilia stability through both actin gene transcription and direct cytoskeletal binding gating IFT entry.","evidence":"KDM3A knockout mouse with cilia phenotype, cytoskeleton binding, IFT imaging, ARP2/3 inhibitor and actin manipulation rescue","pmids":["28246120"],"confidence":"High","gaps":["Molecular nature of the actin interaction undefined","Relationship to ciliopathy disease unconfirmed"]},{"year":2017,"claim":"Showed broad coactivator partnerships with transcription factors (c-Jun/AP-1 with Brg1, Snail, ETV1, ER71) driving tumor and vascular phenotypes, many requiring demethylase activity.","evidence":"ChIP at AP-1/Snail promoters, in vivo tumor and vascular injury models, catalytic mutant analyses","pmids":["28692045","32019811","28135625","16619273","28319067"],"confidence":"High","gaps":["Determinants of which transcription factor KDM3A partners with in a given context unknown","Some early TF-interaction data assign a repressor role inconsistent with later coactivator findings"]},{"year":2018,"claim":"Resolved tissue-specific thermogenic logic, showing S265 phosphorylation drives demethylation-independent acute Ucp1 induction in BAT versus phosphorylation-plus-demethylation chronic induction in beige WAT via a PRDM16-PPARγ complex; also identified JAK2-STAT3 tyrosine-phospho coactivation.","evidence":"S265A and demethylase-mutant knock-in mice, Co-IP of PRDM16-PPARγ complex, 3C, ChIP; in vitro JAK2 kinase assay with Co-IP/ChIP","pmids":["29674659","30377265"],"confidence":"High","gaps":["Site of JAK2 phosphorylation not mapped here","Integration of multiple kinase inputs on KDM3A not unified"]},{"year":2019,"claim":"Established KDM3A as an oxygen-sensitive non-histone demethylase of PGC-1α-K224, linking its high oxygen KM to hypoxic control of mitochondrial biogenesis.","evidence":"Co-IP, in vitro PGC-1α-K224me1 demethylation, oxygen-KM measurement, K224R mutant in cells and tumor xenografts","pmids":["31629659"],"confidence":"High","gaps":["Whether other metabolic regulators are non-histone substrates unknown","In vivo oxygen-gradient relevance not directly measured"]},{"year":2019,"claim":"Mapped post-translational and post-transcriptional control of KDM3A abundance, identifying STUB1 degradation, p300-K421-acetylation/BRD4 stabilization, HUWE1-K918 ubiquitination, and PHF5A-driven splicing stabilization of KDM3A mRNA.","evidence":"Multiple Co-IPs, ubiquitination/acetylation site mapping, ChIP, clinical correlation; proteomics, splicing reporter, RNA-seq for PHF5A axis","pmids":["32522824","32238799","31054974"],"confidence":"High","gaps":["Hierarchy/crosstalk among competing PTMs on KDM3A unresolved","Stimuli triggering each modification not fully defined"]},{"year":2019,"claim":"Broadened KDM3A's coactivator scope to Hippo/YAP-TEAD enhancers (p300 cooperation), condensin/heterochromatin during senescence, and pancreatic tumorigenesis via DCLK1.","evidence":"ChIP-seq with H3K9me2/H3K27ac, Co-IP with p300, Kdm3a KO mouse models, in vivo transformation/xenograft assays","pmids":["30649550","31704649","31442435"],"confidence":"High","gaps":["Whether p300 cooperation is general across all KDM3A enhancers unknown","Direct vs indirect target distinction incomplete in several contexts"]},{"year":2021,"claim":"Defined the KDM3A/KDM3B paralog complex cooperating with OCT4/SOX2 and demethylase-independent splicing scaffolding with ARID1A/SRSF3, integrating enzymatic and non-enzymatic functions.","evidence":"IP-MS of KDM3A-KDM3B complex with ChIP-seq; Co-IP of KDM3A-ARID1A/SRSF3, RIP, S265 phosphorylation, catalytic mutant after DNA damage","pmids":["34042215","34321328","32457453"],"confidence":"High","gaps":["Stoichiometry and architecture of the KDM3A/KDM3B complex undefined","How DNA damage signals to S265 phosphorylation unclear"]},{"year":2023,"claim":"Established iron supply via lysosomal ferritinophagy as a rate-limiting input to KDM3A demethylase activity during adipocyte differentiation, tying metabolic iron status to chromatin output.","evidence":"ChIP-seq, iron chelation/ferritinophagy inhibition, histone mass spectrometry, knockdown with differentiation readout","pmids":["37158274"],"confidence":"High","gaps":["Generality of iron limitation to other cell types untested","Subcellular site of iron loading onto KDM3A unknown"]},{"year":2024,"claim":"Demonstrated demethylase-specific, tissue-selective metabolic functions in vivo: demethylase activity drives Pgc1a/b enhancer activation and beiging in scWAT but is dispensable for acute BAT thermogenesis, with loss causing obesity and insulin resistance.","evidence":"Demethylase-activity mutant knock-in mice, ChIP at Pgc1a/b enhancers, β-adrenergic stimulation, metabolic phenotyping","pmids":["38544573"],"confidence":"High","gaps":["Molecular basis for tissue selectivity of demethylase requirement unresolved","Human metabolic relevance not directly tested"]},{"year":null,"claim":"How the many regulatory inputs (kinase phosphorylations, competing ubiquitin/acetyl marks, dimerization, metal/oxygen status) are integrated to select between KDM3A's enzymatic and scaffold functions at a given locus remains unresolved, as does a high-resolution structural model of the full-length protein and its complexes.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length structure or structural model of regulatory PTMs","Rules governing target-locus selection across contexts unknown","Quantitative crosstalk among competing PTMs not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2,18,25,38]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[15,25]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,11,21,28,40]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,19,31]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,43]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[22,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,40]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,22]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[22,10]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,43,29]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,43,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,11,21,28]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,3,20,25]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,44,38,39]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,17,27,37]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[19,31,26]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[15,34]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[25,38,39]}],"complexes":["KDM3A/KDM3B H3K9 demethylase complex","SWI/SNF (with PPARγ) scaffold complex","PRDM16-PPARγ-JMJD1A complex"],"partners":["KDM3B","PPARG","PRDM16","HUWE1","STUB1","EP300","HNRNPF","ARID1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y4C1","full_name":"Lysine-specific demethylase 3A","aliases":["JmjC domain-containing histone demethylation protein 2A","Jumonji domain-containing protein 1A","[histone H3]-dimethyl-L-lysine(9) demethylase 3A"],"length_aa":1321,"mass_kda":147.3,"function":"Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Preferentially demethylates mono- and dimethylated H3 'Lys-9' residue, with a preference for dimethylated residue, while it has weak or no activity on trimethylated H3 'Lys-9'. Demethylation of Lys residue generates formaldehyde and succinate. Involved in hormone-dependent transcriptional activation, by participating in recruitment to androgen-receptor target genes, resulting in H3 'Lys-9' demethylation and transcriptional activation. Involved in spermatogenesis by regulating expression of target genes such as PRM1 and TNP1 which are required for packaging and condensation of sperm chromatin. Involved in obesity resistance through regulation of metabolic genes such as PPARA and UCP1","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y4C1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM3A","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KDM3A","total_profiled":1310},"omim":[{"mim_id":"611512","title":"LYSINE DEMETHYLASE 3A; KDM3A","url":"https://www.omim.org/entry/611512"},{"mim_id":"604503","title":"JUMONJI DOMAIN-CONTAINING PROTEIN 1C; JMJD1C","url":"https://www.omim.org/entry/604503"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KDM3A"},"hgnc":{"alias_symbol":["TSGA","KIAA0742","JHMD2A"],"prev_symbol":["JMJD1","JMJD1A"]},"alphafold":{"accession":"Q9Y4C1","domains":[{"cath_id":"-","chopping":"2-24_36-184","consensus_level":"medium","plddt":81.7599,"start":2,"end":184},{"cath_id":"-","chopping":"594-753_1268-1321","consensus_level":"medium","plddt":83.5514,"start":594,"end":1321}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4C1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4C1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4C1-F1-predicted_aligned_error_v6.png","plddt_mean":67.