{"gene":"JMJD1C","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2013,"finding":"JMJD1C demethylates MDC1 at Lys45, promoting MDC1-RNF8 interaction, RNF8-dependent MDC1 ubiquitylation, and recruitment of the RAP80-BRCA1 complex to DNA double-strand break sites. JMJD1C is stabilized by interaction with RNF8 and is recruited to DSBs, and is required for local ubiquitylations and RAP80-BRCA1 recruitment but not 53BP1 recruitment. JMJD1C depletion caused resistance to ionizing radiation and PARP inhibitors.","method":"Co-immunoprecipitation, in vitro demethylation assay, laser micro-irradiation/live-cell imaging, shRNA knockdown with functional readouts (ubiquitylation, foci formation, radiation sensitivity)","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro demethylation assay demonstrating catalytic activity, reciprocal Co-IP for protein interactions, and multiple orthogonal functional readouts in a single rigorous study","pmids":["24240613"],"is_preprint":false},{"year":2010,"finding":"JMJD1C specifically demethylates histone H3K9 mono- and di-methylation and mediates transcriptional activation. JMJD1C was identified as a component of WHISTLE-interacting protein complexes (also containing HSP90α) and replaces WHISTLE at the p450c17 promoter to activate steroidogenesis gene expression via SF-1-mediated interactions during mouse testis development.","method":"Immunoaffinity TAP purification, in vitro histone demethylation assay, chromatin immunoprecipitation (ChIP), reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro demethylation assay demonstrating H3K9me1/2 activity, TAP purification identifying complex components, and ChIP showing promoter recruitment, multiple orthogonal methods","pmids":["20530532"],"is_preprint":false},{"year":2015,"finding":"JMJD1C functions as a transcriptional coactivator for RUNX1-RUNX1T1 (AML1-ETO) in acute myeloid leukemia; it is directly recruited to RUNX1-RUNX1T1 target genes and regulates their expression by maintaining low H3K9me2 levels. JMJD1C is also required for RUNX1-RUNX1T1-driven proliferation in vivo in knockout mice.","method":"ChIP-seq, Co-immunoprecipitation, shRNA knockdown, JMJD1C knockout mouse model","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP showing direct recruitment, ChIP-seq demonstrating H3K9me2 regulation at target loci, and in vivo genetic validation in knockout mice across multiple orthogonal methods","pmids":["26494788"],"is_preprint":false},{"year":2016,"finding":"JMJD1C directly interacts with HOXA9 and modulates a HOXA9-controlled gene-expression program required for MLL-AF9 and HOXA9-driven leukemia stem cell self-renewal. Conditional knockout of JMJD1C substantially decreased LSC frequency and caused differentiation, while only minor defects were observed in normal hematopoietic stem cells.","method":"In vivo shRNA screen, conditional JMJD1C knockout mice, Co-immunoprecipitation, gene expression analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic screen and conditional knockout with defined cellular phenotypes, Co-IP demonstrating direct HOXA9 interaction, replicated across MLL-AF9 and HOXA9-driven leukemia models","pmids":["26878175"],"is_preprint":false},{"year":2020,"finding":"JMJD1C is phosphorylated at T505 by mTOR complex in response to feeding/insulin, allowing direct interaction with USF-1 and recruitment to lipogenic gene promoters. JMJD1C demethylates H3K9me2 at these promoters to allow transcriptional activation of lipogenic genes (fatty acid synthase, glycerol-3-phosphate acyltransferase), promoting hepatic and plasma triglyceride synthesis.","method":"In vitro kinase assay, Co-immunoprecipitation, ChIP, site-directed mutagenesis of T505, mouse liver overexpression/knockdown models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — kinase assay identifying mTOR as the T505 kinase, mutagenesis validating the phosphorylation site functionally, Co-IP for USF-1 interaction, and ChIP for promoter recruitment in a single study with multiple orthogonal methods","pmids":["32034158"],"is_preprint":false},{"year":2022,"finding":"Jmjd1c demethylates STAT3 at Lys140 (a non-histone substrate) in B cells to restrain plasma cell differentiation. STAT3 Lys140 hypermethylation caused by Jmjd1c deletion inhibits the interaction of STAT3 with phosphatase Ptpn6, resulting in abnormally sustained STAT3 phosphorylation and activity that promotes plasma cell generation. STAT3 Lys140Arg point mutation completely abrogated the effect of Jmjd1c loss.","method":"Conditional knockout mice, in vitro demethylation assay, site-directed mutagenesis (K140R), Co-immunoprecipitation, flow cytometry","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro demethylation assay on non-histone substrate, mutagenesis (K140R) abolishing the phenotype, Co-IP demonstrating STAT3-Ptpn6 interaction dependency, and conditional KO mouse model across multiple orthogonal methods","pmids":["35995859"],"is_preprint":false},{"year":2017,"finding":"Deltex2 directly inhibits Jmjd1c demethylase activity by promoting Jmjd1c monoubiquitination; mutation of the monoubiquitination site in Jmjd1c abolishes this inhibitory effect. Jmjd1c activity is required for MyoD expression in vivo and in vitro through removal of H3K9me2 at the MyoD locus. Deltex2 and Jmjd1c act in an epistatic relationship to regulate myogenic differentiation.","method":"In vitro demethylation assay, site-directed mutagenesis of ubiquitination site, Co-immunoprecipitation, Deltex2 knockout mice, ChIP, shRNA knockdown","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro demethylase assay, mutagenesis of ubiquitination site abolishing inhibition, genetic epistasis in vivo, and multiple orthogonal methods in a single study","pmids":["28351977"],"is_preprint":false},{"year":2007,"finding":"A novel splice variant of JMJD1C (s-JMJD1C) was identified as a coactivator of the androgen receptor (AR). The interaction with AR was established by yeast two-hybrid screening using AR residues 325-919 as bait, confirmed by GST pull-down and mammalian one-hybrid assays. s-JMJD1C localizes to the nucleus.","method":"Yeast two-hybrid screen, GST pull-down, mammalian one-hybrid assay, RACE-PCR, immunofluorescence","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal yeast two-hybrid and GST pull-down confirming AR interaction, nuclear localization by immunofluorescence, but catalytic activity of this variant not directly demonstrated","pmids":["17353003"],"is_preprint":false},{"year":2013,"finding":"JMJD1C is expressed in hESCs, binds to the miR-302 promoter, and reduces H3K9 methylation at that locus, thereby maintaining miR-302 expression to inhibit neural differentiation. JMJD1C knockdown reduces miR-302 expression, decreases BMP signaling, enhances TGFβ signaling, and enables neural differentiation upon bFGF withdrawal.","method":"ChIP assay, shRNA stable knockdown, miR-302 mimic rescue experiment, signaling pathway analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP demonstrating direct promoter binding and H3K9 demethylation, stable knockdown with defined neural differentiation phenotype, and miR-302 mimic rescue, but single lab","pmids":["24318875"],"is_preprint":false},{"year":2013,"finding":"JMJD1C is required for long-term maintenance of male germ cells in mice. Jmjd1c-deficient males became progressively infertile due to reduction of germ cells after 3 months; JMJD1C is most abundantly expressed in undifferentiated spermatogonia, and its loss leads to age-dependent decreases in ZBTB16-positive spermatogonia and increases in apoptotic germ cells.","method":"Jmjd1c knockout mouse model, immunohistochemistry, flow cytometry, apoptosis assays","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with specific cellular phenotype (spermatogonia maintenance), but limited mechanistic follow-up on direct substrates in this study","pmids":["24006281"],"is_preprint":false},{"year":2015,"finding":"A Rett syndrome-associated de novo JMJD1C mutant shows abnormal subcellular localization, diminished demethylase activity toward MDC1, and reduced binding to MECP2. JMJD1C depletion in neurons compromises dendritic activity.","method":"Functional mutant analysis, in vitro demethylation assay, immunofluorescence localization, Co-immunoprecipitation, neuronal knockdown with morphological readout","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vitro demethylation assay on patient mutant, Co-IP for MECP2 binding, localization study, but single lab with limited sample size","pmids":["26181491"],"is_preprint":false},{"year":2017,"finding":"JMJD1C maintains