{"gene":"JMJD1C","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2013,"finding":"JMJD1C is a histone/protein demethylase that demethylates MDC1 at Lys45, promoting MDC1-RNF8 interaction, RNF8-dependent MDC1 ubiquitylation, and recruitment of the RAP80-BRCA1 complex to DNA double-strand breaks. JMJD1C binds both RNF8 and MDC1 directly, is stabilized by RNF8 interaction, and is recruited to DSBs where it specifically regulates the BRCA1 branch (but not 53BP1 branch) of the DNA damage response.","method":"Co-immunoprecipitation, in vitro demethylation assay, site-specific mutagenesis, laser-induced DSB recruitment imaging, RNAi knockdown with defined epistasis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including direct demethylation assay, Co-IP, site-specific target identification (Lys45), and epistasis within a defined DDR pathway","pmids":["24240613"],"is_preprint":false},{"year":2010,"finding":"JMJD1C specifically demethylates histone H3K9 mono- and di-methylation and mediates transcriptional activation. It forms a complex with WHISTLE (a histone methyltransferase) and HSP90α. In mouse testis, JMJD1C and WHISTLE sequentially occupy the p450c17 promoter via SF-1: WHISTLE represses transcription prepubertally, then JMJD1C replaces it to activate steroidogenesis target genes.","method":"Immunoaffinity TAP purification, in vitro H3K9 demethylation assay, ChIP, co-immunoprecipitation, gene expression analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — in vitro demethylation assay directly established H3K9me1/me2 substrate specificity; TAP identified complex components; ChIP showed sequential promoter occupancy","pmids":["20530532"],"is_preprint":false},{"year":2015,"finding":"JMJD1C functions as a transcriptional coactivator for RUNX1-RUNX1T1 (AML1-ETO) in AML. It is directly recruited by RUNX1-RUNX1T1 to target gene loci and maintains low H3K9me2 levels at these loci to sustain their expression. Loss of JMJD1C in knockout mice impairs RUNX1-RUNX1T1-driven proliferation.","method":"ChIP-seq, co-immunoprecipitation, JMJD1C knockout mouse model, shRNA knockdown, gene expression profiling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus ChIP-seq plus KO mouse model with defined proliferative phenotype; 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 (LSC) self-renewal. Loss of JMJD1C substantially decreases LSC frequency and causes differentiation of these leukemias, while having only minor effects on normal hematopoietic stem cells.","method":"In vivo shRNA screen, conditional mouse knockout, co-immunoprecipitation (JMJD1C–HOXA9), transplantation assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — direct protein interaction demonstrated by Co-IP, in vivo conditional KO with LSC frequency quantification, epistatic relationship with HOXA9","pmids":["26878175"],"is_preprint":false},{"year":2020,"finding":"JMJD1C is phosphorylated at Thr505 by mTOR complex in response to feeding/insulin, enabling its direct interaction with USF-1 and recruitment to lipogenic gene promoters (e.g., FASN, GPAT). At these promoters, JMJD1C demethylates H3K9me2 to increase chromatin accessibility and activate transcription of lipogenic genes, thereby promoting hepatic and plasma triglyceride synthesis.","method":"In vivo phosphorylation mapping, co-immunoprecipitation (JMJD1C–USF-1), ChIP, shRNA knockdown in mouse liver, in vivo lipid measurements, site-directed mutagenesis (T505A)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — site-specific phosphorylation identified and validated by mutagenesis, Co-IP with USF-1, ChIP at lipogenic promoters, in vivo phenotype","pmids":["32034158"],"is_preprint":false},{"year":2022,"finding":"JMJD1C demethylates STAT3 at Lys140 (a non-histone substrate) in B cells, which promotes STAT3 interaction with phosphatase PTPN6 and restricts sustained STAT3 phosphorylation. Loss of JMJD1C causes STAT3 Lys140 hypermethylation, blocking PTPN6 binding, sustaining STAT3 phosphorylation, and driving plasma cell differentiation. STAT3 K140R point mutation completely abrogates the effect of JMJD1C deletion.","method":"B cell-specific Jmjd1c knockout, in vitro demethylation assay on STAT3, co-immunoprecipitation (STAT3–PTPN6), site-directed mutagenesis (K140R), flow cytometry of plasma cells","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1–2 — direct non-histone substrate identified, mutagenesis validates specific lysine, Co-IP links demethylation to phosphatase recruitment; multiple orthogonal