{"gene":"JMJD6","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2007,"finding":"JMJD6 is an iron- and 2-oxoglutarate-dependent dioxygenase (JmjC family) that demethylates histone H3 at arginine 2 (H3R2) and histone H4 at arginine 3 (H4R3) in both biochemical and cell-based assays.","method":"In vitro biochemical demethylase assay and cell-based assays with purified JMJD6","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay plus cell-based assay in a single rigorous study; however, later structural/biochemical studies challenged this activity, lowering confidence somewhat","pmids":["17947579"],"is_preprint":false},{"year":2009,"finding":"JMJD6 catalyzes Fe(II)- and 2-oxoglutarate-dependent lysyl-5-hydroxylation of the splicing factor U2AF65, and this activity modulates alternative RNA splicing of specific endogenous and reporter genes.","method":"Mass spectrometry identification of hydroxylated lysine on U2AF65; in vitro hydroxylase assay; splicing reporter assays in cells with JMJD6 knockdown/overexpression","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with MS validation, cell-based splicing assays, replicated by multiple independent groups","pmids":["19574390"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the JMJD6 catalytic domain in complex with Ni(II) (substituting Fe(II)) reveals a double-stranded beta-helical fold; mutational studies show how active-site geometry favors C-5 lysyl hydroxylation rather than N-epsilon demethylation.","method":"X-ray crystallography; active-site mutagenesis","journal":"Journal of Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation, published in two companion papers by same group (20684070, 20685276)","pmids":["20684070","20685276"],"is_preprint":false},{"year":2010,"finding":"JMJD6 binds efficiently to single-stranded RNA but not to single-stranded DNA, double-stranded RNA, or double-stranded DNA; the crystal structure reveals a novel substrate-binding groove and two positively charged surfaces with a stack of aromatic residues near the active center.","method":"X-ray crystallography; RNA/DNA binding assays; truncation analysis","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with direct binding assays for multiple nucleic acid types","pmids":["20679243"],"is_preprint":false},{"year":2010,"finding":"Jmjd6 is distributed throughout the nucleoplasm outside heterochromatic regions, localizes occasionally to nucleoli, is excluded from the nucleus during mitosis and reappears in telophase, and forms homo-multimers. Jmjd6 does NOT demethylate histone lysine residues H3K4, H3K9, H3K27, H3K36, or H4K20.","method":"Immunolocalization; Western blot; comparison of histone methylation states in wildtype vs. Jmjd6-knockout cells; overexpression of active and inactive forms","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (IHC, WB, KO comparison), single lab; negative result for histone lysine demethylation robustly supported","pmids":["21060799"],"is_preprint":false},{"year":2011,"finding":"JMJD6-catalyzed hydroxylation of RNA-splicing regulatory protein fragments produces 5S-hydroxylysine, a stereochemistry distinct from collagen lysyl hydroxylases (which produce 5R products), indicating a distinct subfamily of lysyl hydroxylases.","method":"Amino acid analysis; NMR stereochemical assignment of hydroxylysine products from in vitro JMJD6 reactions","journal":"ChemBioChem","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with NMR-based stereochemical validation","pmids":["22238144"],"is_preprint":false},{"year":2011,"finding":"Jmjd6 silencing impairs angiogenic functions of endothelial cells by altering splicing of VEGF-receptor 1 (Flt1), increasing levels of soluble Flt1 that inhibits angiogenesis. Jmjd6 physically interacts with splicing factor U2AF65 that binds Flt1 mRNA.","method":"siRNA knockdown; RT-PCR splicing assay; co-immunoprecipitation of Jmjd6 with U2AF65; rescue experiments with VEGF/PlGF or anti-sFlt1 antibodies","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, knockdown with specific phenotypic rescue, multiple orthogonal methods","pmids":["21300889"],"is_preprint":false},{"year":2012,"finding":"JMJD6 cannot demethylate histone arginine residues in vitro but does hydroxylate the histone H4 tail at lysine residues in a 2-OG- and Fe(II)-dependent manner. Homo-oligomerization of Jmjd6 requires its enzymatic (hydroxylase) activity and both N- and C-termini; Jmjd6 autodydroxylates its own N-terminus to form intermolecular covalent bonds mediating oligomerization.","method":"MALDI-TOF mass spectrometry in vitro enzymatic assay; mutational analysis of oligomerization domains","journal":"Journal of Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro assay with MS validation, mutagenesis; single lab, negative result for arginine demethylation","pmids":["22189873"],"is_preprint":false},{"year":2013,"finding":"JMJD6 hydroxylates multiple lysyl residues of histone H3, H4, H2A, and H2B tails in vitro and in vivo. 5-Hydroxylysine on histones inhibits N-acetylation and N-methylation by acetyltransferase and methyltransferase in vitro, suggesting cross-talk between histone modifications.","method":"In vitro hydroxylase assay; amino acid composition analysis of histones from JMJD6-knockout mouse embryos; JMJD6 overexpression in HEK293 cells; in vitro competition assays with acetyltransferase/methyltransferase","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro assay, KO mouse tissues, overexpression, multiple orthogonal methods in one study","pmids":["23303181"],"is_preprint":false},{"year":2013,"finding":"JMJD6 and BRD4 co-occupy a unique cohort of distal enhancers (anti-pause enhancers, A-PEs) and regulate promoter-proximal Pol II pause release. BRD4-dependent JMJD6 recruitment to A-PEs mediates erasure of H4R3me2(s), which is read by 7SK snRNA; JMJD6 also decaps/demethylates 7SK snRNA, releasing the 7SK/HEXIM inhibitory complex and activating P-TEFb.","method":"ChIP-seq; RNA-seq; co-IP of JMJD6 with BRD4 and P-TEFb; 7SK snRNA demethylation/decapping assay; long-range chromatin interaction analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, functional RNA assays, multiple orthogonal approaches in one study","pmids":["24360279"],"is_preprint":false},{"year":2013,"finding":"The polyserine (polyS) domain of Jmjd6 mediates its subnuclear localization; Jmjd6 lacking the polyS domain localizes to the nucleolus (fibrillar centre) and interacts with nucleolar proteins. Homo-oligomerization of Jmjd6 occurs in cells and the structure of oligomers changes without the polyS domain.","method":"Live-cell imaging; co-immunoprecipitation; F2H (fluorescent 2-hybrid) assay; deletion mutagenesis","journal":"Biochemical Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional domain deletions, Co-IP, and F2H assay; single lab","pmids":["23688307"],"is_preprint":false},{"year":2014,"finding":"JMJD6 physically associates with p53 and acts as an alpha-ketoglutarate- and Fe(II)-dependent lysyl hydroxylase to hydroxylate p53 primarily at lysine 382. This hydroxylation antagonizes p53 acetylation, promotes p53 association with its negative regulator MDMX, and represses p53 transcriptional activity.","method":"Co-immunoprecipitation; in vitro hydroxylase assay; mass spectrometry identification of hydroxylation site; p53 acetylation assays; MDMX co-IP; reporter assays; JMJD6 knockdown/overexpression with phenotypic readouts","journal":"PLoS Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution, MS site identification, multiple Co-IPs, functional transcription assays; single lab but multiple orthogonal methods","pmids":["24667498"],"is_preprint":false},{"year":2014,"finding":"Upon estrogenic stimulation, JMJD6 interacts with methylated estrogen receptor alpha (ERα) and acts as an arginine demethylase to demethylate ERα, regulating rapid extranuclear estrogenic responses.","method":"Co-immunoprecipitation; JMJD6 silencing combined with in vitro demethylation assay","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and demethylation assay, single lab, limited methodological breadth","pmids":["24498420"],"is_preprint":false},{"year":2014,"finding":"Jmjd6 interacts with multiple SR and SR-related proteins through their arginine-serine-rich (RS) domains, including U2AF65, Luc7L3, SRSF11, and Acinus S', but not the bona fide RS domain of SRSF1. Jmjd6 modifies constitutive splicing, binds RNA from a reporter plasmid, and co-localizes with nascent RNA.","method":"Co-immunoprecipitation; in vitro binding assay; splicing reporter assay; RNA binding assay; immunofluorescence co-localization with nascent RNA","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IP targets, splicing reporter, RNA binding, co-localization; single lab","pmids":["24914048"],"is_preprint":false},{"year":2015,"finding":"Jmjd6, acting as a lysyl hydroxylase for splicing regulatory proteins, is required for efficient splicing of intron 2 of the Aire gene in medullary thymic epithelial cells; Jmjd6 deficiency results in retention of Aire intron 2, markedly reduced mature Aire protein, and spontaneous multi-organ autoimmunity in mice.","method":"Jmjd6 conditional knockout mouse; RT-PCR splicing analysis; Western blot of Aire protein; phenotypic analysis of autoimmunity","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse model with specific molecular (splicing) and phenotypic (autoimmunity) readouts, multiple methods","pmids":["26531897"],"is_preprint":false},{"year":2015,"finding":"In Xenopus embryogenesis, Jmjd6 interacts with Tcf7l1 (Tcf3), competing with Groucho corepressor for the same binding region on Tcf7l1 to derepress Wnt target genes. Loss of Jmjd6 function causes anteroposterior body axis defects.","method":"Co-immunoprecipitation; reporter gene assays; morpholino loss-of-function in Xenopus embryos; rescue experiments","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, reporter assays, loss-of-function with phenotypic rescue; single lab","pmids":["26157142"],"is_preprint":false},{"year":2017,"finding":"JMJD6 is a novel stress granule (SG) component that interacts with G3BP1 complexes. JMJD6 promotes G3BP1 arginine demethylation (monomethylation and asymmetric dimethylation at three Arg residues) and thereby promotes SG formation; knockdown of JMJD6 represses SG formation, and rescue requires catalytically active but not mutant JMJD6.","method":"Co-immunoprecipitation; mass spectrometry; JMJD6 knockdown; rescue with catalytically active vs. inactive JMJD6; immunofluorescence of SG markers","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, MS, KD with phenotypic rescue using active/inactive mutants; single lab","pmids":["28972166"],"is_preprint":false},{"year":2017,"finding":"JMJD6 and BRD4 interact via the BRD4 extraterminal (ET) domain; NMR reveals a JMJD6 peptide (Lys84–Asn96) adopts an alpha-helix when bound to the ET domain through hydrophobic and electrostatic interactions. Single-stranded RNA binding by JMJD6 induces a conformational change that likely promotes this ET-domain interaction.","method":"NMR structure determination; mutagenesis; RNA binding assays","journal":"Scientific Reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with mutagenesis and functional RNA binding validation","pmids":["29176719"],"is_preprint":false},{"year":2017,"finding":"JMJD6 forms protein complexes with N-Myc and BRD4 in neuroblastoma cells and is important for transcription of E2F2, N-Myc, and c-Myc. JMJD6 gene is associated with transcriptional super-enhancers.","method":"Co-immunoprecipitation; ChIP-seq; gene knockdown with transcriptional readouts","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq, KD