mouse embryonic stem cell identity at least in part by regulating expression of the miR-200 family and miR-290/295 cluster (with help from KLF4) to suppress ERK/MAPK signaling and epithelial-to-mesenchymal transition. Jmjd1c depletion activates ERK/MAPK signaling and EMT, and ERK/MAPK inhibition rescues the differentiation phenotype.","method":"shRNA knockdown, ERK/MAPK inhibitor rescue, microRNA expression analysis, epistasis analysis","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic epistasis via inhibitor rescue, microRNA expression profiling, and KO phenotype, but mechanism linking JMJD1C to miRNA regulation is indirect and single lab","pmids":["28826851"],"is_preprint":false},{"year":2017,"finding":"Jmjd1c depletion in 3T3-L1 cells impairs adipogenesis by interfering with mitotic clonal expansion and by increasing H3K9me2 levels at promoter regions of key adipogenic transcription factors (C/EBPs and PPARγ), reducing their induction and subsequent lipid accumulation and glucose/fatty acid uptake.","method":"shRNA knockdown, ChIP assay for H3K9me2 at adipogenic promoters, triglyceride quantification, glucose/fatty acid uptake assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP demonstrating H3K9me2 changes at specific promoters, functional knockdown phenotype, but single lab and single cell line model","pmids":["28501567"],"is_preprint":false},{"year":2019,"finding":"The catalytic Jumonji (JmjC) domain and zinc finger domain of JMJD1C are required for leukemia cell survival in vitro and in vivo, identified by CRISPR/Cas9 negative-selection screening. H3K36 methylation (H3K36me) serves as a marker for JMJD1C activity at gene loci. Loss of the JmjC domain activates RAS/MAPK and JAK-STAT pathways and upregulates IL-3 receptor genes, leading to IL-3 signaling activation as a resistance mechanism.","method":"CRISPR/Cas9 negative-selection screen, single-cell RNA-seq, ChIP for H3K36me, domain-specific sgRNAs, in vivo transplantation","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR domain-specific screen with in vivo validation, single-cell transcriptomics, and ChIP for activity marker, but mechanistic link between JmjC and H3K36me requires further validation","pmids":["31076406"],"is_preprint":false},{"year":2024,"finding":"JMJD1C is essential for tumor regulatory T (Treg) cell fitness: JMJD1C deletion in Treg cells enhances AKT signals in an H3K9me2 demethylase-dependent manner and enhances STAT3 signals independently of H3K9me2 demethylase activity, leading to robust interferon-γ production and Treg cell fragility in the tumor microenvironment. An oral JMJD1C inhibitor was developed that suppresses tumor growth by targeting intratumoral Treg cells.","method":"Conditional T-cell-specific JMJD1C knockout, ChIP for H3K9me2, AKT/STAT3 signaling analysis, flow cytometry, small-molecule inhibitor","journal":"Nature immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with defined signaling phenotypes, mechanistic dissection of demethylase-dependent vs. independent STAT3 effects, but specific STAT3 substrate site not identified in this study","pmids":["38356061"],"is_preprint":false},{"year":2016,"finding":"JMJD1C exhibits multiple functions during spermatogenesis and interacts with partner proteins including MDC1 and HSP90; loss of JMJD1C leads to decreased histone H4K16 acetylation in spermatids (required for chromatin remodeling onset) and reduced Oct4 expression in spermatogonia, suggesting roles in spermatid maturation and spermatogonial stem cell self-renewal.","method":"Gene-trap knockout mouse model, immunostaining for H4K16ac, Co-immunoprecipitation with MDC1 and HSP90, Oct4 expression analysis","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP interactions with MDC1/HSP90, indirect association between JMJD1C loss and H4K16ac, single lab with limited mechanistic follow-up","pmids":["27649575"],"is_preprint":false},{"year":2018,"finding":"JMJD1C knockdown in colorectal cancer cells regulates ATF2 expression by modulating H3K9me2 (but not H3K9me1) activity at the ATF2 locus, and overexpression of ATF2 reverses the impaired migration and invasion caused by JMJD1C knockdown.","method":"shRNA knockdown, ChIP for H3K9me2/me1, rescue by ATF2 overexpression, in vitro migration/invasion assays","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and rescue experiment demonstrating H3K9me2-ATF2 axis, but single lab, limited mechanistic detail on direct vs indirect regulation","pmids":["29888107"],"is_preprint":false},{"year":2020,"finding":"JMJD1C regulates CAMKK2-AMPK signaling in cardiomyocytes: JMJD1C overexpression represses Camkk2 expression (but not LKB1), and pharmacological inhibition of CAMKK2 blocks the hypertrophic effects of JMJD1C. AMPK knockdown blocks the inhibitory effects of JMJD1C knockdown on Ang II-induced hypertrophy.","method":"shRNA knockdown, gene overexpression, CAMKK2 inhibitor (STO609), AMPK knockdown epistasis, cardiomyocyte size measurement","journal":"Frontiers in physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epistasis through inhibitor and knockdown, but mechanism linking JMJD1C to CAMKK2 transcription is indirect and from a single lab with limited methodological orthogonality","pmids":["32625104"],"is_preprint":false},{"year":2022,"finding":"JMJD1C regulates lipid synthesis genes (FADS2, SCD) in MLL-rearranged AML; FABP5 was identified as a specific interacting protein of JMJD1C that binds its jumonji domain and also regulates JMJD1C mRNA and protein expression.","method":"Mass spectrometry for interacting proteins, Co-immunoprecipitation, domain mapping, shRNA knockdown with lipidomics","journal":"Leukemia & lymphoma","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS identification of FABP5 interaction with jumonji domain, single lab, limited mechanistic characterization of how the interaction affects activity","pmids":["35468015"],"is_preprint":false},{"year":2024,"finding":"JMJD1C promotes PCSK9 transcription in macrophages through H3K9 demethylation at the PCSK9 locus, promoting foam cell formation; JMJD1C knockdown reduced PCSK9 expression and attenuated atherosclerosis in vivo.","method":"ChIP assay for H3K9 methylation at PCSK9 promoter, shRNA knockdown, PCSK9 overexpression rescue, mouse atherosclerosis model","journal":"Journal of physiology and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP demonstrating H3K9 demethylation at PCSK9 locus, rescue experiment, but single lab and indirect mechanistic evidence","pmids":["39511107"],"is_preprint":false},{"year":2024,"finding":"JMJD1C deficiency in B cells increases H3K36me1 modification at gene start sites of BCR signaling, NF-κB, cell cycle, and SLE-associated pathways, leading to B-cell hyperactivation and production of self-reactive antibodies including PF4/heparin-specific platelet-activating antibodies characteristic of heparin-induced thrombocytopenia.","method":"Conditional B-cell JMJD1C knockout, RNA-seq, CUT&Tag for H3K36me1, B-cell functional assays, human HIT patient B-cell transcriptomics","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag demonstrating H3K36me1 as a substrate mark, conditional knockout with defined B-cell phenotype, and translational validation in human HIT patients, multiple orthogonal methods in single lab","pmids":["42095895"],"is_preprint":false},{"year":2026,"finding":"Endothelial-specific deletion of Jmjd1c suppresses Srebf2 transcription by increasing repressive H3K9me2 marks at the Srebf2 locus in endothelial cells, thereby reducing cholesterol biosynthesis and pathological ocular neovascularization. JMJD1C acts as a key regulator of the Jmjd1c-Srebf2 regulatory axis in endothelial cells.","method":"Endothelial-specific Jmjd1c knockout, ChIP-qPCR for H3K9me2, RNA-seq, in vitro angiogenesis assays, in vivo OIR and CNV models","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR demonstrating H3K9me2 changes at Srebf2 locus, endothelial-specific KO with multiple in vitro and in vivo phenotypic readouts, multiple orthogonal methods in single lab","pmids":["41548765"],"is_preprint":false},{"year":2025,"finding":"Jmjd1c positively regulates Socs3 expression by increasing H3K9 demethylation activity at the Socs3 promoter; the Jmjd1c/Socs3/JAK/STAT3 pathway was validated as downstream in neuropathic pain. KLF15 was shown to activate Jmjd1c transcription by binding to a super-enhancer of Jmjd1c.","method":"Dual-luciferase reporter assay, ChIP-seq, RNA-seq, rat neuropathic pain model, ChIP for H3K9 demethylation at Socs3 promoter, gain/loss-of-function experiments","journal":"Genes & diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and reporter assay for Socs3 regulation, but mechanistic detail is limited, single lab, and regulatory pathway not fully biochemically reconstituted","pmids":["40485981"],"is_preprint":false}],"current_model":"JMJD1C (KDM3C/TRIP8) is a JmjC domain-containing histone demethylase that removes mono- and di-methyl marks from histone H3K9 (H3K9me1/2) and also acts on non-histone substrates including MDC1 (Lys45) and STAT3 (Lys140); it is phosphorylated by mTOR at T505 to enable interaction with USF-1 for lipogenic gene activation, can be inhibited by Deltex2-mediated monoubiquitination, and functions as a transcriptional coactivator by recruiting to target gene promoters in complex with partners such as RNF8, RUNX1-RUNX1T1, HOXA9, USF-1, WHISTLE, and AR, with defined roles in DNA damage response (RAP80-BRCA1 branch), leukemia stem cell self-renewal, adipogenesis, lipogenesis, spermatogenesis, B-cell differentiation restraint, and Treg cell fitness."