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM3A","jax_strain_url":"https://www.jax.org/strain/search?query=KDM3A"},"sequence":{"accession":"Q9Y4C1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y4C1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y4C1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4C1"}},"corpus_meta":[{"pmid":"17938240","id":"PMC_17938240","title":"Jmjd1a 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cancer.","date":"2020","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/32569864","citation_count":19,"is_preprint":false},{"pmid":"32577157","id":"PMC_32577157","title":"KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma.","date":"2020","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32577157","citation_count":17,"is_preprint":false},{"pmid":"16988490","id":"PMC_16988490","title":"Identification of Jmjd1a as a STAT3 downstream gene in mES cells.","date":"2006","source":"Cell structure and function","url":"https://pubmed.ncbi.nlm.nih.gov/16988490","citation_count":17,"is_preprint":false},{"pmid":"22318714","id":"PMC_22318714","title":"Ascorbate antagonizes nickel ion to regulate JMJD1A expression in kidney cancer cells.","date":"2012","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/22318714","citation_count":16,"is_preprint":false},{"pmid":"35590288","id":"PMC_35590288","title":"KDM3A-mediated SP1 activates PFKFB4 transcription to promote aerobic glycolysis in osteosarcoma and augment tumor development.","date":"2022","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35590288","citation_count":16,"is_preprint":false},{"pmid":"33239895","id":"PMC_33239895","title":"Histone Demethylase KDM3A Promotes Cervical Cancer Malignancy Through the ETS1/KIF14/Hedgehog Axis.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33239895","citation_count":16,"is_preprint":false},{"pmid":"27692601","id":"PMC_27692601","title":"Deficient expression of JMJD1A histone demethylase in patients with round spermatid maturation arrest.","date":"2016","source":"Reproductive biomedicine 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therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36959678","citation_count":15,"is_preprint":false},{"pmid":"32019811","id":"PMC_32019811","title":"Histone Demethylase JMJD1A Promotes Tumor Progression via Activating Snail in Prostate Cancer.","date":"2020","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/32019811","citation_count":13,"is_preprint":false},{"pmid":"33888871","id":"PMC_33888871","title":"Downregulation of miR-335 exhibited an oncogenic effect via promoting KDM3A/YAP1 networks in clear cell renal cell carcinoma.","date":"2021","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33888871","citation_count":13,"is_preprint":false},{"pmid":"33486545","id":"PMC_33486545","title":"microRNA-155-3p attenuates intervertebral disc degeneration via inhibition of KDM3A and HIF1α.","date":"2021","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/33486545","citation_count":13,"is_preprint":false},{"pmid":"36074918","id":"PMC_36074918","title":"The hypoxia-inducible factor-α prolyl hydroxylase inhibitor FG4592 ameliorates renal fibrosis by inducing the H3K9 demethylase JMJD1A.","date":"2022","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/36074918","citation_count":12,"is_preprint":false},{"pmid":"37305393","id":"PMC_37305393","title":"Mechanism of NURP1 in temozolomide resistance in hypoxia-treated glioma cells via the KDM3A/TFEB axis.","date":"2023","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/37305393","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54020,"output_tokens":13178,"usd":0.179865,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24422,"output_tokens":7613,"usd":0.156218,"stage2_stop_reason":"end_turn"},"total_usd":0.336083,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Jmjd1a (KDM3A) demethylates H3K9me2 at the promoter regions of Tcl1, Tcfcp2l1, and Zfp57 in mouse embryonic stem cells, positively regulating the expression of these pluripotency-associated genes. Jmjd1a depletion leads to ES cell differentiation accompanied by reduction of ES cell-specific gene expression.\",\n      \"method\": \"RNAi knockdown, ChIP assay, gene expression analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal ChIP and knockdown with defined phenotypic readout, replicated across multiple target genes\",\n      \"pmids\": [\"17938240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HIF-1α binds to specific hypoxia-response elements (HREs) in the JMJD1A gene promoter and directly induces JMJD1A expression under hypoxia. JMJD1A protein retains H3K9 demethylase activity under hypoxic conditions.\",\n      \"method\": \"ChIP assay identifying HIF-1α binding to JMJD1A promoter HRE; siRNA knockdown of HIF-1 abolishing hypoxia-induced JMJD1A upregulation; in vitro demethylase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct ChIP demonstrating HIF-1α binding to JMJD1A promoter, HIF-1 siRNA epistasis, replicated across two labs (PMID 18984585, 18538129)\",\n      \"pmids\": [\"18984585\", \"18538129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nickel ions inhibit KDM3A demethylase activity by replacing the catalytic Fe(II) at the active site. Without iron, ~1 molecule of Ni(II) inhibits 1 molecule of KDM3A (IC50 ~2.5 µM). Nickel-bound KDM3A cannot be reactivated by excess iron. Nickel also inhibits KDM3A in intact cells.\",\n      \"method\": \"In vitro demethylase activity assay with varying Ni/Fe concentrations; X-ray absorption spectroscopy on ABH2 showing Ni binds same site as Fe; cell-based inhibition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with stoichiometric analysis plus structural (XAS) validation, consistent with cell-based data\",\n      \"pmids\": [\"20042601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM3A is recruited to the SLC2A3 (GLUT3) locus in a HIF-1-dependent manner and demethylates H3K9me2 at this locus, facilitating chromatin looping and upregulating GLUT3 expression under hypoxia. Knockdown of both HIF-1α and KDM3A suppresses hypoxia-induced glycolytic gene expression.\",\n      \"method\": \"ChIP-seq, ChIP assay, 3C (chromatin conformation capture), RNAi knockdown, DNA microarray\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, 3C, RNAi) in a single study demonstrating direct recruitment and functional demethylation\",\n      \"pmids\": [\"22645302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Jmjd1a directly binds to the Sry gene locus and regulates H3K9me2 marks there, positively controlling Sry expression. Loss of Jmjd1a leads to male-to-female sex reversal in mice due to insufficient Sry expression.\",\n      \"method\": \"Jmjd1a knockout mouse model, ChIP assay at Sry locus, gene expression analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with defined sex-reversal phenotype plus ChIP confirming direct H3K9me2 regulation at Sry locus\",\n      \"pmids\": [\"24009392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM3A forms a complex with KSHV LANA protein in the nucleus. This complex demethylates H3K9me2 at LANA recruitment sites on the KSHV episome, maintaining H3K9 hypomethylation at immediate-early and latent gene promoters and supporting viral gene expression and replication. H3K9 methylation inhibits LANA binding to the H3 tail.