methods","pmids":["35995859"],"is_preprint":false},{"year":2007,"finding":"A splice variant of JMJD1C (s-JMJD1C) binds directly to the androgen receptor (AR) via its ligand-binding domain. s-JMJD1C is a nuclear-localized protein that functions as an AR coactivator, identified by yeast two-hybrid and validated by GST pull-down and mammalian one-hybrid assays.","method":"Yeast two-hybrid screen, GST pull-down, mammalian one-hybrid assay, RACE for splice variant characterization","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct binding confirmed by GST pull-down and one-hybrid; single lab with two methods but no chromatin or demethylase activity assay","pmids":["17353003"],"is_preprint":false},{"year":2013,"finding":"JMJD1C, as an H3K9 demethylase, binds the miR-302 promoter in human embryonic stem cells (hESCs) and reduces H3K9 methylation there to sustain miR-302 expression, thereby repressing neural differentiation. JMJD1C knockdown reduces BMP signaling, enhances TGFβ signaling, and elevates NR2F2, collectively promoting neural differentiation upon bFGF withdrawal.","method":"Stable shRNA knockdown in hESCs, ChIP for H3K9 methylation at miR-302 promoter, BMP/TGFβ signaling assays, differentiation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP directly links JMJD1C to H3K9 demethylation at specific promoter; KD with defined differentiation phenotype; single lab","pmids":["24318875"],"is_preprint":false},{"year":2017,"finding":"Deltex2 directly inhibits Jmjd1c demethylase activity by promoting its monoubiquitination; mutation of the monoubiquitination site in Jmjd1c abolishes Deltex2's inhibitory effect. Jmjd1c is required for MyoD expression in vivo and in vitro by demethylating H3K9me2 at a key regulatory region of the MyoD locus, thereby promoting myogenic differentiation.","method":"Co-immunoprecipitation (Deltex2–Jmjd1c), in vitro demethylase activity assay, site-directed monoubiquitination mutagenesis, ChIP for H3K9me2, genetic rescue experiments in skeletal muscle stem cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — enzymatic inhibition by monoubiquitination validated by mutagenesis, direct Co-IP, ChIP at MyoD locus, and in vivo genetic epistasis","pmids":["28351977"],"is_preprint":false},{"year":2017,"finding":"JMJD1C, with the help of pluripotency factor KLF4, maintains mouse ESC identity by demethylating H3K9 at promoters of the miR-200 family and miR-290/295 cluster, suppressing ERK/MAPK signaling and EMT. Jmjd1c depletion activates ERK/MAPK signaling, and ERK/MAPK inhibition rescues the differentiation phenotype.","method":"shRNA knockdown in mESCs, ChIP for H3K9 methylation, ERK/MAPK signaling assays, epistasis with MEK inhibitor, microRNA expression profiling","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP links JMJD1C to H3K9 demethylation at specific miRNA loci; pathway placement by MEK inhibitor rescue; single lab","pmids":["28826851"],"is_preprint":false},{"year":2015,"finding":"A JMJD1C mutation found in a Rett syndrome patient causes abnormal subcellular localization of JMJD1C, diminished demethylase activity toward MDC1, and reduced binding to MECP2. JMJD1C depletion in neurons compromises dendritic activity.","method":"Functional mutagenesis study, in vitro MDC1 demethylation assay, co-immunoprecipitation (JMJD1C–MECP2), subcellular localization imaging, neuronal knockdown","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding to MECP2 and MDC1 demethylase activity tested for disease mutant; single lab with multiple methods","pmids":["26181491"],"is_preprint":false},{"year":2019,"finding":"The catalytic JmjC domain and zinc finger domain of JMJD1C are required for leukemia cell survival in vitro and in vivo in MLL-rearranged AML. H3K36 methylation serves as a marker for JMJD1C activity at gene loci. Loss of JmjC domain activity leads to increased RAS/MAPK and JAK-STAT pathway activation and upregulation of IL-3 receptor genes, with activating RAS mutations conferring resistance to JMJD1C loss.","method":"CRISPR/Cas9 domain-specific negative-selection screen, single-cell transcriptomics, ChIP for H3K36me, transplantation assays, genetic epistasis with RAS mutations","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR domain screen identifies catalytic requirements; ChIP validates H3K36me as activity marker; single lab","pmids":["31076406"],"is_preprint":false},{"year":2013,"finding":"JMJD1C is required for long-term maintenance of undifferentiated spermatogonia (ZBTB16-positive) in mouse testis. Jmjd1c-deficient males show