with transcriptional phenotype; single lab","pmids":["31346162"],"is_preprint":false},{"year":2017,"finding":"JMJD6 regulates the alternative splicing of PAK1, a MAPK pathway component, in melanoma cells; knockdown affects a panel of alternative splicing events as measured by RNA-seq.","method":"RNA-seq splicing analysis; JMJD6 knockdown; functional assays in melanoma cell lines","journal":"Molecular Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNA-seq with KD, specific splicing target identified but molecular mechanism not fully established; single lab","pmids":["29187213"],"is_preprint":false},{"year":2017,"finding":"JMJD6 co-regulates alternative splicing events together with U2AF65; JMJD6 enzymatic activity (lysine hydroxylation of U2AF65) is required for a subset of co-regulated splicing events but not all, indicating both enzymatic activity-dependent and -independent mechanisms of splicing regulation. Validated in jmjd6 knockout mice.","method":"RASL-Seq splicing profiling; JMJD6/U2AF65 knockdown; JMJD6 knockout mice; co-IP; mutagenesis of catalytic residues","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo KO mouse validation, RASL-Seq, Co-IP, mutagenesis; multiple orthogonal methods","pmids":["27899633"],"is_preprint":false},{"year":2018,"finding":"JMJD6 is required for ERα-bound active enhancer activation and RNA Pol II recruitment: JMJD6 interacts with MED12 in the mediator complex, is necessary for MED12 interaction with CARM1, and CARM1 methylates MED12 at multiple arginine sites to regulate chromatin binding, thereby enabling transcriptional pause release of estrogen target genes.","method":"Co-immunoprecipitation; ChIP-seq; enhancer RNA measurement; JMJD6 knockdown; CARM1 methylation assays; cell proliferation and xenograft assays","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, functional methylation assays, multiple orthogonal methods; single lab","pmids":["29628309"],"is_preprint":false},{"year":2018,"finding":"JMJD6 has intrinsic tyrosine kinase activity and phosphorylates histone H2A.X at tyrosine 39 (H2A.XY39ph), using ATP and GTP as phosphate donors; high JMJD6 promotes autophagy in triple-negative breast cancer cells via regulation of autophagy-related gene expression through the H2A.XY39ph axis.","method":"In vitro kinase assay; mass spectrometry identification of phosphorylation site; JMJD6 knockdown with autophagy readouts; cell growth assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay with MS site identification, but tyrosine kinase activity is a novel/controversial claim reported by a single lab","pmids":["30185813"],"is_preprint":false},{"year":2019,"finding":"Biochemical (MS- and NMR-based kinetic assays) and structural (crystallographic) analyses with purified JMJD6 support assignment as a lysyl hydroxylase; the study did NOT observe N-methyl arginyl N-demethylation activity with purified JMJD6, calling into question its arginine demethylase activity.","method":"MS-based kinetic assay; NMR assay; X-ray crystallography; substrate fragment screening","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure, MS and NMR kinetics, multiple substrates tested; rigorous biochemical study by Schofield group","pmids":["31147442"],"is_preprint":false},{"year":2019,"finding":"JMJD6 homo-oligomerization does not require catalytic activity; the AT hook-like domain (mediating DNA/RNA interaction) is required for JMJD6 chromatin binding and function in adipogenic differentiation, whereas catalytic activity and the polyserine and sumoylation domains are dispensable.","method":"Domain mutagenesis; oligomerization assays; chromatin immunoprecipitation; adipogenic differentiation assays in JMJD6 mutant-rescued cells","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis, ChIP, differentiation assay; single lab, multiple methods","pmids":["31430278"],"is_preprint":false},{"year":2020,"finding":"JMJD6 is recruited to DNA double-strand breaks (DSBs), controls spreading of histone ubiquitination and accumulation of repair proteins around DSBs, and promotes transcriptional silencing. Independently of catalytic activity, JMJD6 interacts with SIRT1 and recruits it to chromatin to downregulate H4K16ac around DSBs, modulating NHEJ and HR efficiency.","method":"Microirradiation with live imaging; co-immunoprecipitation of JMJD6 with SIRT1; ChIP for H4K16ac; NHEJ/HR reporter assays; catalytic mutant rescue","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequences, reciprocal Co-IP, ChIP, catalytic mutant analysis; multiple orthogonal methods","pmids":["31358914"],"is_preprint":false},{"year":2020,"finding":"JMJD6 cleaves methylphosphate capping enzyme (MePCE), a core component of the 7SK snRNP complex, via a novel proteolytic activity. This cleavage releases P-TEFb from the 7SK snRNP complex; downstream effect is phosphorylation of Pol II CTD. Crystal structure of JMJD6 bound to methyl-arginine was determined.","method":"Crystal structure of JMJD6 bound to methyl-arginine; in vitro and in vivo MePCE cleavage assays; binding assays; Jmjd6 KO and overexpression with Pol II CTD phosphorylation readout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure, in vitro reconstitution of cleavage, in vivo validation with KO; multiple orthogonal methods","pmids":["32048991"],"is_preprint":false},{"year":2020,"finding":"JMJD6 is rapidly recruited to nucleolar DNA damage sites and is required for relocation of rDNA into nucleolar caps, rDNA stability, and maintaining rDNA repeat integrity after irradiation. JMJD6 interacts with nucleolar protein Treacle and modulates its interaction with NBS1.","method":"Live-cell imaging after micro-irradiation; mass spectrometry interactome; JMJD6-deficient cells; rDNA repeat analysis by Southern blot/FISH","journal":"PLoS Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, MS-identified Treacle interaction, KO phenotype; single lab","pmids":["32598339"],"is_preprint":false},{"year":2021,"finding":"JMJD6 knockdown reduces recruitment of U2AF65 to AR pre-mRNA and reduces AR-V7 splice variant levels; mutagenesis indicates JMJD6 catalytic activity is required for AR-V7 generation. The JMJD6/U2AF65 axis thus controls AR-V7 splicing in prostate cancer.","method":"siRNA knockdown; mutagenesis of catalytic residues; RIP (RNA immunoprecipitation) of U2AF65 on AR pre-mRNA; RT-PCR for AR-V7; prostate cancer cell growth assays","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, mutagenesis, KD with specific splicing readout; single lab","pmids":["33822745"],"is_preprint":false},{"year":2021,"finding":"JMJD6 negatively regulates antiviral innate immune signaling by recruiting the ubiquitin E3 ligase RNF5 to promote K48-linked ubiquitination and degradation of activated IRF3, thereby reducing type-I interferon production.","method":"Co-immunoprecipitation; ubiquitination assay; proteomic screen; JMJD6 KO via piggyBac transposon in mice; viral replication assays","journal":"PLoS Pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo KO mouse validation; single lab, multiple methods","pmids":["33684176"],"is_preprint":false},{"year":2021,"finding":"JMJD6 is essential for short- and long-term maintenance of the hematopoietic stem cell (HSC) pool; Jmjd6-deficient HSCs fail to expand after injury and lose self-renewal upon serial transplantation. JMJD6 represses mitochondrial OXPHOS, protein synthesis, p53 stabilization, and mTORC1 signaling in HSCs; ROS elevation from OXPHOS causally mediates HSC failure.","method":"Hematopoietic-specific conditional Jmjd6 KO mouse; serial transplantation; metabolic assays (mitochondrial respiration, ROS); N-acetyl-L-cysteine rescue","journal":"Blood Advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse, serial transplantation, metabolic phenotyping, antioxidant rescue; multiple orthogonal methods","pmids":["33560400"],"is_preprint":false},{"year":2022,"finding":"JMJD6 catalyzes lysine hydroxylation at 150 sites on 48 protein substrates identified by mass spectrometry, predominantly within unstructured lysine-rich regions. BRD4 is hydroxylated on 19 lysine sites. Nearly all identified substrates are associated with membraneless organelle formation, suggesting JMJD6 may regulate liquid-liquid phase separation.","method":"Mass spectrometry with lysine propionyl derivatization; nontryptic proteolysis; JMJD6-depleted vs. control cell comparison","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic MS-based substrate identification with appropriate controls; single lab but comprehensive substrate profiling","pmids":["35930668"],"is_preprint":false},{"year":2022,"finding":"JMJD6 interacts with RBM39 and co-occupies the DGAT1 gene promoter with H3K4me3 to induce DGAT1 expression, thereby promoting lipid droplet formation and ccRCC tumorigenesis.","method":"siRNA screen; ChIP-seq; RNA-seq; co-immunoprecipitation of JMJD6 with RBM39; JMJD6 KD with lipid droplet and tumor growth readouts","journal":"Molecular Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq, RNA-seq, in vivo KD model; single lab","pmids":["35764091"],"is_preprint":false},{"year":2022,"finding":"JMJD6 demethylates HURP at R122, promoting Golgi apparatus repositioning (GR) and directional cell migration via a NF-κB-induced centrosome repositioning and subsequent Cdc42 upregulation cascade; PRMT5 methylation of HURP R122 opposes this.","method":"Co-immunoprecipitation; HURP methylation assays; JMJD6 KD; Golgi repositioning assays; cell migration assays; mechanistic epistasis using methylation-mimic/deficiency mutants","journal":"Journal of Cellular Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional mutants, Golgi repositioning assay; single lab, multiple methods","pmids":["36250981"],"is_preprint":false},{"year":2022,"finding":"JMJD6 regulates splicing of its own pre-mRNA to produce isoforms (JMJD6-2 and JMJD6-Ex5) with distinct C-terminal sequences and different interaction partners; JMJD6-2 interacts with SR-like splicing factors (RS-domain proteins) while JMJD6-Ex5 interacts with SMN complex, hnRNPs, UBF, and FCP1. JMJD6-2 but not JMJD6-Ex5 inhibits exon inclusion in a splicing reporter.","method":"Immunoprecipitation followed by LC-MS/MS; HIV-based splicing reporter assay; siRNA knockdown; RT-PCR isoform analysis","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome, functional splicing assay, KD; single lab","pmids":["32927736"],"is_preprint":false},{"year":2023,"finding":"JMJD6 interacts with NF-κB p65 in the cytoplasm and demethylates p65 at arginine 149 (R149), inhibiting nuclear translocation of p65 and thereby suppressing NF-κB signaling and protecting against pathological cardiac hypertrophy.","method":"Co-immunoprecipitation of JMJD6 with p65; in vitro/in vivo demethylation assays; cardiac-specific JMJD6 overexpression in rats; sgRNA-mediated JMJD6 depletion; echocardiography; hypertrophic gene expression assays","journal":"Acta Pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, demethylation assay, in vivo overexpression/depletion with functional cardiac readout; single lab","pmids":["37186122"],"is_preprint":false},{"year":2024,"finding":"JMJD6 acts as a hub connecting pre-mRNA splicing and glutamine metabolism in MYC-driven neuroblastoma: it physically interacts with RNA-binding proteins involved in splicing and protein homeostasis, and controls alternative splicing of glutaminase (GLS) isoforms KGA and GAC (rate-limiting enzymes of glutaminolysis). JMJD6 also complexes with RBM39, linking it to sensitivity to the splicing inhibitor indisulam.","method":"Co-immunoprecipitation; RNA-seq/splicing analysis; metabolic assays; cell transformation assays; indisulam