},"narrative":{"mechanistic_narrative":"JMJD1C is a JmjC-domain histone demethylase that erases mono- and di-methyl marks from histone H3K9 (H3K9me1/2) to convert repressive chromatin into a transcriptionally permissive state at target promoters [PMID:20530532]. Beyond chromatin, it also demethylates non-histone substrates: it removes methylation from MDC1 at Lys45 to promote MDC1-RNF8 interaction, RNF8-dependent ubiquitylation, and recruitment of the RAP80-BRCA1 complex to DNA double-strand breaks, with JMJD1C itself stabilized by RNF8 and required for radiation/PARP-inhibitor sensitivity [PMID:24240613], and it demethylates STAT3 at Lys140 to permit STAT3-Ptpn6 association and limit STAT3 phosphorylation [PMID:35995859]. As a transcriptional coactivator JMJD1C is recruited to promoters by sequence-specific and complex partners — RUNX1-RUNX1T1 [PMID:26494788], HOXA9 [PMID:26878175], USF-1 [PMID:32034158], and the WHISTLE/SF-1 complex [PMID:20530532] — where it lowers H3K9me2 to activate target programs. Its activity is gated by post-translational control: mTOR phosphorylates JMJD1C at T505 in response to feeding/insulin to enable USF-1 binding and lipogenic gene activation [PMID:32034158], while Deltex2-mediated monoubiquitination inhibits its demethylase activity to restrain myogenic differentiation [PMID:28351977]. Through these activities JMJD1C governs leukemia stem-cell self-renewal in MLL-AF9/HOXA9 and RUNX1-RUNX1T1 AML [PMID:26494788, PMID:26878175], lipogenesis and adipogenesis [PMID:32034158, PMID:28501567], spermatogonial maintenance [PMID:24006281], stem-cell identity [PMID:24318875, PMID:28826851], and immune-cell fitness including B-cell differentiation and Treg function [PMID:35995859, PMID:38356061, PMID:42095895]. A de novo JMJD1C mutation associated with Rett-like neurodevelopmental disease shows mislocalization, reduced MDC1 demethylation, and impaired MECP2 binding [PMID:26181491].","teleology":[{"year":2007,"claim":"Established the first physical link between JMJD1C and a sequence-specific transcription factor, framing it as a nuclear nuclear-receptor coactivator before its enzymatic activity was defined.","evidence":"Yeast two-hybrid, GST pull-down, mammalian one-hybrid, and immunofluorescence of a JMJD1C splice variant (s-JMJD1C) with AR","pmids":["17353003"],"confidence":"Medium","gaps":["Catalytic activity of the s-JMJD1C variant was not demonstrated","Endogenous AR-JMJD1C function in cells not tested"]},{"year":2010,"claim":"Defined JMJD1C's core enzymatic identity as an H3K9me1/2 demethylase and showed it operates within a transcription-activating chromatin complex at a steroidogenic promoter.","evidence":"TAP purification, in vitro histone demethylation assay, ChIP and reporter assays in mouse testis context (WHISTLE/SF-1/HSP90α)","pmids":["20530532"],"confidence":"High","gaps":["Genome-wide target spectrum not mapped","In vivo requirement for steroidogenesis not tested"]},{"year":2013,"claim":"Revealed that JMJD1C acts on a non-histone substrate (MDC1 Lys45) to drive the RAP80-BRCA1 branch of the DNA damage response, expanding its mechanism beyond chromatin and linking it to therapy sensitivity.","evidence":"In vitro demethylation assay, reciprocal Co-IP, laser micro-irradiation, shRNA with ubiquitylation/foci/radiation-sensitivity readouts","pmids":["24240613"],"confidence":"High","gaps":["Demethylase regulation at DSBs vs. promoters not distinguished","Structural basis of MDC1 substrate recognition unknown"]},{"year":2013,"claim":"Extended JMJD1C function to stem-cell maintenance, showing promoter-level H3K9 demethylation sustains a miRNA (miR-302) program that suppresses neural differentiation.","evidence":"ChIP, stable shRNA knockdown, miR-302 mimic rescue, signaling pathway analysis in hESCs","pmids":["24318875"],"confidence":"Medium","gaps":["Direct vs. indirect control of miR-302 not fully resolved","Single lab"]},{"year":2013,"claim":"Demonstrated an in vivo physiological requirement for JMJD1C in long-term male germ-cell maintenance.","evidence":"Jmjd1c knockout mouse, immunohistochemistry, flow cytometry, apoptosis assays","pmids":["24006281"],"confidence":"Medium","gaps":["Direct substrates in spermatogonia not identified","Cell-autonomous vs. niche effects unresolved"]},{"year":2015,"claim":"Positioned JMJD1C as an oncogenic coactivator in AML, directly recruited by the RUNX1-RUNX1T1 fusion to maintain low H3K9me2 at target genes and drive leukemic proliferation in vivo.","evidence":"ChIP-seq, Co-IP, shRNA knockdown, JMJD1C knockout mouse","pmids":["26494788"],"confidence":"High","gaps":["Whether demethylase catalysis is strictly required not dissected here","Selectivity over normal hematopoiesis only partly addressed"]},{"year":2015,"claim":"Connected JMJD1C to neurodevelopmental disease by showing a Rett-associated de novo mutant has reduced MDC1 demethylation, altered localization, and impaired MECP2 binding.","evidence":"Patient mutant functional analysis, in vitro demethylation assay, immunofluorescence, Co-IP, neuronal knockdown","pmids":["26181491"],"confidence":"Medium","gaps":["Single patient/limited sample size","Causality for the clinical phenotype not established genetically"]},{"year":2016,"claim":"Showed JMJD1C is selectively required for leukemia stem-cell self-renewal via direct HOXA9 interaction, with minimal effect on normal HSCs — establishing a therapeutic window.","evidence":"In vivo shRNA screen, conditional knockout mice, Co-IP, gene expression analysis in MLL-AF9/HOXA9 models","pmids":["26878175"],"confidence":"High","gaps":["Whether HOXA9 recruitment depends on catalytic activity not resolved","Mechanism of LSC vs. HSC differential dependence unclear"]},{"year":2016,"claim":"Implicated JMJD1C protein interactions (MDC1, HSP90) in distinct spermatogenic stages and linked its loss to altered H4K16 acetylation and Oct4 levels.","evidence":"Gene-trap knockout mouse, immunostaining, Co-IP","pmids":["27649575"],"confidence":"Low","gaps":["Single Co-IP interactions without reciprocal validation","H4K16ac link is correlative, not mechanistic"]},{"year":2017,"claim":"Identified post-translational restraint of JMJD1C activity: Deltex2-mediated monoubiquitination inhibits demethylation, controlling H3K9me2 at the MyoD locus during myogenesis.","evidence":"In vitro demethylation assay, mutagenesis of the ubiquitination site, Co-IP, Deltex2 knockout mice, ChIP, shRNA","pmids":["28351977"],"confidence":"High","gaps":["Deltex2 deubiquitinase counterpart not identified","Whether other contexts use this regulation unknown"]},{"year":2017,"claim":"Broadened JMJD1C's stem-cell role to mouse ESC identity, acting through miR-200 and miR-290/295 (with KLF4) to suppress ERK/MAPK and EMT.","evidence":"shRNA knockdown, ERK/MAPK inhibitor rescue, miRNA expression and epistasis analysis","pmids":["28826851"],"confidence":"Medium","gaps":["Link between JMJD1C and miRNA loci is indirect","Single lab"]},{"year":2017,"claim":"Established a metabolic role in adipogenesis, with JMJD1C controlling H3K9me2 at C/EBP and PPARγ promoters and mitotic clonal expansion.","evidence":"shRNA knockdown in 3T3-L1, ChIP for H3K9me2, triglyceride and uptake assays","pmids":["28501567"],"confidence":"Medium","gaps":["Single cell-line model","Direct promoter occupancy vs. indirect effect not fully separated"]},{"year":2018,"claim":"Extended H3K9me2-dependent target regulation to ATF2 in colorectal cancer migration/invasion.","evidence":"shRNA knockdown, ChIP for H3K9me2/me1, ATF2 overexpression rescue, migration/invasion assays","pmids":["29888107"],"confidence":"Low","gaps":["Direct