progressive reduction of germ cells and increased apoptosis in an age-dependent manner, with JMJD1C most abundantly expressed in undifferentiated spermatogonia.","method":"Jmjd1c knockout mouse model, immunostaining for spermatogonial markers, TUNEL apoptosis assay, histological analysis","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype (spermatogonial loss, apoptosis); single lab","pmids":["24006281"],"is_preprint":false},{"year":2016,"finding":"JMJD1C has multiple spermatogenic functions: it is required for postmeiotic chromatin remodeling (histone H4K16 acetylation) and spermatogonial stem cell self-renewal (OCT4 expression), and it interacts with MDC1 and HSP90 as partner proteins during spermatogenesis.","method":"Gene-trap mouse model, immunostaining for H4K16ac, OCT4, and NANOG in spermatogonia, co-immunoprecipitation (JMJD1C–MDC1, JMJD1C–HSP90)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 — KO phenotype with multiple chromatin readouts plus Co-IP; single lab","pmids":["27649575"],"is_preprint":false},{"year":2025,"finding":"Jmjd1c acts as an anti-nociceptive regulator of neuropathic pain by positively regulating Socs3 expression via H3K9 demethylation at the Socs3 promoter, thereby suppressing JAK/STAT3 signaling. KLF15 activates Jmjd1c transcription by binding to its super-enhancer.","method":"H3K27ac ChIP-Seq, RNA-Seq, ChIP-qPCR for H3K9 methylation at Socs3 promoter, dual-luciferase reporter assay (KLF15–Jmjd1c SE), shRNA knockdown and overexpression in rat NP model","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-qPCR at specific locus, luciferase for upstream activator, in vivo phenotype; single lab","pmids":["40485981"],"is_preprint":false},{"year":2024,"finding":"In tumor Treg cells, JMJD1C deletion enhances AKT signaling through its H3K9me2 demethylase activity and increases STAT3 signaling independently of H3K9me2 demethylase activity, collectively leading to robust IFN-γ production and Treg cell fragility. An oral JMJD1C inhibitor suppresses tumor growth by targeting intratumoral Treg cells.","method":"Treg-specific Jmjd1c knockout, ChIP for H3K9me2, STAT3 pathway analysis, pharmacological inhibition, tumor growth assays","journal":"Nature immunology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with mechanistic dissection of demethylase-dependent vs. independent STAT3 effects; multiple readouts; single lab","pmids":["38356061"],"is_preprint":false},{"year":2017,"finding":"Jmjd1c depletion in 3T3-L1 preadipocytes impairs mitotic clonal expansion and increases H3K9me2 at promoters of key adipogenic transcription factors (C/EBPs and PPARγ), reducing their induction and impairing adipocyte differentiation, lipid droplet formation, and insulin-stimulated glucose/fatty acid uptake.","method":"shRNA knockdown in 3T3-L1, ChIP for H3K9me2 at C/EBP and PPARγ promoters, lipid staining, glucose/fatty acid uptake assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP at specific promoters links JMJD1C loss to H3K9me2 accumulation; defined adipogenic phenotype; single lab","pmids":["28501567"],"is_preprint":false},{"year":2022,"finding":"JMJD1C interacts with FABP5 via its jumonji domain in MLL-rearranged AML cells, and FABP5 regulates JMJD1C mRNA and protein expression. JMJD1C regulates expression of lipid synthesis-associated genes FADS2 and SCD.","method":"Mass spectrometry interactome, co-immunoprecipitation (JMJD1C–FABP5), domain mapping, gene expression analysis, pharmacological rescue with lipids/recombinant FABP5","journal":"Leukemia & lymphoma","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP identifies binding partner; mechanistic follow-up is partial and rescue is indirect; single lab","pmids":["35468015"],"is_preprint":false},{"year":2026,"finding":"Endothelial JMJD1C drives pathological ocular neovascularization by demethylating H3K9me2 at the Srebf2 locus to activate SREBF2-dependent cholesterol biosynthesis in endothelial cells. Endothelial-specific Jmjd1c deletion suppresses Srebf2 transcription, increases H3K9me2 at this locus, and markedly reduces pathological neovascularization in OIR and CNV mouse models.","method":"Endothelial-specific conditional Jmjd1c KO, ChIP-qPCR for H3K9me2 at Srebf2 locus, RNA-seq, in vitro angiogenesis assays, in vivo retinal flat-mount and CNV models","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with ChIP-qPCR at specific locus linking H3K9me2 demethylation to target gene activation; multiple in vitro and in vivo assays; single