\",\n      \"method\": \"Co-immunoprecipitation from nuclear extracts, pulldown with purified proteins, ChIP with KSHV tiling arrays, KDM3A knockdown\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP with purified proteins plus ChIP-chip and functional knockdown in a single study\",\n      \"pmids\": [\"23576503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM3A demethylates H3K9me2 at the promoter of HOXA1 and activates its transcription, promoting G1/S cell cycle progression. KDM3A siRNA reduces HOXA1 and CCND1 expression, resulting in G1 arrest in cancer cells.\",\n      \"method\": \"ChIP assay showing KDM3A binding and H3K9me2 demethylation at HOXA1 promoter; siRNA knockdown with cell cycle analysis\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP binding and demethylation at HOXA1 promoter plus siRNA phenotype, single lab\",\n      \"pmids\": [\"22020899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JMJD1A binds to the MALAT1 gene promoter and demethylates histone H3K9, thereby upregulating MALAT1 expression, which in turn promotes neuroblastoma cell migration and invasion. N-Myc activates JMJD1A expression by binding the JMJD1A promoter.\",\n      \"method\": \"ChIP assay, RT-PCR, Affymetrix microarray, cell migration/invasion assays, JMJD1A inhibitor treatment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at MALAT1 promoter showing H3K9 demethylation, functional cell assays, single lab\",\n      \"pmids\": [\"24742640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM3A is a positive regulator of estrogen receptor (ER) activity in breast cancer. KDM3A depletion abrogates ER recruitment to cis-regulatory elements at target gene promoters and inhibits estrogen-induced gene expression. Catalytic demethylase activity of KDM3A is required for ER-target gene expression and cell growth.\",\n      \"method\": \"RNAi knockdown, ChIP assay, global gene expression analysis, catalytic mutant rescue experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating ER recruitment dependence on KDM3A, catalytic mutant establishing enzymatic requirement, multiple cell line validations\",\n      \"pmids\": [\"25488809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ACK1 tyrosine kinase phosphorylates KDM3A at tyrosine 1114 (Y1114) in a heregulin-dependent manner. This phosphorylation enhances KDM3A demethylase activity, decreasing H3K9me2 marks and increasing transcription of the ER co-regulated gene HOXA1 even in the presence of tamoxifen.\",\n      \"method\": \"In vitro kinase assay, phospho-site mapping, ChIP assay, ACK1 knockdown/inhibitor treatment, mutational analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro phosphorylation assay at defined site plus ChIP and functional inhibitor epistasis in a single study\",\n      \"pmids\": [\"25148682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Kdm3a localizes to cytoplasmic structures in maturing spermatids (acrosome, manchette) in addition to its nuclear role. Kdm3a protein stability, subcellular distribution, and demethylase activity are dependent on Hsp90, identifying it as an Hsp90 client. Loss of Kdm3a demethylase activity causes abnormal acrosome, manchette, and absence of implantation fossa, affecting cytoskeletal components β-actin and γ-tubulin fractionation.\",\n      \"method\": \"Electron microscopy, cellular fractionation, Hsp90 inhibitor treatment, two Kdm3a mouse models (demethylase activity mutant), immunolocalization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two mouse models with defined ultrastructural phenotypes, fractionation, Hsp90 inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"24554764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JMJD1A is phosphorylated at serine 265 (S265) by protein kinase A (PKA) downstream of β-adrenergic signaling. This phosphorylation promotes JMJD1A interaction with the SWI/SNF nucleosome remodelling complex and DNA-bound PPARγ, facilitating long-range chromatin interactions and rapid target gene activation (Adrb1, Ucp1) in brown adipocytes. The S265 phosphorylation-dependent chromatin scaffold function is independent of demethylase activity, while H3K9me2 demethylation is a separate function required for sustained gene activation.\",\n      \"method\": \"PKA phosphorylation assay, Co-IP of JMJD1A with SWI/SNF and PPARγ, ChIP, chromatin conformation capture, S265A mutant rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro phosphorylation, Co-IP of complex, ChIP, chromatin looping, mutant dissection of two functional roles, multiple orthogonal methods\",\n      \"pmids\": [\"25948511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JMJD1A promotes c-Myc transcriptional activation by enhancing androgen receptor (AR) recruitment to the c-Myc gene enhancer and inducing H3K9 demethylation, increasing AR-dependent c-Myc mRNA. In parallel, JMJD1A (including catalytically inactive mutant) binds HUWE1 E3 ubiquitin ligase, attenuating HUWE1-dependent ubiquitination and degradation of c-Myc protein.\",\n      \"method\": \"ChIP assay, Co-IP (JMJD1A-HUWE1), ubiquitination assay, catalytic mutant analysis, knockdown/rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP, ubiquitination assay, catalytic mutant dissecting two distinct mechanisms in one study\",\n      \"pmids\": [\"26279298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JMJD1A demethylates H3K9me2 at the PPARγ gene promoter in hepatic stellate cells, maintaining PPARγ expression and restraining fibrosis. JMJD1A knockdown reinforces H3K9me2 at the PPARγ promoter and increases fibrosis markers; overexpression of wild-type but not catalytically inactive JMJD1A rescues the phenotype.\",\n      \"method\": \"ChIP assay, siRNA/shRNA knockdown, wild-type vs. catalytic mutant overexpression, in vivo mouse liver fibrosis model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus catalytic mutant rescue in vitro and in vivo with defined fibrotic phenotype\",\n      \"pmids\": [\"25609425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM3A maintains expression of KLF2 and IRF4 in multiple myeloma cells through H3K9 demethylation at their loci. KDM3A, KLF2, and IRF4 form a survival axis where KLF2 directly activates IRF4 and IRF4 reciprocally upregulates KLF2. KDM3A/KLF2/IRF4 knockdown also decreases ITGB7 expression, reducing MM cell adhesion to bone marrow stromal cells and homing.\",\n      \"method\": \"ChIP assay showing H3K9 demethylation at KLF2/IRF4 loci, siRNA knockdown (in vitro and in vivo xenograft), luciferase reporter assay for KLF2→IRF4 axis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, functional KO in vitro and in vivo, epistasis among three pathway members, multiple orthogonal methods\",\n      \"pmids\": [\"26728187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM3A demethylates non-histone substrate p53 at monomethylated K372 (p53-K372me1), suppressing p53's pro-apoptotic function. KDM3A also demethylates H3K9 to promote pro-invasive gene transcription. Depletion of KDM3A can reactivate mutant p53 to induce pro-apoptotic gene expression.\",\n      \"method\": \"Co-IP, in vitro demethylation assay on p53-K372me1 peptide, ChIP, RNAi knockdown, gene expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro demethylation assay on p53 substrate plus Co-IP and ChIP, single lab\",\n      \"pmids\": [\"27270439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Normal ECM mechanosensing triggers downregulation and nuclear exit of JMJD1A in carcinoma cells, resulting in epigenetic growth restriction. JMJD1A positively regulates transcription of multiple target genes including YAP/TAZ in a matrix-stiffness-dependent manner.\",\n      \"method\": \"JMJD1A knockdown and localization studies, cell growth assays on different ECM stiffness, gene expression profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct nuclear exit localization tied to functional growth consequence, single lab study\",\n      \"pmids\": [\"27488962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM3A directly demethylates H3K9me2 at the MCAM promoter and also regulates MCAM expression indirectly via the Ets1 transcription factor, promoting Ewing Sarcoma cell migration and metastasis.