treatment with JMJD6-dependent readout","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, splicing analysis, metabolic assays; single lab, multiple methods","pmids":["38488852"],"is_preprint":false},{"year":2024,"finding":"HSF1 directly binds JMJD6 gene and promotes its transcription; JMJD6 in turn reduces HSP70 R469 monomethylation to disrupt HSP70-HSF1 repressive complexes, enabling enhanced HSF1 activation in a positive feedback circuit mediating cellular adaptation to proteotoxic stress.","method":"Genome-wide RNAi screen with HSR reporter; ChIP assay for HSF1 at JMJD6 locus; JMJD6-mediated HSP70 demethylation assay; co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen, ChIP, demethylation assay, Co-IP; single lab","pmids":["38985769"],"is_preprint":false},{"year":2025,"finding":"SPOP mutants impair proteasomal degradation of JMJD6; elevated JMJD6 and ATF4 coordinate enhancer-promoter loop interactions to stimulate glutathione biosynthesis pathway genes (SLC7A11, GCLM, ME1). JMJD6 recruits mediator subunits (Med1/Med14) to assemble de novo enhancers at these loci, conferring ferroptosis resistance independently of androgen receptor.","method":"Co-immunoprecipitation; ChIP-seq; enhancer-promoter loop analysis; JMJD6 depletion; preclinical tumor models with ferroptosis inducers","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, Co-IP, functional ferroptosis assays, in vivo models; single lab","pmids":["39903850"],"is_preprint":false},{"year":2025,"finding":"JMJD6 is acetylated at lysine 375 by the acetyltransferase PCAF; K375 acetylation weakens JMJD6 arginine demethylase activity, enhances METTL14 expression, increases m6A modification of SLC3A2, and thereby promotes ferroptosis sensitivity in lung cancer cells.","method":"Co-immunoprecipitation; GST pulldown; in vitro acetylation assay; ChIP; MeRIP (m6A sequencing); functional ferroptosis assays; JMJD6 overexpression/knockdown","journal":"Journal of Translational Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, GST pulldown, in vitro assay, ChIP, MeRIP; single lab, multiple orthogonal methods","pmids":["40011892"],"is_preprint":false},{"year":2017,"finding":"JMJD6 suppresses Myc-induced apoptosis through inhibition of p19ARF mRNA and protein, leading to reduced p53 levels; JMJD6 binds the p19ARF promoter and exerts its inhibitory function through demethylation of H4R3me2a at this promoter.","method":"Chromatin immunoprecipitation at p19ARF promoter; JMJD6 overexpression/knockdown with p19ARF/p53 readouts; cell viability assays under stress; xenograft tumor assays","journal":"Clinical Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, functional assays, in vivo xenograft; single lab","pmids":["27081402"],"is_preprint":false},{"year":2009,"finding":"Endogenous Jmjd6 is expressed at the cell surface of immature monocyte-like THP-1 cells activated with PMA and translocates to the nucleus upon macrophage differentiation; antibody blockade of surface Jmjd6 suppresses phagocytosis of dead cells in immature macrophages.","method":"Immunocytochemistry; antibody blocking of endogenous surface Jmjd6; phagocytosis assay; time-course subcellular fractionation","journal":"Journal of Cellular Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization with functional consequence (antibody blockade), single lab, single cell type","pmids":["19492415"],"is_preprint":false},{"year":2017,"finding":"JMJD6 demethylates STAT1 arginine methylation, suppressing IFNα-induced interferon-stimulated gene (ISG) activation; overexpression of JMJD6 suppressed STAT1 methylation and ISG activation, while JMJD6 silencing enhanced both.","method":"JMJD6 overexpression/knockdown; STAT1 methylation assay; ISG expression measurement; HCV RNA quantification; in vivo mouse model","journal":"Cellular and Molecular Gastroenterology and Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss of function with methylation and ISG readouts, in vivo mouse validation; single lab","pmids":["29693039"],"is_preprint":false},{"year":2017,"finding":"JMJD6 binds to the HOTAIR promoter region (−123 to −103 bp) and induces HOTAIR transcription; a catalytically dead JMJD6 mutant (H187A) can bind the HOTAIR promoter but fails to activate transcription, demonstrating enzymatic activity-dependent transcriptional regulation.","method":"ChIP; EMSA; deletion constructs of HOTAIR promoter; luciferase reporter; JMJD6 overexpression/siRNA in multiple cell lines; catalytic mutant analysis","journal":"Biochemical Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, EMSA, reporter assay with catalytic mutant; single lab","pmids":["29229759"],"is_preprint":false},{"year":2020,"finding":"Fibronectin is a novel substrate of JMJD6-mediated lysyl hydroxylation; JMJD6-catalyzed hydroxylation of fibronectin precedes its glycosylation, deposition, and degradation in placental mesenchymal cells.","method":"MALDI-TOF mass spectrometry identification of fibronectin as JMJD6 substrate; JMJD6 knockdown recapitulating fibronectin accumulation phenotype; iron rescue (Hinokitiol) experiments","journal":"Frontiers in Cell and Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — MS substrate identification, KD recapitulation, iron rescue; single lab, novel substrate","pmids":["34055782"],"is_preprint":false}],"current_model":"JMJD6 is a nuclear, iron(II)- and 2-oxoglutarate-dependent dioxygenase that primarily functions as a lysyl hydroxylase, catalyzing C-5 hydroxylation of lysine residues in unstructured regions of diverse substrates including U2AF65, other SR/RS-domain splicing factors, histones H2A/B/H3/H4, p53, fibronectin, and BRD4 (among ~48 identified substrates); it also possesses arginine demethylase activity toward substrates including G3BP1, ERα, STAT1, HURP, HSP70, and NF-κB p65 (though its arginine demethylase activity toward purified substrates in vitro remains contested); through these activities it regulates pre-mRNA alternative splicing (via hydroxylation of U2AF65 and interaction with multiple SR proteins), promotes RNA Pol II promoter-proximal pause release (by demethylating H4R3me2s at anti-pause enhancers, decapping 7SK snRNA, and proteolytically cleaving MePCE to release P-TEFb), modulates chromatin architecture around DNA double-strand breaks via SIRT1 recruitment, and participates in stress granule assembly, hematopoietic stem cell maintenance, and innate immune regulation."},"narrative":{"mechanistic_narrative":"JMJD6 is a nuclear Fe(II)- and 2-oxoglutarate-dependent dioxygenase of the JmjC family that couples post-translational modification of unstructured protein regions to the control of RNA processing and transcription [PMID:17947579, PMID:19574390, PMID:35930668]. Its best-defined catalytic activity is C-5 lysyl hydroxylation, established by mass-spectrometric identification of hydroxylated lysines on the splicing factor U2AF65 and corroborated by crystallographic analysis showing an active-site geometry that favors lysyl hydroxylation, producing a distinct 5S-hydroxylysine stereochemistry [PMID:19574390, PMID:20684070, PMID:20685276, PMID:22238144]; rigorous purified-enzyme kinetic and structural studies reassign JMJD6 as a lysyl hydroxylase and fail to detect arginyl demethylation in vitro [PMID:31147442]. Systematic substrate profiling identifies ~150 hydroxylation sites on 48 substrates, concentrated in lysine-rich disordered regions of proteins associated with membraneless organelles, including extensive hydroxylation of BRD4 [PMID:35930668], and histone tails (H2A, H2B, H3, H4) where 5-hydroxylysine antagonizes acetylation and methylation [PMID:23303181]. Through these activities JMJD6 governs alternative pre-mRNA splicing: it physically associates with U2AF65 and additional SR/RS-domain splicing factors and co-regulates splicing through both catalysis-dependent and -independent mechanisms, controlling specific transcripts including Flt1, Aire, AR-V7, and glutaminase isoforms [PMID:21300889, PMID:24914048, PMID:27899633, PMID:26531897, PMID:33822745, PMID:38488852]. JMJD6 is also a central regulator of RNA Pol II promoter-proximal pause release: recruited by BRD4 to anti-pause enhancers via the BRD4 ET domain, it acts on H4R3me2s and on 7SK snRNA and proteolytically cleaves the 7SK snRNP component MePCE to liberate active P-TEFb [PMID:24360279, PMID:29176719, PMID:32048991]. Beyond transcription elongation, JMJD6 modulates the DNA damage response by recruiting SIRT1 to double-strand breaks independently of its catalytic activity and by maintaining rDNA repeat integrity through interaction with Treacle [PMID:31358914, PMID:32598339], modifies p53 activity through K382 hydroxylation that promotes MDMX binding [PMID:24667498], and contributes to stress granule assembly, hematopoietic stem cell maintenance, and innate immune regulation [PMID:28972166, PMID:33560400, PMID:33684176]. Mouse Jmjd6 deficiency causes intron-retention of Aire and spontaneous multi-organ autoimmunity, directly linking its splicing function to immune tolerance [PMID:26531897]. A reported tyrosine kinase activity toward H2A.X Y39 and an arginine demethylase activity toward several substrates remain contested in light of the negative purified-enzyme results [PMID:30185813, PMID:31147442].","teleology":[{"year":2007,"claim":"Established JMJD6 as a JmjC-family Fe(II)/2-OG dioxygenase and proposed its first molecular activity, addressing what enzymatic class it belongs to.","evidence":"In vitro and cell-based histone arginine demethylase assays with purified JMJD6","pmids":["17947579"],"confidence":"High","gaps":["Arginine demethylase activity later not reproduced with purified enzyme","No structural basis provided for the assigned activity"]},{"year":2009,"claim":"Reassigned JMJD6's primary catalytic output to lysyl hydroxylation by identifying U2AF65 as a hydroxylation substrate, linking the enzyme to RNA splicing control.","evidence":"MS identification of hydroxylysine on U2AF65, in vitro hydroxylase assay, and cellular splicing reporters","pmids":["19574390"],"confidence":"High","gaps":["Did not resolve which endogenous splicing programs depend on hydroxylation","Relationship to the earlier demethylase claim unresolved"]},{"year":2010,"claim":"Defined the structural and biochemical basis for substrate selection, showing active-site geometry favors C-5 lysyl hydroxylation and that JMJD6 binds single-stranded RNA, and located it in the nucleoplasm.","evidence":"X-ray crystallography with Ni(II) substitution, mutagenesis, nucleic-acid binding assays, and immunolocalization with KO comparison","pmids":["20684070","20685276","20679243","21060799"],"confidence":"High","gaps":["Functional role of ssRNA binding not yet established","Did not reconcile structure with reported demethylase activity"]},{"year":2011,"claim":"Confirmed a distinct lysyl hydroxylase subfamily by stereochemical analysis and connected JMJD6 splicing function to angiogenesis through Flt1.","evidence":"NMR stereochemical assignment of 5S-hydroxylysine products and siRNA knockdown with reciprocal U2AF65 Co-IP and splicing rescue in endothelial cells","pmids":["22238144","21300889"],"confidence":"High","gaps":["Whether U2AF65 hydroxylation directly drives Flt1 splicing not formally separated from binding","In vivo relevance not tested at this stage"]},{"year":2012,"claim":"Demonstrated histone H4 tail lysyl hydroxylation and that catalysis-dependent autohydroxylation drives homo-oligomerization, clarifying the enzyme's self-assembly.","evidence":"MALDI-TOF in vitro hydroxylase assays and oligomerization-domain mutagenesis","pmids":["22189873"],"confidence":"Medium","gaps":["Negative arginine demethylation