lab","pmids":["41548765"],"is_preprint":false},{"year":2024,"finding":"JMJD1C promotes PCSK9 transcription in macrophages through H3K9 demethylation at the PCSK9 locus, driving foam cell formation and atherosclerosis progression. JMJD1C knockdown reduces plaque area and foam cell formation, effects reversed by PCSK9 overexpression.","method":"ChIP for H3K9 demethylation at PCSK9 promoter, shRNA knockdown in RAW264.7 cells and ApoE-/- mice, PCSK9 rescue overexpression","journal":"Journal of physiology and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 — ChIP at specific locus, rescue experiment; single lab with limited mechanistic depth","pmids":["39511107"],"is_preprint":false},{"year":2024,"finding":"In PNH clones, elevated JMJD1C demethylates H3K36me3 at the CPS1 locus (reducing H3K36me3), suppressing CPS1 expression and promoting metabolic reprogramming that sustains clonal proliferation. JMJD1C knockdown in PIG-A KO K562 cells upregulates CPS1 and H3K36me3 and decreases proliferation.","method":"ChIP analysis of H3K36me3 at CPS1 locus, shRNA knockdown in K562 PIG-A KO cells, CPS1 expression and metabolic measurements, pharmacological inhibition with JIB-04","journal":"British journal of haematology","confidence":"Low","confidence_rationale":"Tier 3 — ChIP links JMJD1C to H3K36me3 at specific locus; single lab, limited mechanistic follow-up","pmids":["38650379"],"is_preprint":false}],"current_model":"JMJD1C (KDM3C) is a JmjC domain-containing demethylase that removes mono- and di-methyl marks from histone H3K9 (and in some contexts H3K36) at specific gene loci to activate transcription, and also demethylates non-histone substrates including MDC1 (at K45, to regulate the RNF8–BRCA1 DNA damage response) and STAT3 (at K140, to restrain its phosphorylation and plasma cell differentiation); its activity is regulated post-translationally by mTOR-mediated phosphorylation at T505 (enabling USF-1 interaction for lipogenic gene activation) and by Deltex2-induced monoubiquitination (which inhibits its demethylase activity), and it acts as a transcriptional coactivator for nuclear receptors, RUNX1-RUNX1T1, HOXA9, and other transcription factors in contexts ranging from leukemic stem cell self-renewal and spermatogenesis to lipogenesis and immune cell differentiation."},"narrative":{"teleology":[{"year":2007,"claim":"The first functional characterization established that a splice variant of JMJD1C directly binds the androgen receptor and acts as a nuclear receptor coactivator, positioning it as a transcriptional regulator.","evidence":"Yeast two-hybrid, GST pull-down, and mammalian one-hybrid in cell lines","pmids":["17353003"],"confidence":"Medium","gaps":["No demethylase activity was demonstrated in this study","Chromatin occupancy at AR target genes not tested","Physiological relevance of the AR interaction in vivo not addressed"]},{"year":2010,"claim":"Defining JMJD1C as a bona fide H3K9me1/me2 demethylase resolved its catalytic identity and revealed its sequential promoter switch with the methyltransferase WHISTLE at steroidogenic genes.","evidence":"In vitro demethylation assay, TAP purification identifying WHISTLE and HSP90α, ChIP at p450c17 promoter in mouse testis","pmids":["20530532"],"confidence":"High","gaps":["Genome-wide target repertoire of JMJD1C not mapped","Whether HSP90α binding modulates catalytic activity was not tested"]},{"year":2013,"claim":"Discovery that JMJD1C demethylates the non-histone substrate MDC1 at Lys45 established a new paradigm in which its catalytic activity directly regulates the RNF8–BRCA1 DNA damage response pathway, broadening its function beyond chromatin.","evidence":"In vitro demethylation assay on MDC1, Co-IP of JMJD1C–RNF8–MDC1, laser-stripe DSB recruitment, site-specific mutagenesis","pmids":["24240613"],"confidence":"High","gaps":["Whether JMJD1C demethylates MDC1 at DSBs in a cell-cycle-dependent manner was not addressed","In vivo physiological consequences of losing this DDR function not tested"]},{"year":2013,"claim":"Demonstration that JMJD1C maintains undifferentiated spermatogonia and sustains miR-302 expression in human ESCs revealed its role in stem cell self-renewal through H3K9 demethylation at specific regulatory loci.","evidence":"Jmjd1c KO mouse testis phenotyping; shRNA knockdown in hESCs with ChIP at miR-302 promoter","pmids":["24006281","24318875"],"confidence":"Medium","gaps":["Genome-wide H3K9me2 changes in spermatogonia not characterized","Whether demethylase activity is required for the spermatogonial phenotype was not directly