vs. indirect ATF2 regulation not resolved","Single lab"]},{"year":2019,"claim":"Genetically defined the JmjC and zinc-finger domains as essential for leukemia survival and surfaced IL-3/RAS-MAPK/JAK-STAT signaling as a resistance route, with H3K36me marking JMJD1C activity.","evidence":"CRISPR/Cas9 negative-selection screen, domain-specific sgRNAs, scRNA-seq, ChIP for H3K36me, in vivo transplantation","pmids":["31076406"],"confidence":"Medium","gaps":["Biochemical basis of JmjC-H3K36me relationship needs validation","Whether H3K36me is a direct substrate unconfirmed here"]},{"year":2020,"claim":"Identified a signal-responsive activation switch: mTOR phosphorylates JMJD1C at T505 upon feeding/insulin to enable USF-1 binding and lipogenic gene activation, linking nutrient sensing to chromatin output.","evidence":"In vitro kinase assay, T505 mutagenesis, Co-IP, ChIP, mouse liver overexpression/knockdown","pmids":["32034158"],"confidence":"High","gaps":["Phosphatase reversing T505 not identified","Structural consequence of phosphorylation on USF-1 binding unknown"]},{"year":2020,"claim":"Implicated JMJD1C in cardiomyocyte hypertrophy through repression of Camkk2 and downstream AMPK signaling.","evidence":"shRNA/overexpression, CAMKK2 inhibitor and AMPK knockdown epistasis, cell-size measurement","pmids":["32625104"],"confidence":"Low","gaps":["Link from JMJD1C to Camkk2 transcription is indirect","Single lab, limited orthogonality"]},{"year":2022,"claim":"Showed JMJD1C demethylates STAT3 at Lys140 to enable STAT3-Ptpn6 interaction, restraining STAT3 activity and plasma-cell differentiation — a second defined non-histone substrate.","evidence":"Conditional knockout mice, in vitro demethylation assay, K140R mutagenesis, Co-IP, flow cytometry","pmids":["35995859"],"confidence":"High","gaps":["Direct methyltransferase placing STAT3 K140me not identified","Generalization beyond B cells not addressed here"]},{"year":2022,"claim":"Linked JMJD1C to lipid-synthesis gene regulation in MLL-rearranged AML and identified FABP5 as a JmjC-domain-binding partner that feeds back on JMJD1C expression.","evidence":"Mass spectrometry, Co-IP, domain mapping, shRNA with lipidomics","pmids":["35468015"],"confidence":"Low","gaps":["Single Co-IP/MS without reciprocal validation","How FABP5 binding alters catalytic activity uncharacterized"]},{"year":2024,"claim":"Dissected demethylase-dependent (AKT, H3K9me2) versus demethylase-independent (STAT3) contributions of JMJD1C to Treg fitness and validated an oral inhibitor that destabilizes intratumoral Tregs.","evidence":"T-cell-specific conditional knockout, ChIP for H3K9me2, AKT/STAT3 analysis, flow cytometry, small-molecule inhibitor","pmids":["38356061"],"confidence":"Medium","gaps":["Specific STAT3 substrate site in Tregs not identified","Selectivity/off-target profile of inhibitor not detailed"]},{"year":2024,"claim":"Implicated JMJD1C loss in B-cell hyperactivation and autoantibody production (HIT) via increased H3K36me1 at start sites of BCR/NF-κB/cell-cycle genes, nominating H3K36me1 as a substrate mark.","evidence":"Conditional B-cell knockout, RNA-seq, CUT&Tag for H3K36me1, human HIT patient transcriptomics","pmids":["42095895"],"confidence":"Medium","gaps":["Direct H3K36me1 demethylation by JMJD1C not biochemically shown","Relationship between H3K9 and H3K36 substrate activities unresolved"]},{"year":2024,"claim":"Extended H3K9-demethylase-dependent transcriptional control to macrophage PCSK9 and foam-cell formation in atherosclerosis.","evidence":"ChIP for H3K9 methylation, shRNA knockdown, PCSK9 rescue, mouse atherosclerosis model","pmids":["39511107"],"confidence":"Low","gaps":["Direct PCSK9 promoter occupancy vs. indirect effect not resolved","Single lab"]},{"year":2025,"claim":"Proposed a KLF15-driven, super-enhancer-controlled Jmjd1c/Socs3/JAK-STAT3 axis in neuropathic pain.","evidence":"Dual-luciferase reporter, ChIP-seq, RNA-seq, rat neuropathic pain model, ChIP at Socs3 promoter","pmids":["40485981"],"confidence":"Low","gaps":["Pathway not biochemically reconstituted","Single lab, limited mechanistic depth"]},{"year":2026,"claim":"Defined an endothelial Jmjd1c-Srebf2 axis controlling cholesterol biosynthesis and pathological neovascularization via H3K9me2 at the Srebf2 locus.","evidence":"Endothelial-specific knockout, ChIP-qPCR for H3K9me2, RNA-seq, angiogenesis and OIR/CNV models","pmids":["41548765"],"confidence":"Medium","gaps":["Direct vs. indirect Srebf2 promoter regulation not fully resolved","Upstream signal recruiting JMJD1C to Srebf2 unknown"]},{"year":null,"claim":"It remains unresolved how JMJD1C's distinct substrate activities (H3K9me1/2, H3K36me, and non-histone targets MDC1 and STAT3) are partitioned across cellular contexts, and what structural and recruitment determinants direct it between DNA-repair, chromatin-activation, and signaling roles.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate selection","Methyltransferases generating the non-histone methyl marks unidentified","Rules governing histone vs. non-histone substrate choice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[1,2,4]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[1,0,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,4,7]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,10]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,4]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,14,20]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,9,8,11]}],"complexes":[],"partners":["RNF8","MDC1","STAT3","USF-1","HOXA9","RUNX1-RUNX1T1","MECP2","FABP5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15652","full_name":"Jumonji domain-containing protein 1C","aliases":["Thyroid receptor-interacting protein 8","TR-interacting protein 8","TRIP-8"],"length_aa":2540,"mass_kda":284.5,"function":"Demethylates lysine in proteins, such as STAT3 or MDC1 (By similarity) (PubMed:24240613). Demethylates MDC1, thereby promoting MDC1-RNF8 interaction and facilitating RNF8-dependent MDC1 ubiquitination essential for double-strand break (DSB) repair (PubMed:24240613). Demethylation of STAT3 at 'Lys-140' facilitates its interactions with the phosphatase PTPN6 and restrains STAT3 activation (By similarity). It is uncertain whether JMJD1C removes methyl groups from histone proteins as the other JMJD1/KDM3 proteins do (PubMed:23593242, PubMed:24240613, PubMed:32034158). Nevertheless, JMJD1C may act as a context-specific histone demethylase. Implicated in lipogenic gene transcription in the liver, where USF1 recruits JMJD1C to lipogenic promoters in response to insulin or feeding stimuli, thereby potentially promoting H3K9me2 demethylation and enhancing chromatin accessibility (PubMed:32034158). Post-translational modifications may regulate JMJD1C's enzymatic activity, contributing to its context-specific functions (PubMed:32034158). Alternatively, JMJD1C may influence chromatin regulation indirectly, acting as a scaffold or co-regulator that recruits or stabilizes other active demethylase complexes modifying histone marks (PubMed:24240613). Plays an indispensable role in spermatogenesis (By similarity) Coactivator of androgen receptor","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15652/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JMJD1C","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2},{"gene":"H1F0","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/JMJD1C","total_profiled":1310},"omim":[{"mim_id":"612369","title":"ALKALINE PHOSPHATASE, PLASMA LEVEL OF, QUANTITATIVE TRAIT LOCUS 4","url":"https://www.omim.org/entry/612369"},{"mim_id":"609766","title":"LYSINE DEMETHYLASE 4D; KDM4D","url":"https://www.omim.org/entry/609766"},{"mim_id":"609765","title":"LYSINE DEMETHYLASE 4B; KDM4B","url":"https://www.omim.org/entry/609765"},{"mim_id":"609764","title":"LYSINE DEMETHYLASE 4A; KDM4A","url":"https://www.omim.org/entry/609764"},{"mim_id":"605469","title":"LYSINE DEMETHYLASE 4C; KDM4C","url":"https://www.omim.org/entry/605469"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/JMJD1C"},"hgnc":{"alias_symbol":["DKFZp761F0118","KIAA1380","FLJ14374","KDM3C"],"prev_symbol":["TRIP8"]},"alphafold":{"accession":"Q15652","domains":[{"cath_id":"-","chopping":"2-20_35-97_104-184","consensus_level":"medium","plddt":82.0288,"start":2,"end":184},{"cath_id":"2.30.30,2.30.30","chopping":"186-253","consensus_level":"medium","plddt":85.3753,"start":186,"end":253},{"cath_id":"-","chopping":"1714-1930_2535-2540","consensus_level":"medium","plddt":83.8017,"start":1714,"end":2540},{"cath_id":"2.60.120.650","chopping":"2159-2390_2454-2484","consensus_level":"high","plddt":91.4677,"start":2159,"end":2484}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15652","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15652-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15652-F1-predicted_aligned_error_v6.png","plddt_mean":49.