result from single lab","Functional significance of oligomerization in cells not established here"]},{"year":2013,"claim":"Connected JMJD6 to histone modification cross-talk and to RNA Pol II pause release, establishing its central transcription-elongation role.","evidence":"In vitro hydroxylase and competition assays plus ChIP-seq, RNA-seq, BRD4/P-TEFb Co-IP, and 7SK snRNA assays; subnuclear domain mapping by F2H and deletion","pmids":["23303181","24360279","23688307"],"confidence":"High","gaps":["Direct enzymatic mechanism of 7SK 'decapping/demethylation' not fully defined","PolyS-dependent localization role in transcription not tested"]},{"year":2014,"claim":"Expanded the substrate and partner repertoire to p53, ERα, and SR/SR-related splicing factors, broadening JMJD6 into transcription and signaling control.","evidence":"Co-IP, in vitro hydroxylase/demethylation assays, MS site mapping, and splicing/reporter assays","pmids":["24667498","24498420","24914048"],"confidence":"High","gaps":["ERα demethylation rests on limited methodological breadth","Whether RS-domain binding requires catalysis not resolved"]},{"year":2015,"claim":"Provided in vivo validation that JMJD6 splicing function controls immune tolerance (Aire) and developmental patterning (Wnt/Tcf7l1).","evidence":"Conditional and morpholino loss-of-function in mouse and Xenopus with splicing, protein, and phenotypic readouts plus Co-IP and rescue","pmids":["26531897","26157142"],"confidence":"High","gaps":["Tcf7l1 derepression mechanism not tied to a catalytic activity","Generality of intron-retention phenotype to other transcripts unclear"]},{"year":2016,"claim":"Linked JMJD6 to oncogenic Myc/p53 regulation via promoter-level histone arginine modification.","evidence":"ChIP at the p19ARF promoter, gain/loss-of-function with p53 readouts, and xenografts","pmids":["27081402"],"confidence":"Medium","gaps":["H4R3me2a demethylation activity contested by purified-enzyme studies","Single lab"]},{"year":2017,"claim":"Resolved how JMJD6 is recruited to chromatin and broadened its roles into stress granules, super-enhancer transcription, and innate immune/interferon control.","evidence":"NMR structure of the JMJD6-BRD4 ET-domain interface; Co-IP/MS, ChIP-seq, knockdown with phenotypic rescue across stress-granule, neuroblastoma, melanoma, and STAT1 systems","pmids":["29176719","28972166","31346162","29187213","29693039","29229759","19492415"],"confidence":"High","gaps":["G3BP1/STAT1 demethylation relies on single-lab assays contested in vitro","Cell-surface localization function reported in only one cell type"]},{"year":2018,"claim":"Defined a Mediator-coupled enhancer-activation mechanism and reported a controversial intrinsic tyrosine kinase activity.","evidence":"MED12/CARM1 Co-IP, ChIP-seq, eRNA and xenograft assays; in vitro kinase assay with MS site mapping for H2A.X Y39","pmids":["29628309","30185813"],"confidence":"Medium","gaps":["Tyrosine kinase activity is a novel single-lab claim not independently confirmed","Mechanism linking MED12 methylation to pause release incompletely defined"]},{"year":2019,"claim":"Sharpened the activity debate and dissected catalysis-dependent versus -independent functions via domain mapping.","evidence":"MS/NMR kinetics and crystallography on purified enzyme (no demethylation observed); systematic domain mutagenesis with ChIP and adipogenic differentiation","pmids":["31147442","31430278"],"confidence":"High","gaps":["Reconciliation of in vitro-negative demethylation with cellular demethylation reports unresolved","AT-hook-mediated chromatin binding mechanism not structurally defined"]},{"year":2020,"claim":"Established catalysis-independent and proteolytic functions of JMJD6 in genome maintenance and elongation control.","evidence":"Microirradiation/live imaging with SIRT1 Co-IP and H4K16ac ChIP; rDNA integrity analyses with Treacle interactome; crystal structure plus in vitro/in vivo MePCE cleavage assays","pmids":["31358914","32598339","32048991"],"confidence":"High","gaps":["Catalytic basis of MePCE proteolysis within a dioxygenase fold not mechanistically explained","How JMJD6 discriminates DSB versus nucleolar recruitment unclear"]},{"year":2021,"claim":"Demonstrated physiological roles in stem-cell maintenance, oncogenic splicing, and antiviral signaling, integrating JMJD6 into metabolism and immunity.","evidence":"Conditional KO mice with serial transplantation and metabolic/ROS rescue; RIP/mutagenesis for AR-V7 splicing; Co-IP/ubiquitination and KO mice for IRF3-RNF5 axis","pmids":["33560400","33822745","33684176"],"confidence":"High","gaps":["Molecular target through which JMJD6 represses OXPHOS in HSCs not identified","Whether IRF3 control requires catalytic activity not established"]},{"year":2022,"claim":"Provided a global substrate map implicating JMJD6 in phase separation and added isoform-, lipid-, and migration-specific functions.","evidence":"MS substrate profiling (150 sites/48 substrates); IP-MS isoform interactome with splicing reporters; RBM39 Co-IP with ChIP-seq/lipid-droplet assays; HURP demethylation and Golgi-repositioning assays","pmids":["35930668","32927736","35764091","36250981"],"confidence":"High","gaps":["Direct demonstration that hydroxylation alters phase separation not provided","HURP R122 demethylation depends on contested demethylase activity"]},{"year":2024,"claim":"Positioned JMJD6 as a hub coupling splicing to metabolism and proteostasis in cancer and stress adaptation.","evidence":"Co-IP, RNA-seq/splicing and metabolic assays for GLS/RBM39 in neuroblastoma; RNAi screen, HSF1 ChIP, and HSP70 demethylation assays","pmids":["38488852","38985769"],"confidence":"Medium","gaps":["HSP70 R469 demethylation relies on contested activity","Direct enzymatic versus scaffolding contribution to GLS splicing not separated"]},{"year":2025,"claim":"Linked JMJD6 stability and modification to enhancer remodeling and ferroptosis regulation in cancer.","evidence":"Co-IP, ChIP-seq, enhancer-promoter loop analysis with SPOP/ATF4; PCAF acetylation, GST pulldown, MeRIP, and ferroptosis assays","pmids":["39903850","40011892"],"confidence":"Medium","gaps":["Whether K375 acetylation modulates hydroxylase versus demethylase function unclear","Mediator recruitment mechanism for de novo enhancers not structurally defined"]},{"year":null,"claim":"The central unresolved question is reconciling JMJD6's robust purified-enzyme lysyl hydroxylase and MePCE-cleavage activities with the numerous cellular arginine-demethylation and tyrosine-kinase claims that purified-enzyme assays have not reproduced.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying structural model explains hydroxylase, proteolytic, and putative demethylase/kinase activities in one fold","Which catalytic activity underlies each in-cell phenotype is largely undetermined","Substrate-recruitment specificity across chromatin, splicing, and damage sites unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[1,2,5,8,23,31]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[26]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,9,17]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,11,31,26]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4,10,27]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,41]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,6,13,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,21,26,38]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[25,27]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[8,9,25]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,29,42]}],"complexes":["7SK snRNP","stress granule"],"partners":["U2AF65","BRD4","P53","SIRT1","G3BP1","MED12","RBM39","MEPCE"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6NYC1","full_name":"Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6","aliases":["Histone arginine demethylase JMJD6","JmjC domain-containing protein 6","Jumonji domain-containing protein 6","Lysyl-hydroxylase JMJD6","Peptide-lysine 5-dioxygenase JMJD6","Phosphatidylserine receptor","Protein PTDSR"],"length_aa":403,"mass_kda":46.5,"function":"Dioxygenase that can both act as a arginine demethylase and a lysyl-hydroxylase (PubMed:17947579, PubMed:20684070, PubMed:21060799, PubMed:22189873, PubMed:24498420). Acts as a lysyl-hydroxylase that catalyzes 5-hydroxylation on specific lysine residues of target proteins such as U2AF2/U2AF65 and LUC7L2. Regulates RNA splicing by mediating 5-hydroxylation of U2AF2/U2AF65, affecting the pre-mRNA splicing activity of U2AF2/U2AF65 (PubMed:19574390). Hydroxylates its own N-terminus, which is required for homooligomerization (PubMed:22189873). Plays a role in the regulation of nucleolar liquid-liquid phase separation (LLPS) by post-translationally modifying LIAT1 at its lysine-rich domain which inhibits LIAT1 nucleolar targeting (By similarity). In addition to peptidyl-lysine 5-dioxygenase activity, may act as an RNA hydroxylase, as suggested by its ability to bind single strand RNA (PubMed:20679243, PubMed:29176719). Also acts as an arginine demethylase which preferentially demethylates asymmetric dimethylation (PubMed:17947579, PubMed:24360279, PubMed:24498420). Demethylates histone H3 at 'Arg-2' (H3R2me) and histone H4 at 'Arg-3' (H4R3me), including mono-, symmetric di- and asymmetric dimethylated forms, thereby playing a role in histone code (PubMed:17947579, PubMed:24360279). However, histone arginine demethylation may not constitute the primary activity in vivo (PubMed:17947579, PubMed:21060799, PubMed:22189873). In collaboration with BRD4, interacts with the positive transcription elongation factor b (P-TEFb) complex in its active form to regulate polymerase II promoter-proximal pause release for transcriptional activation of a large cohort of genes. On distal enhancers, so called anti-pause enhancers, demethylates both histone H4R3me2 and the methyl cap of 7SKsnRNA leading to the dismissal of the 7SKsnRNA:HEXIM1 inhibitor complex. After removal of repressive marks, the complex BRD4:JMJD6 attract and retain the P-TEFb complex on chromatin, leading to its activation, promoter-proximal polymerase II pause release, and transcriptional activation (PubMed:24360279). Demethylates other arginine methylated-proteins such as ESR1 (PubMed:24498420). Has no histone lysine demethylase activity (PubMed:21060799). Required for differentiation of multiple organs during embryogenesis. Acts as a key regulator of hematopoietic differentiation: required for angiogenic sprouting by regulating the pre-mRNA splicing activity of U2AF2/U2AF65 (By similarity). Seems to be necessary for the regulation of macrophage cytokine responses (PubMed:15622002)","subcellular_location":"Nucleus, nucleoplasm; Nucleus, nucleolus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6NYC1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JMJD6","classification":"Not Classified","n_dependent_lines":541,"n_total_lines":1208,"dependency_fraction":0.4478476821192053},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MED19","stoichiometry":10.0},{"gene":"MED14","stoichiometry":4.0},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"MED11","stoichiometry":0.2},{"gene":"MED31","stoichiometry":0.2},{"gene":"MED9","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/JMJD6","total_profiled":1310},"omim":[{"mim_id":"621306","title":"JUMONJI DOMAIN-CONTAINING PROTEIN 7; JMJD7","url":"https://www.omim.org/entry/621306"},{"mim_id":"620928","title":"JUMONJI DOMAIN-CONTAINING PROTEIN 4; JMJD4","url":"https://www.omim.org/entry/620928"},{"mim_id":"604914","title":"JUMONJI DOMAIN-CONTAINING PROTEIN 6; JMJD6","url":"https://www.omim.org/entry/604914"},{"mim_id":"600124","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A2/B1; HNRNPA2B1","url":"https://www.omim.org/entry/600124"},{"mim_id":"191318","title":"U2 SMALL NUCLEAR RNA AUXILIARY FACTOR 2; U2AF2","url":"https://www.omim.org/entry/191318"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":115.0}],"url":"https://www.proteinatlas.org/search/JMJD6"},"hgnc":{"alias_symbol":["PTDSR1","KIAA0585"],"prev_symbol":["PTDSR"]},"alphafold":{"accession":"Q6NYC1","domains":[{"cath_id":"2.60.120.650","chopping":"43-293","consensus_level":"high","plddt":97.7219,"start":43,"end":293}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NYC1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NYC1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NYC1-F1-predicted_aligned_error_v6.png","plddt_mean":87.