tested"]},{"year":2015,"claim":"Identification of JMJD1C as a critical coactivator recruited by RUNX1-RUNX1T1 in AML—maintaining low H3K9me2 at leukemic target loci—established its oncogenic role and therapeutic relevance in leukemia.","evidence":"ChIP-seq, Co-IP, Jmjd1c KO mouse with RUNX1-RUNX1T1-driven proliferation assay","pmids":["26494788"],"confidence":"High","gaps":["Whether H3K9 demethylase activity alone or a scaffolding function is responsible was not dissected","No structural basis for RUNX1-RUNX1T1 interaction determined"]},{"year":2015,"claim":"A Rett syndrome-associated JMJD1C mutation was shown to impair its demethylase activity and MECP2 binding, providing initial evidence linking JMJD1C dysfunction to a neurodevelopmental disorder.","evidence":"Functional mutagenesis, in vitro MDC1 demethylation assay, Co-IP of JMJD1C–MECP2, neuronal knockdown","pmids":["26181491"],"confidence":"Medium","gaps":["Single patient mutation; causal relationship to Rett syndrome not genetically established","Neuronal H3K9me2 target loci not identified","Whether MECP2 binding is direct or bridged was not resolved"]},{"year":2016,"claim":"Establishing JMJD1C as a direct HOXA9 partner required for leukemia stem cell self-renewal in MLL-rearranged AML clarified its oncogenic mechanism and showed therapeutic selectivity over normal HSCs.","evidence":"In vivo shRNA screen, conditional KO, Co-IP of JMJD1C–HOXA9, serial transplantation","pmids":["26878175"],"confidence":"High","gaps":["The specific gene targets co-regulated by JMJD1C and HOXA9 were not fully delineated","Catalytic versus scaffolding contribution not separated"]},{"year":2017,"claim":"Discovery that Deltex2 inhibits JMJD1C by promoting its monoubiquitination revealed the first post-translational mechanism controlling JMJD1C catalytic activity, with functional consequences for MyoD expression and myogenesis.","evidence":"Co-IP, in vitro demethylase assay, monoubiquitination-site mutagenesis, ChIP at MyoD locus, muscle stem cell rescue experiments","pmids":["28351977"],"confidence":"High","gaps":["The E3 ligase catalyzing monoubiquitination was not identified","Whether monoubiquitination regulates JMJD1C in non-muscle contexts was not tested"]},{"year":2017,"claim":"Work in mESCs and preadipocytes extended the H3K9 demethylation paradigm to pluripotency (miR-200/miR-290 family loci via KLF4) and adipogenesis (C/EBP and PPARγ promoters), broadening the physiological scope of JMJD1C function.","evidence":"shRNA in mESCs with ChIP and MEK inhibitor rescue; shRNA in 3T3-L1 with ChIP at adipogenic promoters","pmids":["28826851","28501567"],"confidence":"Medium","gaps":["Whether KLF4 directly recruits JMJD1C was not tested biochemically","In vivo adipogenesis phenotype not confirmed in KO mice"]},{"year":2019,"claim":"Domain-resolution CRISPR screening in MLL-rearranged AML showed that both the JmjC catalytic domain and zinc finger domain are essential for leukemia survival, and identified H3K36 methylation as a potential JMJD1C activity mark, expanding its substrate range beyond H3K9.","evidence":"CRISPR/Cas9 domain-specific negative-selection screen, ChIP for H3K36me, single-cell transcriptomics, RAS epistasis","pmids":["31076406"],"confidence":"Medium","gaps":["Direct H3K36 demethylation by JMJD1C not demonstrated in vitro in this study","Whether H3K36 and H3K9 demethylation are context-dependent was not resolved"]},{"year":2020,"claim":"Identification of mTOR-mediated Thr505 phosphorylation as a nutrient-responsive switch enabling JMJD1C–USF-1 interaction at lipogenic promoters established a signaling-to-chromatin mechanism for feeding-induced lipogenesis.","evidence":"In vivo phosphorylation mapping, T505A mutagenesis, Co-IP with USF-1, ChIP at FASN/GPAT, hepatic triglyceride measurements in mice","pmids":["32034158"],"confidence":"High","gaps":["Whether additional kinases regulate JMJD1C was not explored","Structural basis of USF-1 recognition of phospho-T505 not determined"]},{"year":2022,"claim":"Demonstration that JMJD1C demethylates STAT3 at Lys140 to enable PTPN6 phosphatase docking established a second non-histone demethylation event with direct signaling consequences, explaining how JMJD1C restrains plasma cell differentiation.","evidence":"B cell-specific Jmjd1c KO, in vitro STAT3 demethylation assay, K140R mutagenesis, Co-IP of STAT3–PTPN6, flow cytometry","pmids":["35995859"],"confidence":"High","gaps":["Whether JMJD1C demethylates STAT3 in non-B cell contexts was not tested","Full set of