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JMJD1C","jax_strain_url":"https://www.jax.org/strain/search?query=JMJD1C"},"sequence":{"accession":"Q15652","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15652.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15652/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15652"}},"corpus_meta":[{"pmid":"24240613","id":"PMC_24240613","title":"JMJD1C 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undifferentiated ES cells and diffuse-type gastric cancer.","date":"2007","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17549425","citation_count":27,"is_preprint":false},{"pmid":"36934091","id":"PMC_36934091","title":"JMJD1C promotes smooth muscle cell proliferation by activating glycolysis in pulmonary arterial hypertension.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36934091","citation_count":26,"is_preprint":false},{"pmid":"32122211","id":"PMC_32122211","title":"Inhibition of histone demethylase JMJD1C attenuates cardiac hypertrophy and fibrosis induced by angiotensin II.","date":"2020","source":"Journal of receptor and signal transduction research","url":"https://pubmed.ncbi.nlm.nih.gov/32122211","citation_count":26,"is_preprint":false},{"pmid":"28123852","id":"PMC_28123852","title":"Histone demethylase JMJD1C regulates esophageal cancer proliferation Via YAP1 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JMJD1C is stabilized by interaction with RNF8 and is recruited to DSBs, and is required for local ubiquitylations and RAP80-BRCA1 recruitment but not 53BP1 recruitment. JMJD1C depletion caused resistance to ionizing radiation and PARP inhibitors.\",\n      \"method\": \"Co-immunoprecipitation, in vitro demethylation assay, laser micro-irradiation/live-cell imaging, shRNA knockdown with functional readouts (ubiquitylation, foci formation, radiation sensitivity)\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro demethylation assay demonstrating catalytic activity, reciprocal Co-IP for protein interactions, and multiple orthogonal functional readouts in a single rigorous study\",\n      \"pmids\": [\"24240613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"JMJD1C specifically demethylates histone H3K9 mono- and di-methylation and mediates transcriptional activation. JMJD1C was identified as a component of WHISTLE-interacting protein complexes (also containing HSP90α) and replaces WHISTLE at the p450c17 promoter to activate steroidogenesis gene expression via SF-1-mediated interactions during mouse testis development.\",\n      \"method\": \"Immunoaffinity TAP purification, in vitro histone demethylation assay, chromatin immunoprecipitation (ChIP), reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro demethylation assay demonstrating H3K9me1/2 activity, TAP purification identifying complex components, and ChIP showing promoter recruitment, multiple orthogonal methods\",\n      \"pmids\": [\"20530532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JMJD1C functions as a transcriptional coactivator for RUNX1-RUNX1T1 (AML1-ETO) in acute myeloid leukemia; it is directly recruited to RUNX1-RUNX1T1 target genes and regulates their expression by maintaining low H3K9me2 levels. JMJD1C is also required for RUNX1-RUNX1T1-driven proliferation in vivo in knockout mice.\",\n      \"method\": \"ChIP-seq, Co-immunoprecipitation, shRNA knockdown, JMJD1C knockout mouse model\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP showing direct recruitment, ChIP-seq demonstrating H3K9me2 regulation at target loci, and in vivo genetic validation in knockout mice across multiple orthogonal methods\",\n      \"pmids\": [\"26494788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"JMJD1C directly interacts with HOXA9 and modulates a HOXA9-controlled gene-expression program required for MLL-AF9 and HOXA9-driven leukemia stem cell self-renewal. Conditional knockout of JMJD1C substantially decreased LSC frequency and caused differentiation, while only minor defects were observed in normal hematopoietic stem cells.\",\n      \"method\": \"In vivo shRNA screen, conditional JMJD1C knockout mice, Co-immunoprecipitation, gene expression analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic screen and conditional knockout with defined cellular phenotypes, Co-IP demonstrating direct HOXA9 interaction, replicated across MLL-AF9 and HOXA9-driven leukemia models\",\n      \"pmids\": [\"26878175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD1C is phosphorylated at T505 by mTOR complex in response to feeding/insulin, allowing direct interaction with USF-1 and recruitment to lipogenic gene promoters. JMJD1C demethylates H3K9me2 at these promoters to allow transcriptional activation of lipogenic genes (fatty acid synthase, glycerol-3-phosphate acyltransferase), promoting hepatic and plasma triglyceride synthesis.\",\n      \"method\": \"In vitro kinase assay, Co-immunoprecipitation, ChIP, site-directed mutagenesis of T505, mouse liver overexpression/knockdown models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — kinase assay identifying mTOR as the T505 kinase, mutagenesis validating the phosphorylation site functionally, Co-IP for USF-1 interaction, and ChIP for promoter recruitment in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"32034158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Jmjd1c demethylates STAT3 at Lys140 (a non-histone substrate) in B cells to restrain plasma cell differentiation. STAT3 Lys140 hypermethylation caused by Jmjd1c deletion inhibits the interaction of STAT3 with phosphatase Ptpn6, resulting in abnormally sustained STAT3 phosphorylation and activity that promotes plasma cell generation. STAT3 Lys140Arg point mutation completely abrogated the effect of Jmjd1c loss.\",\n      \"method\": \"Conditional knockout mice, in vitro demethylation assay, site-directed mutagenesis (K140R), Co-immunoprecipitation, flow cytometry\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro demethylation assay on non-histone substrate, mutagenesis (K140R) abolishing the phenotype, Co-IP demonstrating STAT3-Ptpn6 interaction dependency, and conditional KO mouse model across multiple orthogonal methods\",\n      \"pmids\": [\"35995859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Deltex2 directly inhibits Jmjd1c demethylase activity by promoting Jmjd1c monoubiquitination; mutation of the monoubiquitination site in Jmjd1c abolishes this inhibitory effect. Jmjd1c activity is required for MyoD expression in vivo and in vitro through removal of H3K9me2 at the MyoD locus. Deltex2 and Jmjd1c act in an epistatic relationship to regulate myogenic differentiation.\",\n      \"method\": \"In vitro demethylation assay, site-directed mutagenesis of ubiquitination site, Co-immunoprecipitation, Deltex2 knockout mice, ChIP, shRNA knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro demethylase assay, mutagenesis of ubiquitination site abolishing inhibition, genetic epistasis in vivo, and multiple orthogonal methods in a single study\",\n      \"pmids\": [\"28351977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A novel splice variant of JMJD1C (s-JMJD1C) was identified as a coactivator of the androgen receptor (AR). The interaction with AR was established by yeast two-hybrid screening using AR residues 325-919 as bait, confirmed by GST pull-down and mammalian one-hybrid assays. s-JMJD1C localizes to the nucleus.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down, mammalian one-hybrid assay, RACE-PCR, immunofluorescence\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal yeast two-hybrid and GST pull-down confirming AR interaction, nuclear localization by immunofluorescence, but catalytic activity of this variant not directly demonstrated\",\n      \"pmids\": [\"17353003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JMJD1C is expressed in hESCs, binds to the miR-302 promoter, and reduces H3K9 methylation at that locus, thereby maintaining miR-302 expression to inhibit neural differentiation. JMJD1C knockdown reduces miR-302 expression, decreases BMP signaling, enhances TGFβ signaling, and enables neural differentiation upon bFGF withdrawal.