\",\n      \"method\": \"ChIP assay at MCAM promoter, RNAi knockdown, in vitro migration assay, in vivo experimental metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct H3K9me2 demethylation at MCAM promoter plus functional in vitro and in vivo metastasis assays\",\n      \"pmids\": [\"28319067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Control of H3K9 methylation state by JMJD1A homodimerization: JMJD1A forms a homodimer through its catalytic domains, placing two active sites in proximity. This enables substrate channeling—efficient conversion of H3K9me2 to unmethylated H3K9 by reducing release of the monomethylated intermediate. Inactivating one active site in the dimer significantly reduces demethylation rate without changing affinity for the intermediate.\",\n      \"method\": \"In vitro demethylation assay, size-exclusion chromatography/native gel demonstrating homodimerization, heterodimer (WT + inactive mutant) enzymatic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with active site mutagenesis and substrate kinetics demonstrating substrate channeling mechanism\",\n      \"pmids\": [\"24214985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD1A (KDM3A) promotes alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF). JMJD1A interacts with HNRNPF and promotes its recruitment to a cryptic exon 3b on AR pre-mRNA. Knockdown of JMJD1A or HNRNPF inhibits AR-V7 splicing but not full-length AR in a minigene reporter assay.\",\n      \"method\": \"Co-IP (JMJD1A-HNRNPF), RIP (RNA immunoprecipitation), minigene reporter assay, siRNA knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, RIP, functional minigene assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29712835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM3A is recruited to the promoter of glycolytic gene PGK1, demethylates H3K9me2, and cooperates with HIF1α to induce glycolytic gene expression. A catalytically inactive JMJD1A mutant (H1120Y) fails to demethylate H3K9me2 at the PGK1 promoter and fails to cooperate with HIF1α, establishing that demethylase activity is required for HIF1α coactivation.\",\n      \"method\": \"ChIP assay at PGK1 promoter, catalytic mutant (H1120Y) analysis, siRNA knockdown, cell proliferation/colony formation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP with direct H3K9me2 demethylation readout plus catalytic mutant demonstrating enzymatic requirement\",\n      \"pmids\": [\"28263974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM3A promotes tumorigenesis in the PI3K-activated liver by recruiting c-Jun to AP-1 binding sites of target genes (Cd44, Mmp7, Pdgfrb) and facilitating Brg1 (SWI/SNF component) binding, in a Kdm3a-dependent manner, without affecting c-Jun expression. Loss of Kdm3a attenuates tumor formation in Pik3ca transgenic mice.\",\n      \"method\": \"ChIP assay showing KDM3A, c-Jun, and Brg1 binding at AP-1 sites, Kdm3a knockout in Pik3ca transgenic mice, transcriptome analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct recruitment of c-Jun and Brg1/SWI/SNF by KDM3A, in vivo tumor model epistasis\",\n      \"pmids\": [\"28692045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM3A coordinates cilia stability by regulating actin gene expression (nuclear function) and by directly binding to the actin cytoskeleton (non-nuclear function), creating an 'actin gate' involving ARP2/3 activity that controls IFT protein recruitment into cilia. Loss of KDM3A causes abnormally wide range of cilia lengths, delayed disassembly, and accumulation of IFT proteins. Promoting actin filament formation rescues KDM3A mutant ciliary defects.\",\n      \"method\": \"KDM3A knockout mouse model (phenocopying ciliopathy), actin cytoskeleton binding assay, IFT protein accumulation imaging, ARP2/3 inhibitor rescue, actin depolymerization mimicry experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with defined cilia phenotype, direct binding to cytoskeleton, rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"28246120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2-mediated KDM3A phosphorylation induced by IL-6 alters histone H3K9 methylation as the predominant epigenetic event in JAK2-STAT3 pathway activation.\",\n      \"method\": \"In vitro kinase assay (JAK2 phosphorylating KDM3A), Co-IP, ChIP showing H3K9 methylation changes, cell-based IL-6 stimulation experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro JAK2 kinase assay plus Co-IP and ChIP demonstrating functional consequence, single lab\",\n      \"pmids\": [\"30377265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD1A coordinates acute and chronic cold adaptation through two mechanisms requiring S265 phosphorylation by PKA: (1) phosphorylation-dependent but demethylation-independent acute Ucp1 induction in BAT via long-range chromatin interactions; (2) phosphorylation plus H3K9me2 demethylation for chronic Ucp1 expression in beige subcutaneous WAT via a PRDM16-PPARγ-P-JMJD1A complex.\",\n      \"method\": \"S265A phospho-mutant mouse model, ChIP, chromatin conformation capture, Co-IP of JMJD1A-PRDM16-PPARγ complex, cold exposure experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-mutant mouse model, Co-IP of complex, ChIP, chromatin looping, multiple orthogonal methods dissecting two mechanistic arms\",\n      \"pmids\": [\"29674659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM3A binds PGC-1α and demethylates monomethylated K224 of PGC-1α (a non-histone substrate) under normoxic conditions. Hypoxia inhibits KDM3A (which has high KM for oxygen), causing accumulation of PGC-1α K224 monomethylation that decreases PGC-1α activity for NRF1/NRF2-dependent transcription of TFAM, TFB1M, TFB2M, reducing mitochondrial biogenesis. PGC-1α K224R mutant significantly increases mitochondrial biogenesis and tumor cell apoptosis.\",\n      \"method\": \"Co-IP (KDM3A-PGC-1α), in vitro demethylation assay on PGC-1α K224me1, oxygen-dependent activity assay, PGC-1α K224R mutant in cells and brain tumor xenograft model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of non-histone demethylation, Co-IP, oxygen-KM measurement, K224R mutant rescue, in vivo tumor model\",\n      \"pmids\": [\"31629659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHF5A acetylation at K29 (by p300 in response to nutrient stress) strengthens U2 snRNP interactions and induces alternative splicing that stabilizes KDM3A mRNA, increasing KDM3A protein expression. This PHF5A acetylation → KDM3A upregulation axis promotes colorectal cancer stress resistance.\",\n      \"method\": \"Proteomics identifying PHF5A hyperacetylation, Co-IP (PHF5A-U2 snRNP components), splicing reporter assay, RNA-seq, KDM3A rescue experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, RNA-seq, splicing reporter, and rescue experiments establishing post-transcriptional regulation of KDM3A\",\n      \"pmids\": [\"31054974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM3A binds to the DCLK1 promoter and activates DCLK1 expression. KDM3A knockdown reduces DCLK1 levels in pancreatic cancer cells; overexpression of KDM3A in normal pancreatic ductal cells enables tumor and metastasis formation in vivo.\",\n      \"method\": \"ChIP identifying KDM3A binding sites at DCLK1 promoter, siRNA knockdown, KDM3A overexpression in HPNE cells, orthotopic xenograft model\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at DCLK1 promoter plus in vivo functional transformation assay\",\n      \"pmids\": [\"31442435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM3A demethylates H3K9me2 at enhancers of hippo pathway target genes and promotes H3K27ac deposition there. KDM3A associates with p300 and is required for p300 recruitment to enhancers. KDM3A depletion causes H3K9me2 accumulation mainly at TEAD1-binding enhancers, reducing TEAD1 binding and impairing transcription. KDM3A also upregulates YAP1 expression.