non-histone substrates remains unknown"]},{"year":2024,"claim":"Treg-specific deletion revealed a dual mechanism in tumor immunity: JMJD1C loss enhances AKT signaling via H3K9me2 demethylase activity and boosts STAT3 signaling through a demethylase-independent mechanism, inducing Treg fragility and anti-tumor immunity.","evidence":"Treg-specific Jmjd1c KO, ChIP for H3K9me2, STAT3 pathway dissection, oral JMJD1C inhibitor in tumor models","pmids":["38356061"],"confidence":"Medium","gaps":["The demethylase-independent mechanism of STAT3 regulation in Tregs is undefined","Selectivity and pharmacology of the oral JMJD1C inhibitor not deeply characterized"]},{"year":null,"claim":"Key unresolved questions include the complete catalog of JMJD1C non-histone substrates, the structural basis for its interactions with transcription factors and regulation by post-translational modifications, and whether its H3K36 demethylase activity is physiologically significant.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of JMJD1C or its complexes exists","Full non-histone substrate repertoire uncharacterized","H3K36 demethylation not validated by direct in vitro assay","Relative contributions of catalytic versus scaffolding functions unresolved in most contexts"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4,5,8]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,2,4,8,16]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,6,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,6,7]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,2,4]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,4,7,8,9,16]},{"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":[2,3,4,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,11]}],"complexes":[],"partners":["MDC1","RNF8","HOXA9","RUNX1","USF1","STAT3","HSP90AA1","DTX2"],"other_free_text":[]},"mechanistic_narrative":"JMJD1C is a JmjC domain-containing lysine demethylase that removes mono- and di-methyl marks from histone H3K9 at specific gene promoters to activate transcription, functioning as a chromatin-based coactivator across diverse biological contexts including leukemia stem cell self-renewal, spermatogenesis, lipogenesis, adipogenesis, embryonic stem cell maintenance, and immune cell differentiation [PMID:20530532, PMID:26494788, PMID:26878175, PMID:32034158, PMID:24006281, PMID:28826851]. Beyond histone substrates, JMJD1C demethylates the non-histone proteins MDC1 at Lys45—enabling RNF8-dependent ubiquitylation and BRCA1 recruitment during the DNA damage response—and STAT3 at Lys140, which promotes PTPN6 phosphatase engagement to restrain STAT3 phosphorylation and plasma cell differentiation [PMID:24240613, PMID:35995859]. JMJD1C activity is regulated post-translationally by mTOR-mediated phosphorylation at Thr505, which licenses interaction with the transcription factor USF-1 at lipogenic promoters, and by Deltex2-induced monoubiquitination, which inhibits its catalytic demethylase function [PMID:32034158, PMID:28351977]. In leukemia, JMJD1C is recruited by RUNX1-RUNX1T1 and HOXA9 to sustain oncogenic gene expression programs, and its catalytic JmjC and zinc finger domains are essential for MLL-rearranged AML cell survival [PMID:26494788, PMID:26878175, PMID:31076406]."},"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 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JMJD1C binds both RNF8 and MDC1 directly, is stabilized by RNF8 interaction, and is recruited to DSBs where it specifically regulates the BRCA1 branch (but not 53BP1 branch) of the DNA damage response.\",\n      \"method\": \"Co-immunoprecipitation, in vitro demethylation assay, site-specific mutagenesis, laser-induced DSB recruitment imaging, RNAi knockdown with defined epistasis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including direct demethylation assay, Co-IP, site-specific target identification (Lys45), and epistasis within a defined DDR pathway\",\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. It forms a complex with WHISTLE (a histone methyltransferase) and HSP90α. In mouse testis, JMJD1C and WHISTLE sequentially occupy the p450c17 promoter via SF-1: WHISTLE represses transcription prepubertally, then JMJD1C replaces it to activate steroidogenesis target genes.