\",\n      \"method\": \"ChIP assay, shRNA stable knockdown, miR-302 mimic rescue experiment, signaling pathway analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP demonstrating direct promoter binding and H3K9 demethylation, stable knockdown with defined neural differentiation phenotype, and miR-302 mimic rescue, but single lab\",\n      \"pmids\": [\"24318875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JMJD1C is required for long-term maintenance of male germ cells in mice. Jmjd1c-deficient males became progressively infertile due to reduction of germ cells after 3 months; JMJD1C is most abundantly expressed in undifferentiated spermatogonia, and its loss leads to age-dependent decreases in ZBTB16-positive spermatogonia and increases in apoptotic germ cells.\",\n      \"method\": \"Jmjd1c knockout mouse model, immunohistochemistry, flow cytometry, apoptosis assays\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with specific cellular phenotype (spermatogonia maintenance), but limited mechanistic follow-up on direct substrates in this study\",\n      \"pmids\": [\"24006281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A Rett syndrome-associated de novo JMJD1C mutant shows abnormal subcellular localization, diminished demethylase activity toward MDC1, and reduced binding to MECP2. JMJD1C depletion in neurons compromises dendritic activity.\",\n      \"method\": \"Functional mutant analysis, in vitro demethylation assay, immunofluorescence localization, Co-immunoprecipitation, neuronal knockdown with morphological readout\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vitro demethylation assay on patient mutant, Co-IP for MECP2 binding, localization study, but single lab with limited sample size\",\n      \"pmids\": [\"26181491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD1C maintains mouse embryonic stem cell identity at least in part by regulating expression of the miR-200 family and miR-290/295 cluster (with help from KLF4) to suppress ERK/MAPK signaling and epithelial-to-mesenchymal transition. Jmjd1c depletion activates ERK/MAPK signaling and EMT, and ERK/MAPK inhibition rescues the differentiation phenotype.\",\n      \"method\": \"shRNA knockdown, ERK/MAPK inhibitor rescue, microRNA expression analysis, epistasis analysis\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic epistasis via inhibitor rescue, microRNA expression profiling, and KO phenotype, but mechanism linking JMJD1C to miRNA regulation is indirect and single lab\",\n      \"pmids\": [\"28826851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Jmjd1c depletion in 3T3-L1 cells impairs adipogenesis by interfering with mitotic clonal expansion and by increasing H3K9me2 levels at promoter regions of key adipogenic transcription factors (C/EBPs and PPARγ), reducing their induction and subsequent lipid accumulation and glucose/fatty acid uptake.\",\n      \"method\": \"shRNA knockdown, ChIP assay for H3K9me2 at adipogenic promoters, triglyceride quantification, glucose/fatty acid uptake assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP demonstrating H3K9me2 changes at specific promoters, functional knockdown phenotype, but single lab and single cell line model\",\n      \"pmids\": [\"28501567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The catalytic Jumonji (JmjC) domain and zinc finger domain of JMJD1C are required for leukemia cell survival in vitro and in vivo, identified by CRISPR/Cas9 negative-selection screening. H3K36 methylation (H3K36me) serves as a marker for JMJD1C activity at gene loci. Loss of the JmjC domain activates RAS/MAPK and JAK-STAT pathways and upregulates IL-3 receptor genes, leading to IL-3 signaling activation as a resistance mechanism.\",\n      \"method\": \"CRISPR/Cas9 negative-selection screen, single-cell RNA-seq, ChIP for H3K36me, domain-specific sgRNAs, in vivo transplantation\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR domain-specific screen with in vivo validation, single-cell transcriptomics, and ChIP for activity marker, but mechanistic link between JmjC and H3K36me requires further validation\",\n      \"pmids\": [\"31076406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JMJD1C is essential for tumor regulatory T (Treg) cell fitness: JMJD1C deletion in Treg cells enhances AKT signals in an H3K9me2 demethylase-dependent manner and enhances STAT3 signals independently of H3K9me2 demethylase activity, leading to robust interferon-γ production and Treg cell fragility in the tumor microenvironment. An oral JMJD1C inhibitor was developed that suppresses tumor growth by targeting intratumoral Treg cells.\",\n      \"method\": \"Conditional T-cell-specific JMJD1C knockout, ChIP for H3K9me2, AKT/STAT3 signaling analysis, flow cytometry, small-molecule inhibitor\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with defined signaling phenotypes, mechanistic dissection of demethylase-dependent vs. independent STAT3 effects, but specific STAT3 substrate site not identified in this study\",\n      \"pmids\": [\"38356061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"JMJD1C exhibits multiple functions during spermatogenesis and interacts with partner proteins including MDC1 and HSP90; loss of JMJD1C leads to decreased histone H4K16 acetylation in spermatids (required for chromatin remodeling onset) and reduced Oct4 expression in spermatogonia, suggesting roles in spermatid maturation and spermatogonial stem cell self-renewal.\",\n      \"method\": \"Gene-trap knockout mouse model, immunostaining for H4K16ac, Co-immunoprecipitation with MDC1 and HSP90, Oct4 expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP interactions with MDC1/HSP90, indirect association between JMJD1C loss and H4K16ac, single lab with limited mechanistic follow-up\",\n      \"pmids\": [\"27649575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD1C knockdown in colorectal cancer cells regulates ATF2 expression by modulating H3K9me2 (but not H3K9me1) activity at the ATF2 locus, and overexpression of ATF2 reverses the impaired migration and invasion caused by JMJD1C knockdown.\",\n      \"method\": \"shRNA knockdown, ChIP for H3K9me2/me1, rescue by ATF2 overexpression, in vitro migration/invasion assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and rescue experiment demonstrating H3K9me2-ATF2 axis, but single lab, limited mechanistic detail on direct vs indirect regulation\",\n      \"pmids\": [\"29888107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD1C regulates CAMKK2-AMPK signaling in cardiomyocytes: JMJD1C overexpression represses Camkk2 expression (but not LKB1), and pharmacological inhibition of CAMKK2 blocks the hypertrophic effects of JMJD1C. AMPK knockdown blocks the inhibitory effects of JMJD1C knockdown on Ang II-induced hypertrophy.\",\n      \"method\": \"shRNA knockdown, gene overexpression, CAMKK2 inhibitor (STO609), AMPK knockdown epistasis, cardiomyocyte size measurement\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epistasis through inhibitor and knockdown, but mechanism linking JMJD1C to CAMKK2 transcription is indirect and from a single lab with limited methodological orthogonality\",\n      \"pmids\": [\"32625104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JMJD1C regulates lipid synthesis genes (FADS2, SCD) in MLL-rearranged AML; FABP5 was identified as a specific interacting protein of JMJD1C that binds its jumonji domain and also regulates JMJD1C mRNA and protein expression.\",\n      \"method\": \"Mass spectrometry for interacting proteins, Co-immunoprecipitation, domain mapping, shRNA knockdown with lipidomics\",\n      \"journal\": \"Leukemia & lymphoma\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS identification of FABP5 interaction with jumonji domain, single lab, limited mechanistic characterization of how the interaction affects activity\",\n      \"pmids\": [\"35468015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JMJD1C promotes PCSK9 transcription in macrophages through H3K9 demethylation at the PCSK9 locus, promoting foam cell formation; JMJD1C knockdown reduced PCSK9 expression and attenuated atherosclerosis in vivo.\",\n      \"method\": \"ChIP assay for H3K9 methylation at PCSK9 promoter, shRNA knockdown, PCSK9 overexpression rescue, mouse atherosclerosis model\",\n      \"journal\": \"Journal of physiology and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP demonstrating H3K9 demethylation at PCSK9 locus, rescue experiment, but single lab and indirect mechanistic evidence\",\n      \"pmids\": [\"39511107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JMJD1C deficiency in B cells increases H3K36me1 modification at gene start sites of BCR signaling, NF-κB, cell cycle, and SLE-associated pathways, leading to B-cell hyperactivation and production of self-reactive antibodies including PF4/heparin-specific platelet-activating antibodies characteristic of heparin-induced thrombocytopenia.