\",\n      \"method\": \"ChIP-seq (H3K9me2, H3K27ac, H3K4me3), Co-IP (KDM3A-p300), siRNA knockdown, YAP1 rescue experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq with multiple histone marks, Co-IP demonstrating p300 interaction, functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"30649550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM3A and KDM4C regulate heterochromatin reorganization during MSC senescence by transcriptionally activating condensin components NCAPD2 and NCAPG2 through H3K9 demethylation. Kdm3a-/- mouse MSCs exhibit defective chromosome organization and exacerbated DNA damage response, associated with accelerated bone aging.\",\n      \"method\": \"KDM3A/KDM4C knockdown and Kdm3a-/- mouse model, ChIP assay at condensin gene promoters, DNA damage response assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined phenotype plus ChIP, single lab\",\n      \"pmids\": [\"31704649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD1A protein stability is regulated by the E3 ubiquitin ligase STUB1, which mediates JMJD1A degradation. The acetyltransferase p300 acetylates JMJD1A at lysine 421 (K421), recruiting BRD4 to block STUB1-mediated degradation and promoting JMJD1A recruitment to AR target sites. Additionally, HUWE1 induces K27-/K29-linked noncanonical ubiquitination of JMJD1A at lysine-918.\",\n      \"method\": \"Co-IP (JMJD1A-STUB1, JMJD1A-p300, JMJD1A-BRD4), ubiquitination assay, acetylation mapping (K421), ChIP, CRPC clinical specimen correlation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IPs, defined acetylation site (K421) and ubiquitination site (K918), functional consequence on AR activity, multiple orthogonal methods\",\n      \"pmids\": [\"32522824\", \"32238799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM3A regulates alternative splicing of cell-cycle genes following DNA damage. KDM3A undergoes PKA-mediated phosphorylation at S265 upon DNA damage, which is required for proper cell-cycle regulation. KDM3A regulates SAT1 alternative splicing through a demethylase-independent mechanism requiring its interaction with ARID1A (SWI/SNF subunit) and SRSF3 splicing factor; KDM3A is essential for SRSF3 binding to SAT1 pre-mRNA.\",\n      \"method\": \"RNA-seq, Co-IP (KDM3A-ARID1A, KDM3A-SRSF3), phosphorylation assay at S265, catalytic mutant analysis, RIP (SRSF3 on SAT1 pre-mRNA)\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of splicing complex, RIP, phosphorylation assay, catalytic mutant dissecting enzymatic vs. scaffold functions, multiple methods\",\n      \"pmids\": [\"34321328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM3A and KDM3B form a complex (demonstrated by IP-MS) that performs H3K9 demethylation cooperatively. OCT4 and SOX2 co-operate with the KDM3A/KDM3B-containing complex to maintain H3K9 hypomethylation at pluripotency gene loci and sustain the pluripotency gene regulatory network in porcine iPSCs.\",\n      \"method\": \"IP-mass spectrometry (KDM3A-KDM3B complex), ChIP-seq (H3K9me2/me3), co-depletion of KDM3A and KDM3B, gene expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS demonstrating complex plus ChIP-seq and co-depletion phenotype, single lab\",\n      \"pmids\": [\"34042215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MDFI and MDFIC proteins interact with JMJD1A. JMJD1A influences transcription of several genes co-regulated by MDFI or MDFIC, including the HIC1 tumor suppressor gene which is co-stimulated by JMJD1A and MDFIC. Catalytically inactive JMJD1A mutant does not cooperate with ETV1 to induce MMP1, establishing demethylase requirement for this co-activation.\",\n      \"method\": \"Co-IP (JMJD1A-MDFI/MDFIC), RNA-seq, luciferase reporter with JMJD1A catalytic mutant, gene expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and reporter assay with catalytic mutant, single lab\",\n      \"pmids\": [\"32457453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM3A promotes anoikis in epithelial cells following matrix detachment by transcriptionally activating BNIP3 and BNIP3L via H3K9 demethylation. Integrin signaling in attached cells maintains low KDM3A expression; upon detachment, reduced integrin signaling increases KDM3A expression. KDM3A knockdown substantially reduces apoptosis following detachment; KDM3A ectopic expression induces cell death in attached cells.\",\n      \"method\": \"RNAi screen identifying KDM3A, ChIP assay at BNIP3/BNIP3L promoters, ectopic KDM3A expression, mouse breast cancer metastasis model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large-scale RNAi discovery plus ChIP validation, gain-of-function, and in vivo metastasis model\",\n      \"pmids\": [\"27472901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In hypoxic myeloma cells, the HIF-1α→KDM3A→MALAT1 axis promotes antiapoptotic phenotype independent of IRF4. KDM3A expression is HIF-1α-dependent, and KDM3A knockdown induces myeloma cell apoptosis under chronic hypoxia, while knockdown increases H3K9 methylation at MALAT1 locus.\",\n      \"method\": \"siRNA knockdown, ChIP at MALAT1 locus, gene expression analysis, apoptosis assays under chronic hypoxia\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and siRNA epistasis, single lab\",\n      \"pmids\": [\"29444873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD1A promotes Snail transcriptional activation by directly binding to the Snail gene promoter and demethylating H3K9me1 and H3K9me2 at its specific promoter region, thereby promoting prostate cancer progression.\",\n      \"method\": \"ChIP assay at Snail promoter, Co-IP (JMJD1A-Snail gene complex), siRNA knockdown, ectopic expression, xenograft model\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at defined promoter plus functional in vivo data, single lab\",\n      \"pmids\": [\"32019811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD1A promotes β-catenin expression, interacts with β-catenin to enhance its transactivation, and demethylates H3K9me2 at c-Myc and MMP9 gene promoters to activate Wnt/β-catenin target genes. A catalytic mutant (H1120Y) fails to demethylate H3K9me2 at these promoters and fails to promote CRC progression, establishing demethylase activity requirement.\",\n      \"method\": \"ChIP assay at c-Myc and MMP9 promoters, Co-IP (JMJD1A-β-catenin), H1120Y catalytic mutant analysis, xenograft tumor model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP with H3K9me2 readout, catalytic mutant establishing enzymatic requirement, in vivo model\",\n      \"pmids\": [\"29802196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"JMJD1A is a major iron-dependent epigenetic enzyme for adipocyte differentiation, demethylating H3K9me2 at Pparg and other adipogenesis gene loci. Iron supply through lysosome-mediated ferritinophagy is crucial for JMJD1A activity during early adipocyte differentiation; iron deficiency suppresses H3K9me2 demethylation and blocks terminal differentiation.\",\n      \"method\": \"JMJD1A knockdown, ChIP-seq (H3K9me2), iron chelation/ferritinophagy inhibition, mass spectrometry of histone marks, integrated genome-wide analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq, iron manipulation, knockdown with defined differentiation phenotype, mass spectrometry validation, multiple orthogonal methods\",\n      \"pmids\": [\"37158274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JMJD1A mediates β-adrenergic-induced H3K9 demethylation at Pgc1a/b enhancers in subcutaneous white adipose tissue (scWAT), promoting PGC-1α/β-dependent mitochondrial biogenesis and beige adipocyte formation. Disruption of JMJD1A demethylase activity in mice impairs Pgc1a/b activation in scWAT and causes obesity, insulin resistance, and metabolic disorders, whereas JMJD1A demethylase activity is dispensable for BAT thermogenesis during acute cold stress.\",\n      \"method\": \"JMJD1A demethylase-activity mutant knock-in mice, ChIP at Pgc1a/b enhancers, β-adrenergic stimulation, metabolic phenotyping\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — demethylase-specific mutant mouse model, ChIP at target enhancers, metabolic phenotyping dissecting tissue-specific roles\",\n      \"pmids\": [\"38544573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TSGA/Jmjd1a (KDM3A) is a nuclear protein that contains functional transcription repression domains and interacts with the ETS transcription factor ER71 both in vitro and in vivo via its N-terminus (TSGA) and ER71's C-terminus. TSGA impairs ER71-mediated transcriptional activation from the MMP-1 promoter.