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JMJD6","jax_strain_url":"https://www.jax.org/strain/search?query=JMJD6"},"sequence":{"accession":"Q6NYC1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6NYC1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6NYC1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NYC1"}},"corpus_meta":[{"pmid":"17947579","id":"PMC_17947579","title":"JMJD6 is a histone 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America","url":"https://pubmed.ncbi.nlm.nih.gov/21300889","citation_count":123,"is_preprint":false},{"pmid":"24667498","id":"PMC_24667498","title":"JMJD6 promotes colon carcinogenesis through negative regulation of p53 by hydroxylation.","date":"2014","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/24667498","citation_count":116,"is_preprint":false},{"pmid":"15615595","id":"PMC_15615595","title":"Identification of cardiac malformations in mice lacking Ptdsr using a novel high-throughput magnetic resonance imaging technique.","date":"2004","source":"BMC developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15615595","citation_count":116,"is_preprint":false},{"pmid":"23303181","id":"PMC_23303181","title":"Lysyl 5-hydroxylation, a novel histone modification, by Jumonji domain containing 6 (JMJD6).","date":"2013","source":"The Journal of biological 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\"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay plus cell-based assay in a single rigorous study; however, later structural/biochemical studies challenged this activity, lowering confidence somewhat\",\n      \"pmids\": [\"17947579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JMJD6 catalyzes Fe(II)- and 2-oxoglutarate-dependent lysyl-5-hydroxylation of the splicing factor U2AF65, and this activity modulates alternative RNA splicing of specific endogenous and reporter genes.\",\n      \"method\": \"Mass spectrometry identification of hydroxylated lysine on U2AF65; in vitro hydroxylase assay; splicing reporter assays in cells with JMJD6 knockdown/overexpression\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with MS validation, cell-based splicing assays, replicated by multiple independent groups\",\n      \"pmids\": [\"19574390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the JMJD6 catalytic domain in complex with Ni(II) (substituting Fe(II)) reveals a double-stranded beta-helical fold; mutational studies show how active-site geometry favors C-5 lysyl hydroxylation rather than N-epsilon demethylation.\",\n      \"method\": \"X-ray crystallography; active-site mutagenesis\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation, published in two companion papers by same group (20684070, 20685276)\",\n      \"pmids\": [\"20684070\", \"20685276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"JMJD6 binds efficiently to single-stranded RNA but not to single-stranded DNA, double-stranded RNA, or double-stranded DNA; the crystal structure reveals a novel substrate-binding groove and two positively charged surfaces with a stack of aromatic residues near the active center.\",\n      \"method\": \"X-ray crystallography; RNA/DNA binding assays; truncation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with direct binding assays for multiple nucleic acid types\",\n      \"pmids\": [\"20679243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Jmjd6 is distributed throughout the nucleoplasm outside heterochromatic regions, localizes occasionally to nucleoli, is excluded from the nucleus during mitosis and reappears in telophase, and forms homo-multimers. Jmjd6 does NOT demethylate histone lysine residues H3K4, H3K9, H3K27, H3K36, or H4K20.\",\n      \"method\": \"Immunolocalization; Western blot; comparison of histone methylation states in wildtype vs. Jmjd6-knockout cells; overexpression of active and inactive forms\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (IHC, WB, KO comparison), single lab; negative result for histone lysine demethylation robustly supported\",\n      \"pmids\": [\"21060799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JMJD6-catalyzed hydroxylation of RNA-splicing regulatory protein fragments produces 5S-hydroxylysine, a stereochemistry distinct from collagen lysyl hydroxylases (which produce 5R products), indicating a distinct subfamily of lysyl hydroxylases.\",\n      \"method\": \"Amino acid analysis; NMR stereochemical assignment of hydroxylysine products from in vitro JMJD6 reactions\",\n      \"journal\": \"ChemBioChem\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with NMR-based stereochemical validation\",\n      \"pmids\": [\"22238144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Jmjd6 silencing impairs angiogenic functions of endothelial cells by altering splicing of VEGF-receptor 1 (Flt1), increasing levels of soluble Flt1 that inhibits angiogenesis. Jmjd6 physically interacts with splicing factor U2AF65 that binds Flt1 mRNA.\",\n      \"method\": \"siRNA knockdown; RT-PCR splicing assay; co-immunoprecipitation of Jmjd6 with U2AF65; rescue experiments with VEGF/PlGF or anti-sFlt1 antibodies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, knockdown with specific phenotypic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"21300889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JMJD6 cannot demethylate histone arginine residues in vitro but does hydroxylate the histone H4 tail at lysine residues in a 2-OG- and Fe(II)-dependent manner. Homo-oligomerization of Jmjd6 requires its enzymatic (hydroxylase) activity and both N- and C-termini; Jmjd6 autodydroxylates its own N-terminus to form intermolecular covalent bonds mediating oligomerization.\",\n      \"method\": \"MALDI-TOF mass spectrometry in vitro enzymatic assay; mutational analysis of oligomerization domains\",\n      \"journal\": \"Journal of Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro assay with MS validation, mutagenesis; single lab, negative result for arginine demethylation\",\n      \"pmids\": [\"22189873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JMJD6 hydroxylates multiple lysyl residues of histone H3, H4, H2A, and H2B tails in vitro and in vivo. 5-Hydroxylysine on histones inhibits N-acetylation and N-methylation by acetyltransferase and methyltransferase in vitro, suggesting cross-talk between histone modifications.\",\n      \"method\": \"In vitro hydroxylase assay; amino acid composition analysis of histones from JMJD6-knockout mouse embryos; JMJD6 overexpression in HEK293 cells; in vitro competition assays with acetyltransferase/methyltransferase\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro assay, KO mouse tissues, overexpression, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23303181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JMJD6 and BRD4 co-occupy a unique cohort of distal enhancers (anti-pause enhancers, A-PEs) and regulate promoter-proximal Pol II pause release. BRD4-dependent JMJD6 recruitment to A-PEs mediates erasure of H4R3me2(s), which is read by 7SK snRNA; JMJD6 also decaps/demethylates 7SK snRNA, releasing the 7SK/HEXIM inhibitory complex and activating P-TEFb.\",\n      \"method\": \"ChIP-seq; RNA-seq; co-IP of JMJD6 with BRD4 and P-TEFb; 7SK snRNA demethylation/decapping assay; long-range chromatin interaction analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, functional RNA assays, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"24360279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The polyserine (polyS) domain of Jmjd6 mediates its subnuclear localization; Jmjd6 lacking the polyS domain localizes to the nucleolus (fibrillar centre) and interacts with nucleolar proteins. Homo-oligomerization of Jmjd6 occurs in cells and the structure of oligomers changes without the polyS domain.\",\n      \"method\": \"Live-cell imaging; co-immunoprecipitation; F2H (fluorescent 2-hybrid) assay; deletion mutagenesis\",\n      \"journal\": \"Biochemical Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional domain deletions, Co-IP, and F2H assay; single lab\",\n      \"pmids\": [\"23688307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JMJD6 physically associates with p53 and acts as an alpha-ketoglutarate- and Fe(II)-dependent lysyl hydroxylase to hydroxylate p53 primarily at lysine 382. This hydroxylation antagonizes p53 acetylation, promotes p53 association with its negative regulator MDMX, and represses p53 transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation; in vitro hydroxylase assay; mass spectrometry identification of hydroxylation site; p53 acetylation assays; MDMX co-IP; reporter assays; JMJD6 knockdown/overexpression with phenotypic readouts\",\n      \"journal\": \"PLoS Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution, MS site identification, multiple Co-IPs, functional transcription assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24667498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Upon estrogenic stimulation, JMJD6 interacts with methylated estrogen receptor alpha (ERα) and acts as an arginine demethylase to demethylate ERα, regulating rapid extranuclear estrogenic responses.\",\n      \"method\": \"Co-immunoprecipitation; JMJD6 silencing combined with in vitro demethylation assay\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and demethylation assay, single lab, limited methodological breadth\",\n      \"pmids\": [\"24498420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Jmjd6 interacts with multiple SR and SR-related proteins through their arginine-serine-rich (RS) domains, including U2AF65, Luc7L3, SRSF11, and Acinus S', but not the bona fide RS domain of SRSF1. Jmjd6 modifies constitutive splicing, binds RNA from a reporter plasmid, and co-localizes with nascent RNA.\",\n      \"method\": \"Co-immunoprecipitation; in vitro binding assay; splicing reporter assay; RNA binding assay; immunofluorescence co-localization with nascent RNA\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IP targets, splicing reporter, RNA binding, co-localization; single lab\",\n      \"pmids\": [\"24914048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Jmjd6, acting as a lysyl hydroxylase for splicing regulatory proteins, is required for efficient splicing of intron 2 of the Aire gene in medullary thymic epithelial cells; Jmjd6 deficiency results in retention of Aire intron 2, markedly reduced mature Aire protein, and spontaneous multi-organ autoimmunity in mice.\",\n      \"method\": \"Jmjd6 conditional knockout mouse; RT-PCR splicing analysis; Western blot of Aire protein; phenotypic analysis of autoimmunity\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with specific molecular (splicing) and phenotypic (autoimmunity) readouts, multiple methods\",\n      \"pmids\": [\"26531897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In Xenopus embryogenesis, Jmjd6 interacts with Tcf7l1 (Tcf3), competing with Groucho corepressor for the same binding region on Tcf7l1 to derepress Wnt target genes. Loss of Jmjd6 function causes anteroposterior body axis defects.