\",\n      \"method\": \"Conditional B-cell JMJD1C knockout, RNA-seq, CUT&Tag for H3K36me1, B-cell functional assays, human HIT patient B-cell transcriptomics\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag demonstrating H3K36me1 as a substrate mark, conditional knockout with defined B-cell phenotype, and translational validation in human HIT patients, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"42095895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Endothelial-specific deletion of Jmjd1c suppresses Srebf2 transcription by increasing repressive H3K9me2 marks at the Srebf2 locus in endothelial cells, thereby reducing cholesterol biosynthesis and pathological ocular neovascularization. JMJD1C acts as a key regulator of the Jmjd1c-Srebf2 regulatory axis in endothelial cells.\",\n      \"method\": \"Endothelial-specific Jmjd1c knockout, ChIP-qPCR for H3K9me2, RNA-seq, in vitro angiogenesis assays, in vivo OIR and CNV models\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR demonstrating H3K9me2 changes at Srebf2 locus, endothelial-specific KO with multiple in vitro and in vivo phenotypic readouts, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"41548765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Jmjd1c positively regulates Socs3 expression by increasing H3K9 demethylation activity at the Socs3 promoter; the Jmjd1c/Socs3/JAK/STAT3 pathway was validated as downstream in neuropathic pain. KLF15 was shown to activate Jmjd1c transcription by binding to a super-enhancer of Jmjd1c.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP-seq, RNA-seq, rat neuropathic pain model, ChIP for H3K9 demethylation at Socs3 promoter, gain/loss-of-function experiments\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and reporter assay for Socs3 regulation, but mechanistic detail is limited, single lab, and regulatory pathway not fully biochemically reconstituted\",\n      \"pmids\": [\"40485981\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JMJD1C (KDM3C/TRIP8) is a JmjC domain-containing histone demethylase that removes mono- and di-methyl marks from histone H3K9 (H3K9me1/2) and also acts on non-histone substrates including MDC1 (Lys45) and STAT3 (Lys140); it is phosphorylated by mTOR at T505 to enable interaction with USF-1 for lipogenic gene activation, can be inhibited by Deltex2-mediated monoubiquitination, and functions as a transcriptional coactivator by recruiting to target gene promoters in complex with partners such as RNF8, RUNX1-RUNX1T1, HOXA9, USF-1, WHISTLE, and AR, with defined roles in DNA damage response (RAP80-BRCA1 branch), leukemia stem cell self-renewal, adipogenesis, lipogenesis, spermatogenesis, B-cell differentiation restraint, and Treg cell fitness.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"JMJD1C is a JmjC-domain histone demethylase that erases mono- and di-methyl marks from histone H3K9 (H3K9me1/2) to convert repressive chromatin into a transcriptionally permissive state at target promoters [#1]. Beyond chromatin, it also demethylates non-histone substrates: it removes methylation from MDC1 at Lys45 to promote MDC1-RNF8 interaction, RNF8-dependent ubiquitylation, and recruitment of the RAP80-BRCA1 complex to DNA double-strand breaks, with JMJD1C itself stabilized by RNF8 and required for radiation/PARP-inhibitor sensitivity [#0], and it demethylates STAT3 at Lys140 to permit STAT3-Ptpn6 association and limit STAT3 phosphorylation [#5]. As a transcriptional coactivator JMJD1C is recruited to promoters by sequence-specific and complex partners — RUNX1-RUNX1T1 [#2], HOXA9 [#3], USF-1 [#4], and the WHISTLE/SF-1 complex [#1] — where it lowers H3K9me2 to activate target programs. Its activity is gated by post-translational control: mTOR phosphorylates JMJD1C at T505 in response to feeding/insulin to enable USF-1 binding and lipogenic gene activation [#4], while Deltex2-mediated monoubiquitination inhibits its demethylase activity to restrain myogenic differentiation [#6]. Through these activities JMJD1C governs leukemia stem-cell self-renewal in MLL-AF9/HOXA9 and RUNX1-RUNX1T1 AML [#2, #3], lipogenesis and adipogenesis [#4, #12], spermatogonial maintenance [#9], stem-cell identity [#8, #11], and immune-cell fitness including B-cell differentiation and Treg function [#5, #14, #20]. A de novo JMJD1C mutation associated with Rett-like neurodevelopmental disease shows mislocalization, reduced MDC1 demethylation, and impaired MECP2 binding [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the first physical link between JMJD1C and a sequence-specific transcription factor, framing it as a nuclear nuclear-receptor coactivator before its enzymatic activity was defined.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, mammalian one-hybrid, and immunofluorescence of a JMJD1C splice variant (s-JMJD1C) with AR\",\n      \"pmids\": [\"17353003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic activity of the s-JMJD1C variant was not demonstrated\", \"Endogenous AR-JMJD1C function in cells not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined JMJD1C's core enzymatic identity as an H3K9me1/2 demethylase and showed it operates within a transcription-activating chromatin complex at a steroidogenic promoter.\",\n      \"evidence\": \"TAP purification, in vitro histone demethylation assay, ChIP and reporter assays in mouse testis context (WHISTLE/SF-1/HSP90\\u03b1)\",\n      \"pmids\": [\"20530532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide target spectrum not mapped\", \"In vivo requirement for steroidogenesis not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed that JMJD1C acts on a non-histone substrate (MDC1 Lys45) to drive the RAP80-BRCA1 branch of the DNA damage response, expanding its mechanism beyond chromatin and linking it to therapy sensitivity.\",\n      \"evidence\": \"In vitro demethylation assay, reciprocal Co-IP, laser micro-irradiation, shRNA with ubiquitylation/foci/radiation-sensitivity readouts\",\n      \"pmids\": [\"24240613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demethylase regulation at DSBs vs. promoters not distinguished\", \"Structural basis of MDC1 substrate recognition unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended JMJD1C function to stem-cell maintenance, showing promoter-level H3K9 demethylation sustains a miRNA (miR-302) program that suppresses neural differentiation.\",\n      \"evidence\": \"ChIP, stable shRNA knockdown, miR-302 mimic rescue, signaling pathway analysis in hESCs\",\n      \"pmids\": [\"24318875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect control of miR-302 not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated an in vivo physiological requirement for JMJD1C in long-term male germ-cell maintenance.\",\n      \"evidence\": \"Jmjd1c knockout mouse, immunohistochemistry, flow cytometry, apoptosis assays\",\n      \"pmids\": [\"24006281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrates in spermatogonia not identified\", \"Cell-autonomous vs. niche effects unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Positioned JMJD1C as an oncogenic coactivator in AML, directly recruited by the RUNX1-RUNX1T1 fusion to maintain low H3K9me2 at target genes and drive leukemic proliferation in vivo.\",\n      \"evidence\": \"ChIP-seq, Co-IP, shRNA knockdown, JMJD1C knockout mouse\",\n      \"pmids\": [\"26494788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether demethylase catalysis is strictly required not dissected here\", \"Selectivity over normal hematopoiesis only partly addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected JMJD1C to neurodevelopmental disease by showing a Rett-associated de novo mutant has reduced MDC1 demethylation, altered localization, and impaired MECP2 binding.\",\n      \"evidence\": \"Patient mutant functional analysis, in vitro demethylation assay, immunofluorescence, Co-IP, neuronal knockdown\",\n      \"pmids\": [\"26181491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient/limited sample size\", \"Causality for the clinical phenotype not established genetically\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed JMJD1C is selectively required for leukemia stem-cell self-renewal via direct HOXA9 interaction, with minimal effect on normal HSCs — establishing a therapeutic window.