\",\n      \"method\": \"Immunoaffinity TAP purification, in vitro H3K9 demethylation assay, ChIP, co-immunoprecipitation, gene expression analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro demethylation assay directly established H3K9me1/me2 substrate specificity; TAP identified complex components; ChIP showed sequential promoter occupancy\",\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 AML. It is directly recruited by RUNX1-RUNX1T1 to target gene loci and maintains low H3K9me2 levels at these loci to sustain their expression. Loss of JMJD1C in knockout mice impairs RUNX1-RUNX1T1-driven proliferation.\",\n      \"method\": \"ChIP-seq, co-immunoprecipitation, JMJD1C knockout mouse model, shRNA knockdown, gene expression profiling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus ChIP-seq plus KO mouse model with defined proliferative phenotype; 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 (LSC) self-renewal. Loss of JMJD1C substantially decreases LSC frequency and causes differentiation of these leukemias, while having only minor effects on normal hematopoietic stem cells.\",\n      \"method\": \"In vivo shRNA screen, conditional mouse knockout, co-immunoprecipitation (JMJD1C–HOXA9), transplantation assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction demonstrated by Co-IP, in vivo conditional KO with LSC frequency quantification, epistatic relationship with HOXA9\",\n      \"pmids\": [\"26878175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD1C is phosphorylated at Thr505 by mTOR complex in response to feeding/insulin, enabling its direct interaction with USF-1 and recruitment to lipogenic gene promoters (e.g., FASN, GPAT). At these promoters, JMJD1C demethylates H3K9me2 to increase chromatin accessibility and activate transcription of lipogenic genes, thereby promoting hepatic and plasma triglyceride synthesis.\",\n      \"method\": \"In vivo phosphorylation mapping, co-immunoprecipitation (JMJD1C–USF-1), ChIP, shRNA knockdown in mouse liver, in vivo lipid measurements, site-directed mutagenesis (T505A)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — site-specific phosphorylation identified and validated by mutagenesis, Co-IP with USF-1, ChIP at lipogenic promoters, in vivo phenotype\",\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, which promotes STAT3 interaction with phosphatase PTPN6 and restricts sustained STAT3 phosphorylation. Loss of JMJD1C causes STAT3 Lys140 hypermethylation, blocking PTPN6 binding, sustaining STAT3 phosphorylation, and driving plasma cell differentiation. STAT3 K140R point mutation completely abrogates the effect of JMJD1C deletion.\",\n      \"method\": \"B cell-specific Jmjd1c knockout, in vitro demethylation assay on STAT3, co-immunoprecipitation (STAT3–PTPN6), site-directed mutagenesis (K140R), flow cytometry of plasma cells\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct non-histone substrate identified, mutagenesis validates specific lysine, Co-IP links demethylation to phosphatase recruitment; multiple orthogonal methods\",\n      \"pmids\": [\"35995859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A splice variant of JMJD1C (s-JMJD1C) binds directly to the androgen receptor (AR) via its ligand-binding domain. s-JMJD1C is a nuclear-localized protein that functions as an AR coactivator, identified by yeast two-hybrid and validated by GST pull-down and mammalian one-hybrid assays.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down, mammalian one-hybrid assay, RACE for splice variant characterization\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct binding confirmed by GST pull-down and one-hybrid; single lab with two methods but no chromatin or demethylase activity assay\",\n      \"pmids\": [\"17353003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JMJD1C, as an H3K9 demethylase, binds the miR-302 promoter in human embryonic stem cells (hESCs) and reduces H3K9 methylation there to sustain miR-302 expression, thereby repressing neural differentiation. JMJD1C knockdown reduces BMP signaling, enhances TGFβ signaling, and elevates NR2F2, collectively promoting neural differentiation upon bFGF withdrawal.\",\n      \"method\": \"Stable shRNA knockdown in hESCs, ChIP for H3K9 methylation at miR-302 promoter, BMP/TGFβ signaling assays, differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP directly links JMJD1C to H3K9 demethylation at specific promoter; KD with defined differentiation phenotype; single lab\",\n      \"pmids\": [\"24318875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Deltex2 directly inhibits Jmjd1c demethylase activity by promoting its monoubiquitination; mutation of the monoubiquitination site in Jmjd1c abolishes Deltex2's inhibitory effect. Jmjd1c is required for MyoD expression in vivo and in vitro by demethylating H3K9me2 at a key regulatory region of the MyoD locus, thereby promoting myogenic differentiation.