\",\n      \"method\": \"Co-immunoprecipitation; reporter gene assays; morpholino loss-of-function in Xenopus embryos; rescue experiments\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, reporter assays, loss-of-function with phenotypic rescue; single lab\",\n      \"pmids\": [\"26157142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD6 is a novel stress granule (SG) component that interacts with G3BP1 complexes. JMJD6 promotes G3BP1 arginine demethylation (monomethylation and asymmetric dimethylation at three Arg residues) and thereby promotes SG formation; knockdown of JMJD6 represses SG formation, and rescue requires catalytically active but not mutant JMJD6.\",\n      \"method\": \"Co-immunoprecipitation; mass spectrometry; JMJD6 knockdown; rescue with catalytically active vs. inactive JMJD6; immunofluorescence of SG markers\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, MS, KD with phenotypic rescue using active/inactive mutants; single lab\",\n      \"pmids\": [\"28972166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD6 and BRD4 interact via the BRD4 extraterminal (ET) domain; NMR reveals a JMJD6 peptide (Lys84–Asn96) adopts an alpha-helix when bound to the ET domain through hydrophobic and electrostatic interactions. Single-stranded RNA binding by JMJD6 induces a conformational change that likely promotes this ET-domain interaction.\",\n      \"method\": \"NMR structure determination; mutagenesis; RNA binding assays\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with mutagenesis and functional RNA binding validation\",\n      \"pmids\": [\"29176719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD6 forms protein complexes with N-Myc and BRD4 in neuroblastoma cells and is important for transcription of E2F2, N-Myc, and c-Myc. JMJD6 gene is associated with transcriptional super-enhancers.\",\n      \"method\": \"Co-immunoprecipitation; ChIP-seq; gene knockdown with transcriptional readouts\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq, KD with transcriptional phenotype; single lab\",\n      \"pmids\": [\"31346162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD6 regulates the alternative splicing of PAK1, a MAPK pathway component, in melanoma cells; knockdown affects a panel of alternative splicing events as measured by RNA-seq.\",\n      \"method\": \"RNA-seq splicing analysis; JMJD6 knockdown; functional assays in melanoma cell lines\",\n      \"journal\": \"Molecular Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNA-seq with KD, specific splicing target identified but molecular mechanism not fully established; single lab\",\n      \"pmids\": [\"29187213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD6 co-regulates alternative splicing events together with U2AF65; JMJD6 enzymatic activity (lysine hydroxylation of U2AF65) is required for a subset of co-regulated splicing events but not all, indicating both enzymatic activity-dependent and -independent mechanisms of splicing regulation. Validated in jmjd6 knockout mice.\",\n      \"method\": \"RASL-Seq splicing profiling; JMJD6/U2AF65 knockdown; JMJD6 knockout mice; co-IP; mutagenesis of catalytic residues\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo KO mouse validation, RASL-Seq, Co-IP, mutagenesis; multiple orthogonal methods\",\n      \"pmids\": [\"27899633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD6 is required for ERα-bound active enhancer activation and RNA Pol II recruitment: JMJD6 interacts with MED12 in the mediator complex, is necessary for MED12 interaction with CARM1, and CARM1 methylates MED12 at multiple arginine sites to regulate chromatin binding, thereby enabling transcriptional pause release of estrogen target genes.\",\n      \"method\": \"Co-immunoprecipitation; ChIP-seq; enhancer RNA measurement; JMJD6 knockdown; CARM1 methylation assays; cell proliferation and xenograft assays\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, functional methylation assays, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"29628309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD6 has intrinsic tyrosine kinase activity and phosphorylates histone H2A.X at tyrosine 39 (H2A.XY39ph), using ATP and GTP as phosphate donors; high JMJD6 promotes autophagy in triple-negative breast cancer cells via regulation of autophagy-related gene expression through the H2A.XY39ph axis.\",\n      \"method\": \"In vitro kinase assay; mass spectrometry identification of phosphorylation site; JMJD6 knockdown with autophagy readouts; cell growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay with MS site identification, but tyrosine kinase activity is a novel/controversial claim reported by a single lab\",\n      \"pmids\": [\"30185813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Biochemical (MS- and NMR-based kinetic assays) and structural (crystallographic) analyses with purified JMJD6 support assignment as a lysyl hydroxylase; the study did NOT observe N-methyl arginyl N-demethylation activity with purified JMJD6, calling into question its arginine demethylase activity.\",\n      \"method\": \"MS-based kinetic assay; NMR assay; X-ray crystallography; substrate fragment screening\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure, MS and NMR kinetics, multiple substrates tested; rigorous biochemical study by Schofield group\",\n      \"pmids\": [\"31147442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JMJD6 homo-oligomerization does not require catalytic activity; the AT hook-like domain (mediating DNA/RNA interaction) is required for JMJD6 chromatin binding and function in adipogenic differentiation, whereas catalytic activity and the polyserine and sumoylation domains are dispensable.\",\n      \"method\": \"Domain mutagenesis; oligomerization assays; chromatin immunoprecipitation; adipogenic differentiation assays in JMJD6 mutant-rescued cells\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis, ChIP, differentiation assay; single lab, multiple methods\",\n      \"pmids\": [\"31430278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD6 is recruited to DNA double-strand breaks (DSBs), controls spreading of histone ubiquitination and accumulation of repair proteins around DSBs, and promotes transcriptional silencing. Independently of catalytic activity, JMJD6 interacts with SIRT1 and recruits it to chromatin to downregulate H4K16ac around DSBs, modulating NHEJ and HR efficiency.\",\n      \"method\": \"Microirradiation with live imaging; co-immunoprecipitation of JMJD6 with SIRT1; ChIP for H4K16ac; NHEJ/HR reporter assays; catalytic mutant rescue\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequences, reciprocal Co-IP, ChIP, catalytic mutant analysis; multiple orthogonal methods\",\n      \"pmids\": [\"31358914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD6 cleaves methylphosphate capping enzyme (MePCE), a core component of the 7SK snRNP complex, via a novel proteolytic activity. This cleavage releases P-TEFb from the 7SK snRNP complex; downstream effect is phosphorylation of Pol II CTD. Crystal structure of JMJD6 bound to methyl-arginine was determined.\",\n      \"method\": \"Crystal structure of JMJD6 bound to methyl-arginine; in vitro and in vivo MePCE cleavage assays; binding assays; Jmjd6 KO and overexpression with Pol II CTD phosphorylation readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure, in vitro reconstitution of cleavage, in vivo validation with KO; multiple orthogonal methods\",\n      \"pmids\": [\"32048991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD6 is rapidly recruited to nucleolar DNA damage sites and is required for relocation of rDNA into nucleolar caps, rDNA stability, and maintaining rDNA repeat integrity after irradiation. JMJD6 interacts with nucleolar protein Treacle and modulates its interaction with NBS1.\",\n      \"method\": \"Live-cell imaging after micro-irradiation; mass spectrometry interactome; JMJD6-deficient cells; rDNA repeat analysis by Southern blot/FISH\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, MS-identified Treacle interaction, KO phenotype; single lab\",\n      \"pmids\": [\"32598339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JMJD6 knockdown reduces recruitment of U2AF65 to AR pre-mRNA and reduces AR-V7 splice variant levels; mutagenesis indicates JMJD6 catalytic activity is required for AR-V7 generation. The JMJD6/U2AF65 axis thus controls AR-V7 splicing in prostate cancer.\",\n      \"method\": \"siRNA knockdown; mutagenesis of catalytic residues; RIP (RNA immunoprecipitation) of U2AF65 on AR pre-mRNA; RT-PCR for AR-V7; prostate cancer cell growth assays\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, mutagenesis, KD with specific splicing readout; single lab\",\n      \"pmids\": [\"33822745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JMJD6 negatively regulates antiviral innate immune signaling by recruiting the ubiquitin E3 ligase RNF5 to promote K48-linked ubiquitination and degradation of activated IRF3, thereby reducing type-I interferon production.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; proteomic screen; JMJD6 KO via piggyBac transposon in mice; viral replication assays\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo KO mouse validation; single lab, multiple methods\",\n      \"pmids\": [\"33684176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JMJD6 is essential for short- and long-term maintenance of the hematopoietic stem cell (HSC) pool; Jmjd6-deficient HSCs fail to expand after injury and lose self-renewal upon serial transplantation. JMJD6 represses mitochondrial OXPHOS, protein synthesis, p53 stabilization, and mTORC1 signaling in HSCs; ROS elevation from OXPHOS causally mediates HSC failure.\",\n      \"method\": \"Hematopoietic-specific conditional Jmjd6 KO mouse; serial transplantation; metabolic assays (mitochondrial respiration, ROS); N-acetyl-L-cysteine rescue\",\n      \"journal\": \"Blood Advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse, serial transplantation, metabolic phenotyping, antioxidant rescue; multiple orthogonal methods\",\n      \"pmids\": [\"33560400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JMJD6 catalyzes lysine hydroxylation at 150 sites on 48 protein substrates identified by mass spectrometry, predominantly within unstructured lysine-rich regions. BRD4 is hydroxylated on 19 lysine sites. Nearly all identified substrates are associated with membraneless organelle formation, suggesting JMJD6 may regulate liquid-liquid phase separation.\",\n      \"method\": \"Mass spectrometry with lysine propionyl derivatization; nontryptic proteolysis; JMJD6-depleted vs. control cell comparison\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic MS-based substrate identification with appropriate controls; single lab but comprehensive substrate profiling\",\n      \"pmids\": [\"35930668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JMJD6 interacts with RBM39 and co-occupies the DGAT1 gene promoter with H3K4me3 to induce DGAT1 expression, thereby promoting lipid droplet formation and ccRCC tumorigenesis.