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, reporter gene assay, immunostaining\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vitro pulldown and Co-IP defining interaction domain, reporter assay for functional consequence, single lab\",\n      \"pmids\": [\"16619273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM3A regulates H3K9me2 at the proximal promoter regions of AGTR1 and ROCK2 to control their transcription, mediating the Rho/ROCK and AngII/AGTR1 signaling pathways in vascular smooth muscle cells. KDM3A overexpression accelerates while knockdown reduces neointima formation after carotid artery balloon injury in diabetic rats.\",\n      \"method\": \"ChIP assay at AGTR1 and ROCK2 promoters, adenoviral KDM3A overexpression and lentiviral siRNA knockdown in vivo and in vitro, rat carotid artery injury model\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at defined promoters plus in vivo vascular model, single lab\",\n      \"pmids\": [\"28135625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM3A activates the JMJD1A-mediated demethylation of H3K9me2 at Erk2 and Klf2 promoters in bone marrow MSCs, elevating their expression and promoting osteogenic differentiation.\",\n      \"method\": \"ChIP assay at Erk2 and Klf2 promoters, miR-199a-3p targeting of KDM3A (dual-luciferase), overexpression and knockdown in MSCs\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at defined promoters plus functional differentiation assay, single lab\",\n      \"pmids\": [\"33410908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD1A and JMJD1B preferentially target H3K9 demethylation in gene-dense euchromatic regions of chromosomes, establishing global H3K9 hypomethylation in euchromatin. G9a-mediated H3K9 overmethylation is the direct cause of cell death and perturbed gene expression in JMJD1A/JMJD1B-depleted ESCs, established by epistasis using G9a heterozygous mutation or chemical inhibitor rescue.\",\n      \"method\": \"Double knockout ESCs and embryos, ChIP-seq (H3K9me1/me2), G9a heterozygous rescue, G9a inhibitor rescue\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double KO model with defined lethality, ChIP-seq, clear genetic epistasis with G9a\",\n      \"pmids\": [\"29526734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The GLP/G9a H3K9 methyltransferase complex catalyzes H3K9 methylation at the Sry locus. Heterozygous GLP mutation or chemical GLP/G9a inhibitor rescues sex-reversal in Jmjd1a-deficient mice by restoring Sry expression, demonstrating that Jmjd1a/KDM3A and GLP/G9a form a methylation-demethylation balance at the Sry locus.\",\n      \"method\": \"Genetic epistasis (Jmjd1a KO × Glp heterozygous mice), GLP/G9a chemical inhibitor treatment in Jmjd1a-deficient embryos, ChIP assay at Sry locus\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis rescue plus chemical epistasis and ChIP, clearly demonstrates opposing enzyme balance at defined locus\",\n      \"pmids\": [\"28949961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Vitamin C specifically induces rapid, reversible demethylation of H3K9me2 (but not other histone methylation marks) in naïve embryonic stem cells via Kdm3a and Kdm3b. Kdm3a and Kdm3b are required for vitamin C-induced H3K9me2 demethylation at chromosomal domains, gene promoters, and repeat elements. This H3K9me2 demethylation is independent of Tet-mediated DNA demethylation at specific loci.\",\n      \"method\": \"Western blot, immunofluorescence, mass spectrometry of histone marks, ChIP-seq, Kdm3a/Kdm3b knockdown, epistasis with Tet enzyme inhibition\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal quantification methods, ChIP-seq, KDM3A/B knockdown epistasis establishing specificity\",\n      \"pmids\": [\"28706564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM3A binds to the ETS1 promoter and removes H3K9me2 to promote ETS1 transcription, protecting against myocardial I/R injury. KDM3A knockout exacerbates cardiac dysfunction, mitochondrial apoptosis, ROS, and inflammation both in vivo and in vitro.\",\n      \"method\": \"ChIP-PCR at ETS1 promoter, KDM3A knockout/overexpression (in vitro and rat in vivo I/R model), H3K9me2 demethylation assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-PCR at defined promoter plus in vivo KO model, single lab\",\n      \"pmids\": [\"35338235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM3A activates DCLK1 expression by demethylating H3K9me2 at its promoter; DCLK1 in turn suppresses FXYD3 expression. Let-7i targets and downregulates KDM3A mRNA, reversing this axis in lung cancer cells.\",\n      \"method\": \"ChIP assay at DCLK1 promoter, dual-luciferase reporter (let-7i targeting KDM3A 3'UTR), siRNA knockdown, xenograft model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at DCLK1 promoter, reporter assay, single lab\",\n      \"pmids\": [\"33350586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NUPR1 promotes TFEB transcription in hypoxic glioma cells by binding to KDM3A, which reduces H3K9me2 levels at the TFEB promoter, thereby augmenting autophagy and TMZ resistance.\",\n      \"method\": \"Co-IP (NUPR1-KDM3A interaction), ChIP at TFEB promoter (KDM3A binding and H3K9me2 levels), siRNA knockdown, xenograft model\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP at defined promoter, single lab\",\n      \"pmids\": [\"37305393\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM3A (JMJD1A/JHDM2A/JMJD1) is a JmjC-domain Fe(II)/2-oxoglutarate-dependent dioxygenase that catalyzes removal of mono- and di-methyl marks from histone H3K9 (H3K9me1/me2), as well as monomethyl marks from non-histone substrates including PGC-1α K224 and p53 K372; its catalytic activity is oxygen-sensitive (high KM for O2) and is inhibited by nickel ions displacing the active-site iron; it is transcriptionally induced by HIF-1α binding to promoter HREs under hypoxia; it operates as a signal-sensing scaffold that is phosphorylated at S265 by PKA downstream of β-adrenergic signaling, enabling demethylase-independent recruitment of SWI/SNF and PPARγ for rapid chromatin looping, and is phosphorylated at Y1114 by ACK1 tyrosine kinase to enhance its demethylase activity; protein stability is regulated by STUB1-mediated ubiquitin-proteasomal degradation, counteracted by p300-dependent K421 acetylation that recruits BRD4, and by HUWE1-mediated noncanonical K918 ubiquitination; KDM3A forms homodimers that enable substrate channeling for efficient H3K9me2→H3K9me0 conversion, forms a complex with KDM3B in pluripotent cells co-operating with OCT4/SOX2, interacts with splicing factors HNRNPF and SRSF3 (via ARID1A/SWI/SNF) to regulate alternative splicing independently of demethylase activity, and coordinates actin dynamics with intraflagellar transport to regulate cilia stability through both transcriptional (actin gene expression) and direct cytoskeletal binding functions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM3A (JMJD1A/JHDM2A) is an iron(II)/2-oxoglutarate-dependent JmjC dioxygenase that removes mono- and di-methyl marks from histone H3K9, acting as a transcriptional coactivator that converts repressive H3K9me1/me2 into permissive chromatin at the promoters and enhancers of developmental, metabolic, and oncogenic gene programs [#0, #43]. Its catalytic mechanism depends on a metal center: nickel ions inhibit activity by displacing the active-site iron [#2], and iron availability supplied by lysosomal ferritinophagy limits its demethylase output during adipogenesis [#38]. Catalysis is rendered efficient by homodimerization, which juxtaposes two active sites to channel the monomethyl intermediate to the fully demethylated product [#18]. KDM3A operates in dynamic opposition to the GLP/G9a H3K9 methyltransferase, and this methylation–demethylation balance governs euchromatic H3K9 hypomethylation, pluripotency gene expression, and a developmental