\",\n      \"evidence\": \"In vivo shRNA screen, conditional knockout mice, Co-IP, gene expression analysis in MLL-AF9/HOXA9 models\",\n      \"pmids\": [\"26878175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HOXA9 recruitment depends on catalytic activity not resolved\", \"Mechanism of LSC vs. HSC differential dependence unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Implicated JMJD1C protein interactions (MDC1, HSP90) in distinct spermatogenic stages and linked its loss to altered H4K16 acetylation and Oct4 levels.\",\n      \"evidence\": \"Gene-trap knockout mouse, immunostaining, Co-IP\",\n      \"pmids\": [\"27649575\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP interactions without reciprocal validation\", \"H4K16ac link is correlative, not mechanistic\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified post-translational restraint of JMJD1C activity: Deltex2-mediated monoubiquitination inhibits demethylation, controlling H3K9me2 at the MyoD locus during myogenesis.\",\n      \"evidence\": \"In vitro demethylation assay, mutagenesis of the ubiquitination site, Co-IP, Deltex2 knockout mice, ChIP, shRNA\",\n      \"pmids\": [\"28351977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Deltex2 deubiquitinase counterpart not identified\", \"Whether other contexts use this regulation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Broadened JMJD1C's stem-cell role to mouse ESC identity, acting through miR-200 and miR-290/295 (with KLF4) to suppress ERK/MAPK and EMT.\",\n      \"evidence\": \"shRNA knockdown, ERK/MAPK inhibitor rescue, miRNA expression and epistasis analysis\",\n      \"pmids\": [\"28826851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between JMJD1C and miRNA loci is indirect\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established a metabolic role in adipogenesis, with JMJD1C controlling H3K9me2 at C/EBP and PPAR\\u03b3 promoters and mitotic clonal expansion.\",\n      \"evidence\": \"shRNA knockdown in 3T3-L1, ChIP for H3K9me2, triglyceride and uptake assays\",\n      \"pmids\": [\"28501567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell-line model\", \"Direct promoter occupancy vs. indirect effect not fully separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended H3K9me2-dependent target regulation to ATF2 in colorectal cancer migration/invasion.\",\n      \"evidence\": \"shRNA knockdown, ChIP for H3K9me2/me1, ATF2 overexpression rescue, migration/invasion assays\",\n      \"pmids\": [\"29888107\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct vs. indirect ATF2 regulation not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetically defined the JmjC and zinc-finger domains as essential for leukemia survival and surfaced IL-3/RAS-MAPK/JAK-STAT signaling as a resistance route, with H3K36me marking JMJD1C activity.\",\n      \"evidence\": \"CRISPR/Cas9 negative-selection screen, domain-specific sgRNAs, scRNA-seq, ChIP for H3K36me, in vivo transplantation\",\n      \"pmids\": [\"31076406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical basis of JmjC-H3K36me relationship needs validation\", \"Whether H3K36me is a direct substrate unconfirmed here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a signal-responsive activation switch: mTOR phosphorylates JMJD1C at T505 upon feeding/insulin to enable USF-1 binding and lipogenic gene activation, linking nutrient sensing to chromatin output.\",\n      \"evidence\": \"In vitro kinase assay, T505 mutagenesis, Co-IP, ChIP, mouse liver overexpression/knockdown\",\n      \"pmids\": [\"32034158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase reversing T505 not identified\", \"Structural consequence of phosphorylation on USF-1 binding unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated JMJD1C in cardiomyocyte hypertrophy through repression of Camkk2 and downstream AMPK signaling.\",\n      \"evidence\": \"shRNA/overexpression, CAMKK2 inhibitor and AMPK knockdown epistasis, cell-size measurement\",\n      \"pmids\": [\"32625104\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Link from JMJD1C to Camkk2 transcription is indirect\", \"Single lab, limited orthogonality\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed JMJD1C demethylates STAT3 at Lys140 to enable STAT3-Ptpn6 interaction, restraining STAT3 activity and plasma-cell differentiation — a second defined non-histone substrate.\",\n      \"evidence\": \"Conditional knockout mice, in vitro demethylation assay, K140R mutagenesis, Co-IP, flow cytometry\",\n      \"pmids\": [\"35995859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct methyltransferase placing STAT3 K140me not identified\", \"Generalization beyond B cells not addressed here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked JMJD1C to lipid-synthesis gene regulation in MLL-rearranged AML and identified FABP5 as a JmjC-domain-binding partner that feeds back on JMJD1C expression.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, domain mapping, shRNA with lipidomics\",\n      \"pmids\": [\"35468015\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP/MS without reciprocal validation\", \"How FABP5 binding alters catalytic activity uncharacterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Dissected demethylase-dependent (AKT, H3K9me2) versus demethylase-independent (STAT3) contributions of JMJD1C to Treg fitness and validated an oral inhibitor that destabilizes intratumoral Tregs.\",\n      \"evidence\": \"T-cell-specific conditional knockout, ChIP for H3K9me2, AKT/STAT3 analysis, flow cytometry, small-molecule inhibitor\",\n      \"pmids\": [\"38356061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific STAT3 substrate site in Tregs not identified\", \"Selectivity/off-target profile of inhibitor not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated JMJD1C loss in B-cell hyperactivation and autoantibody production (HIT) via increased H3K36me1 at start sites of BCR/NF-\\u03baB/cell-cycle genes, nominating H3K36me1 as a substrate mark.\",\n      \"evidence\": \"Conditional B-cell knockout, RNA-seq, CUT&Tag for H3K36me1, human HIT patient transcriptomics\",\n      \"pmids\": [\"42095895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct H3K36me1 demethylation by JMJD1C not biochemically shown\", \"Relationship between H3K9 and H3K36 substrate activities unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended H3K9-demethylase-dependent transcriptional control to macrophage PCSK9 and foam-cell formation in atherosclerosis.\",\n      \"evidence\": \"ChIP for H3K9 methylation, shRNA knockdown, PCSK9 rescue, mouse atherosclerosis model\",\n      \"pmids\": [\"39511107\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct PCSK9 promoter occupancy vs. indirect effect not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a KLF15-driven, super-enhancer-controlled Jmjd1c/Socs3/JAK-STAT3 axis in neuropathic pain.\",\n      \"evidence\": \"Dual-luciferase reporter, ChIP-seq, RNA-seq, rat neuropathic pain model, ChIP at Socs3 promoter\",\n      \"pmids\": [\"40485981\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway not biochemically reconstituted\", \"Single lab, limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined an endothelial Jmjd1c-Srebf2 axis controlling cholesterol biosynthesis and pathological neovascularization via H3K9me2 at the Srebf2 locus.\",\n      \"evidence\": \"Endothelial-specific knockout, ChIP-qPCR for H3K9me2, RNA-seq, angiogenesis and OIR/CNV models\",\n      \"pmids\": [\"41548765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect Srebf2 promoter regulation not fully resolved\", \"Upstream signal recruiting JMJD1C to Srebf2 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how JMJD1C's distinct substrate activities (H3K9me1/2, H3K36me, and non-histone targets MDC1 and STAT3) are partitioned across cellular contexts, and what structural and recruitment determinants direct it between DNA-repair, chromatin-activation, and signaling roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate selection\", \"Methyltransferases generating the non-histone methyl marks unidentified\", \"Rules governing histone vs. non-histone substrate choice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 0, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 4, 7]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 14, 20]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 9, 8, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RNF8\", \"MDC1\", \"STAT3\", \"USF-1\", \"HOXA9\", \"RUNX1-RUNX1T1\", \"MECP2\", \"FABP5\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}