\",\n      \"method\": \"siRNA screen; ChIP-seq; RNA-seq; co-immunoprecipitation of JMJD6 with RBM39; JMJD6 KD with lipid droplet and tumor growth readouts\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq, RNA-seq, in vivo KD model; single lab\",\n      \"pmids\": [\"35764091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JMJD6 demethylates HURP at R122, promoting Golgi apparatus repositioning (GR) and directional cell migration via a NF-κB-induced centrosome repositioning and subsequent Cdc42 upregulation cascade; PRMT5 methylation of HURP R122 opposes this.\",\n      \"method\": \"Co-immunoprecipitation; HURP methylation assays; JMJD6 KD; Golgi repositioning assays; cell migration assays; mechanistic epistasis using methylation-mimic/deficiency mutants\",\n      \"journal\": \"Journal of Cellular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional mutants, Golgi repositioning assay; single lab, multiple methods\",\n      \"pmids\": [\"36250981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JMJD6 regulates splicing of its own pre-mRNA to produce isoforms (JMJD6-2 and JMJD6-Ex5) with distinct C-terminal sequences and different interaction partners; JMJD6-2 interacts with SR-like splicing factors (RS-domain proteins) while JMJD6-Ex5 interacts with SMN complex, hnRNPs, UBF, and FCP1. JMJD6-2 but not JMJD6-Ex5 inhibits exon inclusion in a splicing reporter.\",\n      \"method\": \"Immunoprecipitation followed by LC-MS/MS; HIV-based splicing reporter assay; siRNA knockdown; RT-PCR isoform analysis\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome, functional splicing assay, KD; single lab\",\n      \"pmids\": [\"32927736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"JMJD6 interacts with NF-κB p65 in the cytoplasm and demethylates p65 at arginine 149 (R149), inhibiting nuclear translocation of p65 and thereby suppressing NF-κB signaling and protecting against pathological cardiac hypertrophy.\",\n      \"method\": \"Co-immunoprecipitation of JMJD6 with p65; in vitro/in vivo demethylation assays; cardiac-specific JMJD6 overexpression in rats; sgRNA-mediated JMJD6 depletion; echocardiography; hypertrophic gene expression assays\",\n      \"journal\": \"Acta Pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, demethylation assay, in vivo overexpression/depletion with functional cardiac readout; single lab\",\n      \"pmids\": [\"37186122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JMJD6 acts as a hub connecting pre-mRNA splicing and glutamine metabolism in MYC-driven neuroblastoma: it physically interacts with RNA-binding proteins involved in splicing and protein homeostasis, and controls alternative splicing of glutaminase (GLS) isoforms KGA and GAC (rate-limiting enzymes of glutaminolysis). JMJD6 also complexes with RBM39, linking it to sensitivity to the splicing inhibitor indisulam.\",\n      \"method\": \"Co-immunoprecipitation; RNA-seq/splicing analysis; metabolic assays; cell transformation assays; indisulam treatment with JMJD6-dependent readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, splicing analysis, metabolic assays; single lab, multiple methods\",\n      \"pmids\": [\"38488852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSF1 directly binds JMJD6 gene and promotes its transcription; JMJD6 in turn reduces HSP70 R469 monomethylation to disrupt HSP70-HSF1 repressive complexes, enabling enhanced HSF1 activation in a positive feedback circuit mediating cellular adaptation to proteotoxic stress.\",\n      \"method\": \"Genome-wide RNAi screen with HSR reporter; ChIP assay for HSF1 at JMJD6 locus; JMJD6-mediated HSP70 demethylation assay; co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen, ChIP, demethylation assay, Co-IP; single lab\",\n      \"pmids\": [\"38985769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPOP mutants impair proteasomal degradation of JMJD6; elevated JMJD6 and ATF4 coordinate enhancer-promoter loop interactions to stimulate glutathione biosynthesis pathway genes (SLC7A11, GCLM, ME1). JMJD6 recruits mediator subunits (Med1/Med14) to assemble de novo enhancers at these loci, conferring ferroptosis resistance independently of androgen receptor.\",\n      \"method\": \"Co-immunoprecipitation; ChIP-seq; enhancer-promoter loop analysis; JMJD6 depletion; preclinical tumor models with ferroptosis inducers\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, Co-IP, functional ferroptosis assays, in vivo models; single lab\",\n      \"pmids\": [\"39903850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"JMJD6 is acetylated at lysine 375 by the acetyltransferase PCAF; K375 acetylation weakens JMJD6 arginine demethylase activity, enhances METTL14 expression, increases m6A modification of SLC3A2, and thereby promotes ferroptosis sensitivity in lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation; GST pulldown; in vitro acetylation assay; ChIP; MeRIP (m6A sequencing); functional ferroptosis assays; JMJD6 overexpression/knockdown\",\n      \"journal\": \"Journal of Translational Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, GST pulldown, in vitro assay, ChIP, MeRIP; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40011892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD6 suppresses Myc-induced apoptosis through inhibition of p19ARF mRNA and protein, leading to reduced p53 levels; JMJD6 binds the p19ARF promoter and exerts its inhibitory function through demethylation of H4R3me2a at this promoter.\",\n      \"method\": \"Chromatin immunoprecipitation at p19ARF promoter; JMJD6 overexpression/knockdown with p19ARF/p53 readouts; cell viability assays under stress; xenograft tumor assays\",\n      \"journal\": \"Clinical Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, functional assays, in vivo xenograft; single lab\",\n      \"pmids\": [\"27081402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Endogenous Jmjd6 is expressed at the cell surface of immature monocyte-like THP-1 cells activated with PMA and translocates to the nucleus upon macrophage differentiation; antibody blockade of surface Jmjd6 suppresses phagocytosis of dead cells in immature macrophages.\",\n      \"method\": \"Immunocytochemistry; antibody blocking of endogenous surface Jmjd6; phagocytosis assay; time-course subcellular fractionation\",\n      \"journal\": \"Journal of Cellular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization with functional consequence (antibody blockade), single lab, single cell type\",\n      \"pmids\": [\"19492415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD6 demethylates STAT1 arginine methylation, suppressing IFNα-induced interferon-stimulated gene (ISG) activation; overexpression of JMJD6 suppressed STAT1 methylation and ISG activation, while JMJD6 silencing enhanced both.\",\n      \"method\": \"JMJD6 overexpression/knockdown; STAT1 methylation assay; ISG expression measurement; HCV RNA quantification; in vivo mouse model\",\n      \"journal\": \"Cellular and Molecular Gastroenterology and Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss of function with methylation and ISG readouts, in vivo mouse validation; single lab\",\n      \"pmids\": [\"29693039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD6 binds to the HOTAIR promoter region (−123 to −103 bp) and induces HOTAIR transcription; a catalytically dead JMJD6 mutant (H187A) can bind the HOTAIR promoter but fails to activate transcription, demonstrating enzymatic activity-dependent transcriptional regulation.\",\n      \"method\": \"ChIP; EMSA; deletion constructs of HOTAIR promoter; luciferase reporter; JMJD6 overexpression/siRNA in multiple cell lines; catalytic mutant analysis\",\n      \"journal\": \"Biochemical Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, EMSA, reporter assay with catalytic mutant; single lab\",\n      \"pmids\": [\"29229759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fibronectin is a novel substrate of JMJD6-mediated lysyl hydroxylation; JMJD6-catalyzed hydroxylation of fibronectin precedes its glycosylation, deposition, and degradation in placental mesenchymal cells.\",\n      \"method\": \"MALDI-TOF mass spectrometry identification of fibronectin as JMJD6 substrate; JMJD6 knockdown recapitulating fibronectin accumulation phenotype; iron rescue (Hinokitiol) experiments\",\n      \"journal\": \"Frontiers in Cell and Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — MS substrate identification, KD recapitulation, iron rescue; single lab, novel substrate\",\n      \"pmids\": [\"34055782\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JMJD6 is a nuclear, iron(II)- and 2-oxoglutarate-dependent dioxygenase that primarily functions as a lysyl hydroxylase, catalyzing C-5 hydroxylation of lysine residues in unstructured regions of diverse substrates including U2AF65, other SR/RS-domain splicing factors, histones H2A/B/H3/H4, p53, fibronectin, and BRD4 (among ~48 identified substrates); it also possesses arginine demethylase activity toward substrates including G3BP1, ERα, STAT1, HURP, HSP70, and NF-κB p65 (though its arginine demethylase activity toward purified substrates in vitro remains contested); through these activities it regulates pre-mRNA alternative splicing (via hydroxylation of U2AF65 and interaction with multiple SR proteins), promotes RNA Pol II promoter-proximal pause release (by demethylating H4R3me2s at anti-pause enhancers, decapping 7SK snRNA, and proteolytically cleaving MePCE to release P-TEFb), modulates chromatin architecture around DNA double-strand breaks via SIRT1 recruitment, and participates in stress granule assembly, hematopoietic stem cell maintenance, and innate immune regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JMJD6 is a nuclear Fe(II)- and 2-oxoglutarate-dependent dioxygenase of the JmjC family that couples post-translational modification of unstructured protein regions to the control of RNA processing and transcription [#0, #1, #31]. Its best-defined catalytic activity is C-5 lysyl hydroxylation, established by mass-spectrometric identification of hydroxylated lysines on the splicing factor U2AF65 and corroborated by crystallographic analysis showing an active-site geometry that favors lysyl hydroxylation, producing a distinct 5S-hydroxylysine stereochemistry [#1, #2, #5]; rigorous purified-enzyme kinetic and structural studies reassign JMJD6 as a lysyl hydroxylase and fail to detect arginyl demethylation in vitro [#23]. Systematic substrate profiling identifies ~150 hydroxylation sites on 48 substrates, concentrated in lysine-rich disordered regions of proteins associated with membraneless organelles, including extensive hydroxylation of BRD4 [#31], and histone tails (H2A, H2B, H3, H4) where 5-hydroxylysine antagonizes acetylation and methylation [#8]. Through these activities JMJD6 governs alternative pre-mRNA splicing: it physically associates with U2AF65 and additional SR/RS-domain splicing factors and co-regulates splicing through both catalysis-dependent and -independent mechanisms, controlling specific transcripts including Flt1, Aire, AR-V7, and glutaminase isoforms [#6, #13, #20, #14, #28, #36]. JMJD6 is also a central regulator of RNA Pol II promoter-proximal pause release: recruited by BRD4 to anti-pause enhancers via the BRD4 ET domain, it acts on H4R3me2s and on 7SK snRNA and proteolytically cleaves the 7SK snRNP component MePCE to liberate active P-TEFb [#9, #17, #26]. Beyond transcription elongation, JMJD6 modulates the DNA damage response by recruiting SIRT1 to double-strand breaks independently of its catalytic activity and by maintaining rDNA repeat integrity through interaction with Treacle [#25, #27], modifies p53 activity through K382 hydroxylation that promotes MDMX binding [#11], and contributes to stress granule assembly, hematopoietic stem cell maintenance, and innate immune regulation [#16, #30, #29]. Mouse Jmjd6 deficiency causes intron-retention of Aire and spontaneous multi-organ autoimmunity, directly linking its splicing function to immune tolerance [#14]. A reported tyrosine kinase activity toward H2A.X Y39 and an arginine demethylase activity toward several substrates remain contested in light of the negative purified-enzyme results [#22, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established JMJD6 as a JmjC-family Fe(II)/2-OG dioxygenase and proposed its first molecular activity, addressing what enzymatic class it belongs to.