switch exemplified by Sry-dependent male sex determination, where loss of KDM3A causes male-to-female sex reversal in mice [#43, #44, #4]. Beyond chromatin, KDM3A demethylates non-histone substrates: it removes monomethylation from p53-K372 to suppress apoptosis [#15] and from PGC-1\\u03b1-K224, an oxygen-sensitive reaction whose loss under hypoxia restrains mitochondrial biogenesis [#25]. KDM3A is a hub for signal-responsive transcription, being transcriptionally induced by HIF-1\\u03b1 under hypoxia to drive glycolytic genes [#1, #3, #20], and post-translationally tuned by phosphorylation \\u2014 PKA at S265 downstream of \\u03b2-adrenergic signaling enables a demethylase-independent scaffold function that recruits SWI/SNF and PPAR\\u03b3 to drive chromatin looping in adipocyte thermogenesis [#11, #24], while ACK1 (Y1114) and JAK2 tyrosine phosphorylation enhance its coactivator output [#9, #23]. Protein abundance is set by STUB1-mediated degradation, antagonized by p300-dependent K421 acetylation that recruits BRD4, and by HUWE1-mediated noncanonical K918 ubiquitination [#30]. KDM3A also acts through demethylase-independent routes, scaffolding splicing factors HNRNPF and SRSF3 (via ARID1A/SWI/SNF) to control alternative splicing [#19, #31] and coordinating actin dynamics with intraflagellar transport to maintain cilia stability [#22]. Across many cancers KDM3A behaves as a pro-tumorigenic coactivator for receptor- and oncogene-driven programs including ER, AR, c-Myc, Wnt/\\u03b2-catenin, and Hippo/YAP-TEAD [#8, #12, #37, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established KDM3A as an H3K9me2 demethylase that activates transcription, answering whether this JmjC protein had a defined chromatin-modifying function with biological consequence.\",\n      \"evidence\": \"RNAi knockdown and ChIP at pluripotency gene promoters in mouse ES cells with differentiation readout\",\n      \"pmids\": [\"17938240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve substrate specificity between me1 and me2\", \"No structural basis for catalysis\", \"Genome-wide target scope unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed KDM3A downstream of hypoxia signaling by showing HIF-1\\u03b1 directly induces its expression, linking the demethylase to oxygen sensing.\",\n      \"evidence\": \"ChIP of HIF-1\\u03b1 at JMJD1A promoter HREs, HIF-1 siRNA epistasis, in vitro demethylase assay (replicated across two labs)\",\n      \"pmids\": [\"18984585\", \"18538129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which target genes KDM3A regulates under hypoxia\", \"Direct enzymatic role at hypoxic loci not yet shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the metal-dependent catalytic mechanism and a mode of inhibition by demonstrating nickel displaces active-site iron, explaining environmental modulation of activity.\",\n      \"evidence\": \"In vitro stoichiometric Ni/Fe demethylase assays, XAS structural validation, cell-based inhibition\",\n      \"pmids\": [\"20042601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of nickel exposure unaddressed\", \"Did not measure oxygen dependence of catalysis\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected HIF-1\\u03b1-induced KDM3A to glycolytic gene activation via direct demethylation and chromatin looping, establishing it as a functional hypoxia effector.\",\n      \"evidence\": \"ChIP-seq, 3C, and RNAi at the GLUT3 locus\",\n      \"pmids\": [\"22645302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of recruitment to specific loci not defined\", \"Whether looping requires demethylase activity unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated a developmental switch role by showing KDM3A controls Sry expression, with loss causing sex reversal \\u2014 establishing a non-redundant in vivo function.\",\n      \"evidence\": \"Jmjd1a knockout mice with sex-reversal phenotype and ChIP at the Sry locus\",\n      \"pmids\": [\"24009392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Opposing methyltransferase not yet identified\", \"Recruitment mechanism to Sry unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed the catalytic basis for efficient me2-to-me0 conversion through homodimerization-driven substrate channeling.\",\n      \"evidence\": \"In vitro demethylation kinetics with size-exclusion, native gel, and WT/inactive heterodimer analysis\",\n      \"pmids\": [\"24214985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of the dimer\", \"Whether dimerization is regulated in cells unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended KDM3A function to viral chromatin by showing it partners with KSHV LANA to keep viral promoters H3K9-hypomethylated, broadening its coactivator repertoire.\",\n      \"evidence\": \"Reciprocal Co-IP with purified proteins, ChIP-chip on KSHV episome, knockdown\",\n      \"pmids\": [\"23576503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-virus context\", \"Generalizability to host loci not addressed here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established KDM3A as a catalytically required coactivator of nuclear hormone receptor signaling (ER) and identified a tyrosine kinase (ACK1) input that boosts its activity, defining signal-to-chromatin coupling in cancer.\",\n      \"evidence\": \"ChIP, catalytic mutant rescue for ER target genes; in vitro ACK1 kinase assay mapping Y1114 with ChIP/inhibitor epistasis\",\n      \"pmids\": [\"25488809\", \"25148682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Y1114 phosphorylation enhances catalysis mechanistically unclear\", \"Reciprocal regulation of ACK1 not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Uncovered cytoplasmic and chaperone-dependent dimensions of KDM3A, showing Hsp90-client status and roles in spermatid cytoskeletal structures beyond chromatin.\",\n      \"evidence\": \"Two Kdm3a mouse models, EM, fractionation, Hsp90 inhibition, immunolocalization\",\n      \"pmids\": [\"24554764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cytoskeletal binding partners not defined here\", \"Separation of nuclear vs cytoplasmic contributions incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovered the demethylase-independent scaffold function: PKA-driven S265 phosphorylation recruits SWI/SNF and PPAR\\u03b3 to enable rapid chromatin looping, dissociating scaffold from enzymatic roles.\",\n      \"evidence\": \"PKA phosphorylation assay, Co-IP, ChIP, 3C, S265A mutant rescue in brown adipocytes\",\n      \"pmids\": [\"25948511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for phospho-dependent complex assembly unknown\", \"Generality beyond adipocytes not yet tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed KDM3A stabilizes c-Myc protein via a catalysis-independent interaction with HUWE1, in addition to activating c-Myc transcription, revealing dual oncogenic mechanisms.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, ChIP, catalytic mutant analysis\",\n      \"pmids\": [\"26279298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How KDM3A blocks HUWE1 catalysis not defined\", \"Whether this competes with HUWE1 acting on KDM3A itself unaddressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the first non-histone substrate, p53-K372me1, establishing KDM3A as a protein demethylase that suppresses apoptosis.\",\n      \"evidence\": \"In vitro demethylation of p53-K372me1 peptide, Co-IP, ChIP, RNAi\",\n      \"pmids\": [\"27270439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specificity determinants for non-histone substrates unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Expanded the oncogenic and mechanosensing repertoire, linking KDM3A levels and nuclear localization to ECM stiffness, anoikis (BNIP3/BNIP3L), and myeloma survival axes.\",\n      \"evidence\": \"Knockdown/localization on varying ECM, RNAi screen with ChIP at BNIP3/BNIP3L, HIF-1\\u03b1\\u2192KDM3A\\u2192MALAT1 epistasis, KLF2/IRF4 ChIP and in vivo models\",\n      \"pmids\": [\"27488962\", \"27472901\", \"29444873\", \"26728187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling mechanosignaling to KDM3A abundance/localization unresolved\", \"Context-dependence of pro- vs anti-survival roles not reconciled\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined demethylase-independent splicing control through HNRNPF recruitment to AR pre-mRNA, broadening KDM3A function into RNA processing.