\",\n      \"evidence\": \"In vitro and cell-based histone arginine demethylase assays with purified JMJD6\",\n      \"pmids\": [\"17947579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Arginine demethylase activity later not reproduced with purified enzyme\", \"No structural basis provided for the assigned activity\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Reassigned JMJD6's primary catalytic output to lysyl hydroxylation by identifying U2AF65 as a hydroxylation substrate, linking the enzyme to RNA splicing control.\",\n      \"evidence\": \"MS identification of hydroxylysine on U2AF65, in vitro hydroxylase assay, and cellular splicing reporters\",\n      \"pmids\": [\"19574390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which endogenous splicing programs depend on hydroxylation\", \"Relationship to the earlier demethylase claim unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the structural and biochemical basis for substrate selection, showing active-site geometry favors C-5 lysyl hydroxylation and that JMJD6 binds single-stranded RNA, and located it in the nucleoplasm.\",\n      \"evidence\": \"X-ray crystallography with Ni(II) substitution, mutagenesis, nucleic-acid binding assays, and immunolocalization with KO comparison\",\n      \"pmids\": [\"20684070\", \"20685276\", \"20679243\", \"21060799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of ssRNA binding not yet established\", \"Did not reconcile structure with reported demethylase activity\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Confirmed a distinct lysyl hydroxylase subfamily by stereochemical analysis and connected JMJD6 splicing function to angiogenesis through Flt1.\",\n      \"evidence\": \"NMR stereochemical assignment of 5S-hydroxylysine products and siRNA knockdown with reciprocal U2AF65 Co-IP and splicing rescue in endothelial cells\",\n      \"pmids\": [\"22238144\", \"21300889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether U2AF65 hydroxylation directly drives Flt1 splicing not formally separated from binding\", \"In vivo relevance not tested at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated histone H4 tail lysyl hydroxylation and that catalysis-dependent autohydroxylation drives homo-oligomerization, clarifying the enzyme's self-assembly.\",\n      \"evidence\": \"MALDI-TOF in vitro hydroxylase assays and oligomerization-domain mutagenesis\",\n      \"pmids\": [\"22189873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative arginine demethylation result from single lab\", \"Functional significance of oligomerization in cells not established here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected JMJD6 to histone modification cross-talk and to RNA Pol II pause release, establishing its central transcription-elongation role.\",\n      \"evidence\": \"In vitro hydroxylase and competition assays plus ChIP-seq, RNA-seq, BRD4/P-TEFb Co-IP, and 7SK snRNA assays; subnuclear domain mapping by F2H and deletion\",\n      \"pmids\": [\"23303181\", \"24360279\", \"23688307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic mechanism of 7SK 'decapping/demethylation' not fully defined\", \"PolyS-dependent localization role in transcription not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expanded the substrate and partner repertoire to p53, ERα, and SR/SR-related splicing factors, broadening JMJD6 into transcription and signaling control.\",\n      \"evidence\": \"Co-IP, in vitro hydroxylase/demethylation assays, MS site mapping, and splicing/reporter assays\",\n      \"pmids\": [\"24667498\", \"24498420\", \"24914048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ERα demethylation rests on limited methodological breadth\", \"Whether RS-domain binding requires catalysis not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided in vivo validation that JMJD6 splicing function controls immune tolerance (Aire) and developmental patterning (Wnt/Tcf7l1).\",\n      \"evidence\": \"Conditional and morpholino loss-of-function in mouse and Xenopus with splicing, protein, and phenotypic readouts plus Co-IP and rescue\",\n      \"pmids\": [\"26531897\", \"26157142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tcf7l1 derepression mechanism not tied to a catalytic activity\", \"Generality of intron-retention phenotype to other transcripts unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked JMJD6 to oncogenic Myc/p53 regulation via promoter-level histone arginine modification.\",\n      \"evidence\": \"ChIP at the p19ARF promoter, gain/loss-of-function with p53 readouts, and xenografts\",\n      \"pmids\": [\"27081402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"H4R3me2a demethylation activity contested by purified-enzyme studies\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved how JMJD6 is recruited to chromatin and broadened its roles into stress granules, super-enhancer transcription, and innate immune/interferon control.\",\n      \"evidence\": \"NMR structure of the JMJD6-BRD4 ET-domain interface; Co-IP/MS, ChIP-seq, knockdown with phenotypic rescue across stress-granule, neuroblastoma, melanoma, and STAT1 systems\",\n      \"pmids\": [\"29176719\", \"28972166\", \"31346162\", \"29187213\", \"29693039\", \"29229759\", \"19492415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"G3BP1/STAT1 demethylation relies on single-lab assays contested in vitro\", \"Cell-surface localization function reported in only one cell type\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a Mediator-coupled enhancer-activation mechanism and reported a controversial intrinsic tyrosine kinase activity.\",\n      \"evidence\": \"MED12/CARM1 Co-IP, ChIP-seq, eRNA and xenograft assays; in vitro kinase assay with MS site mapping for H2A.X Y39\",\n      \"pmids\": [\"29628309\", \"30185813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tyrosine kinase activity is a novel single-lab claim not independently confirmed\", \"Mechanism linking MED12 methylation to pause release incompletely defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Sharpened the activity debate and dissected catalysis-dependent versus -independent functions via domain mapping.\",\n      \"evidence\": \"MS/NMR kinetics and crystallography on purified enzyme (no demethylation observed); systematic domain mutagenesis with ChIP and adipogenic differentiation\",\n      \"pmids\": [\"31147442\", \"31430278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of in vitro-negative demethylation with cellular demethylation reports unresolved\", \"AT-hook-mediated chromatin binding mechanism not structurally defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established catalysis-independent and proteolytic functions of JMJD6 in genome maintenance and elongation control.\",\n      \"evidence\": \"Microirradiation/live imaging with SIRT1 Co-IP and H4K16ac ChIP; rDNA integrity analyses with Treacle interactome; crystal structure plus in vitro/in vivo MePCE cleavage assays\",\n      \"pmids\": [\"31358914\", \"32598339\", \"32048991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic basis of MePCE proteolysis within a dioxygenase fold not mechanistically explained\", \"How JMJD6 discriminates DSB versus nucleolar recruitment unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated physiological roles in stem-cell maintenance, oncogenic splicing, and antiviral signaling, integrating JMJD6 into metabolism and immunity.\",\n      \"evidence\": \"Conditional KO mice with serial transplantation and metabolic/ROS rescue; RIP/mutagenesis for AR-V7 splicing; Co-IP/ubiquitination and KO mice for IRF3-RNF5 axis\",\n      \"pmids\": [\"33560400\", \"33822745\", \"33684176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target through which JMJD6 represses OXPHOS in HSCs not identified\", \"Whether IRF3 control requires catalytic activity not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a global substrate map implicating JMJD6 in phase separation and added isoform-, lipid-, and migration-specific functions.\",\n      \"evidence\": \"MS substrate profiling (150 sites/48 substrates); IP-MS isoform interactome with splicing reporters; RBM39 Co-IP with ChIP-seq/lipid-droplet assays; HURP demethylation and Golgi-repositioning assays\",\n      \"pmids\": [\"35930668\", \"32927736\", \"35764091\", \"36250981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that hydroxylation alters phase separation not provided\", \"HURP R122 demethylation depends on contested demethylase activity\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Positioned JMJD6 as a hub coupling splicing to metabolism and proteostasis in cancer and stress adaptation.\",\n      \"evidence\": \"Co-IP, RNA-seq/splicing and metabolic assays for GLS/RBM39 in neuroblastoma; RNAi screen, HSF1 ChIP, and HSP70 demethylation assays\",\n      \"pmids\": [\"38488852\", \"38985769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HSP70 R469 demethylation relies on contested activity\", \"Direct enzymatic versus scaffolding contribution to GLS splicing not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked JMJD6 stability and modification to enhancer remodeling and ferroptosis regulation in cancer.\",\n      \"evidence\": \"Co-IP, ChIP-seq, enhancer-promoter loop analysis with SPOP/ATF4; PCAF acetylation, GST pulldown, MeRIP, and ferroptosis assays\",\n      \"pmids\": [\"39903850\", \"40011892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether K375 acetylation modulates hydroxylase versus demethylase function unclear\", \"Mediator recruitment mechanism for de novo enhancers not structurally defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central unresolved question is reconciling JMJD6's robust purified-enzyme lysyl hydroxylase and MePCE-cleavage activities with the numerous cellular arginine-demethylation and tyrosine-kinase claims that purified-enzyme assays have not reproduced.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unifying structural model explains hydroxylase, proteolytic, and putative demethylase/kinase activities in one fold\", \"Which catalytic activity underlies each in-cell phenotype is largely undetermined\", \"Substrate-recruitment specificity across chromatin, splicing, and damage sites unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 2, 5, 8, 23, 31]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 9, 17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 11, 31, 26]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4, 10, 27]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 6, 13, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 21, 26, 38]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [25, 27]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [8, 9, 25]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 29, 42]}\n    ],\n    \"complexes\": [\"7SK snRNP\", \"stress granule\"],\n    \"partners\": [\"U2AF65\", \"BRD4\", \"P53\", \"SIRT1\", \"G3BP1\", \"MED12\", \"RBM39\", \"MePCE\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}