\",\n      \"evidence\": \"Co-IP, RIP, minigene reporter, siRNA in prostate cancer cells\",\n      \"pmids\": [\"29712835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether chromatin recruitment couples to splicing not shown\", \"Breadth of splicing targets undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established the actin/cilia axis, showing KDM3A controls cilia stability through both actin gene transcription and direct cytoskeletal binding gating IFT entry.\",\n      \"evidence\": \"KDM3A knockout mouse with cilia phenotype, cytoskeleton binding, IFT imaging, ARP2/3 inhibitor and actin manipulation rescue\",\n      \"pmids\": [\"28246120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the actin interaction undefined\", \"Relationship to ciliopathy disease unconfirmed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed broad coactivator partnerships with transcription factors (c-Jun/AP-1 with Brg1, Snail, ETV1, ER71) driving tumor and vascular phenotypes, many requiring demethylase activity.\",\n      \"evidence\": \"ChIP at AP-1/Snail promoters, in vivo tumor and vascular injury models, catalytic mutant analyses\",\n      \"pmids\": [\"28692045\", \"32019811\", \"28135625\", \"16619273\", \"28319067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of which transcription factor KDM3A partners with in a given context unknown\", \"Some early TF-interaction data assign a repressor role inconsistent with later coactivator findings\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved tissue-specific thermogenic logic, showing S265 phosphorylation drives demethylation-independent acute Ucp1 induction in BAT versus phosphorylation-plus-demethylation chronic induction in beige WAT via a PRDM16-PPAR\\u03b3 complex; also identified JAK2-STAT3 tyrosine-phospho coactivation.\",\n      \"evidence\": \"S265A and demethylase-mutant knock-in mice, Co-IP of PRDM16-PPAR\\u03b3 complex, 3C, ChIP; in vitro JAK2 kinase assay with Co-IP/ChIP\",\n      \"pmids\": [\"29674659\", \"30377265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site of JAK2 phosphorylation not mapped here\", \"Integration of multiple kinase inputs on KDM3A not unified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established KDM3A as an oxygen-sensitive non-histone demethylase of PGC-1\\u03b1-K224, linking its high oxygen KM to hypoxic control of mitochondrial biogenesis.\",\n      \"evidence\": \"Co-IP, in vitro PGC-1\\u03b1-K224me1 demethylation, oxygen-KM measurement, K224R mutant in cells and tumor xenografts\",\n      \"pmids\": [\"31629659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other metabolic regulators are non-histone substrates unknown\", \"In vivo oxygen-gradient relevance not directly measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped post-translational and post-transcriptional control of KDM3A abundance, identifying STUB1 degradation, p300-K421-acetylation/BRD4 stabilization, HUWE1-K918 ubiquitination, and PHF5A-driven splicing stabilization of KDM3A mRNA.\",\n      \"evidence\": \"Multiple Co-IPs, ubiquitination/acetylation site mapping, ChIP, clinical correlation; proteomics, splicing reporter, RNA-seq for PHF5A axis\",\n      \"pmids\": [\"32522824\", \"32238799\", \"31054974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy/crosstalk among competing PTMs on KDM3A unresolved\", \"Stimuli triggering each modification not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Broadened KDM3A's coactivator scope to Hippo/YAP-TEAD enhancers (p300 cooperation), condensin/heterochromatin during senescence, and pancreatic tumorigenesis via DCLK1.\",\n      \"evidence\": \"ChIP-seq with H3K9me2/H3K27ac, Co-IP with p300, Kdm3a KO mouse models, in vivo transformation/xenograft assays\",\n      \"pmids\": [\"30649550\", \"31704649\", \"31442435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p300 cooperation is general across all KDM3A enhancers unknown\", \"Direct vs indirect target distinction incomplete in several contexts\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the KDM3A/KDM3B paralog complex cooperating with OCT4/SOX2 and demethylase-independent splicing scaffolding with ARID1A/SRSF3, integrating enzymatic and non-enzymatic functions.\",\n      \"evidence\": \"IP-MS of KDM3A-KDM3B complex with ChIP-seq; Co-IP of KDM3A-ARID1A/SRSF3, RIP, S265 phosphorylation, catalytic mutant after DNA damage\",\n      \"pmids\": [\"34042215\", \"34321328\", \"32457453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the KDM3A/KDM3B complex undefined\", \"How DNA damage signals to S265 phosphorylation unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established iron supply via lysosomal ferritinophagy as a rate-limiting input to KDM3A demethylase activity during adipocyte differentiation, tying metabolic iron status to chromatin output.\",\n      \"evidence\": \"ChIP-seq, iron chelation/ferritinophagy inhibition, histone mass spectrometry, knockdown with differentiation readout\",\n      \"pmids\": [\"37158274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of iron limitation to other cell types untested\", \"Subcellular site of iron loading onto KDM3A unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated demethylase-specific, tissue-selective metabolic functions in vivo: demethylase activity drives Pgc1a/b enhancer activation and beiging in scWAT but is dispensable for acute BAT thermogenesis, with loss causing obesity and insulin resistance.\",\n      \"evidence\": \"Demethylase-activity mutant knock-in mice, ChIP at Pgc1a/b enhancers, \\u03b2-adrenergic stimulation, metabolic phenotyping\",\n      \"pmids\": [\"38544573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for tissue selectivity of demethylase requirement unresolved\", \"Human metabolic relevance not directly tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many regulatory inputs (kinase phosphorylations, competing ubiquitin/acetyl marks, dimerization, metal/oxygen status) are integrated to select between KDM3A's enzymatic and scaffold functions at a given locus remains unresolved, as does a high-resolution structural model of the full-length protein and its complexes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length structure or structural model of regulatory PTMs\", \"Rules governing target-locus selection across contexts unknown\", \"Quantitative crosstalk among competing PTMs not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2, 18, 25, 38]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [15, 25]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 11, 21, 28, 40]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 19, 31]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 43]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [22, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 40]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 22]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [22, 10]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 43, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 43, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 11, 21, 28]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 3, 20, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 44, 38, 39]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 17, 27, 37]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [19, 31, 26]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [15, 34]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [25, 38, 39]}\n    ],\n    \"complexes\": [\"KDM3A/KDM3B H3K9 demethylase complex\", \"SWI/SNF (with PPAR\\u03b3) scaffold complex\", \"PRDM16-PPAR\\u03b3-JMJD1A complex\"],\n    \"partners\": [\"KDM3B\", \"PPARG\", \"PRDM16\", \"HUWE1\", \"STUB1\", \"EP300\", \"HNRNPF\", \"ARID1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}