\",\n      \"method\": \"Co-immunoprecipitation (Deltex2–Jmjd1c), in vitro demethylase activity assay, site-directed monoubiquitination mutagenesis, ChIP for H3K9me2, genetic rescue experiments in skeletal muscle stem cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic inhibition by monoubiquitination validated by mutagenesis, direct Co-IP, ChIP at MyoD locus, and in vivo genetic epistasis\",\n      \"pmids\": [\"28351977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD1C, with the help of pluripotency factor KLF4, maintains mouse ESC identity by demethylating H3K9 at promoters of the miR-200 family and miR-290/295 cluster, suppressing ERK/MAPK signaling and EMT. Jmjd1c depletion activates ERK/MAPK signaling, and ERK/MAPK inhibition rescues the differentiation phenotype.\",\n      \"method\": \"shRNA knockdown in mESCs, ChIP for H3K9 methylation, ERK/MAPK signaling assays, epistasis with MEK inhibitor, microRNA expression profiling\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP links JMJD1C to H3K9 demethylation at specific miRNA loci; pathway placement by MEK inhibitor rescue; single lab\",\n      \"pmids\": [\"28826851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A JMJD1C mutation found in a Rett syndrome patient causes abnormal subcellular localization of JMJD1C, diminished demethylase activity toward MDC1, and reduced binding to MECP2. JMJD1C depletion in neurons compromises dendritic activity.\",\n      \"method\": \"Functional mutagenesis study, in vitro MDC1 demethylation assay, co-immunoprecipitation (JMJD1C–MECP2), subcellular localization imaging, neuronal knockdown\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding to MECP2 and MDC1 demethylase activity tested for disease mutant; single lab with multiple methods\",\n      \"pmids\": [\"26181491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The catalytic JmjC domain and zinc finger domain of JMJD1C are required for leukemia cell survival in vitro and in vivo in MLL-rearranged AML. H3K36 methylation serves as a marker for JMJD1C activity at gene loci. Loss of JmjC domain activity leads to increased RAS/MAPK and JAK-STAT pathway activation and upregulation of IL-3 receptor genes, with activating RAS mutations conferring resistance to JMJD1C loss.\",\n      \"method\": \"CRISPR/Cas9 domain-specific negative-selection screen, single-cell transcriptomics, ChIP for H3K36me, transplantation assays, genetic epistasis with RAS mutations\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR domain screen identifies catalytic requirements; ChIP validates H3K36me as activity marker; single lab\",\n      \"pmids\": [\"31076406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JMJD1C is required for long-term maintenance of undifferentiated spermatogonia (ZBTB16-positive) in mouse testis. Jmjd1c-deficient males show progressive reduction of germ cells and increased apoptosis in an age-dependent manner, with JMJD1C most abundantly expressed in undifferentiated spermatogonia.\",\n      \"method\": \"Jmjd1c knockout mouse model, immunostaining for spermatogonial markers, TUNEL apoptosis assay, histological analysis\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype (spermatogonial loss, apoptosis); single lab\",\n      \"pmids\": [\"24006281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"JMJD1C has multiple spermatogenic functions: it is required for postmeiotic chromatin remodeling (histone H4K16 acetylation) and spermatogonial stem cell self-renewal (OCT4 expression), and it interacts with MDC1 and HSP90 as partner proteins during spermatogenesis.\",\n      \"method\": \"Gene-trap mouse model, immunostaining for H4K16ac, OCT4, and NANOG in spermatogonia, co-immunoprecipitation (JMJD1C–MDC1, JMJD1C–HSP90)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — KO phenotype with multiple chromatin readouts plus Co-IP; single lab\",\n      \"pmids\": [\"27649575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Jmjd1c acts as an anti-nociceptive regulator of neuropathic pain by positively regulating Socs3 expression via H3K9 demethylation at the Socs3 promoter, thereby suppressing JAK/STAT3 signaling. KLF15 activates Jmjd1c transcription by binding to its super-enhancer.\",\n      \"method\": \"H3K27ac ChIP-Seq, RNA-Seq, ChIP-qPCR for H3K9 methylation at Socs3 promoter, dual-luciferase reporter assay (KLF15–Jmjd1c SE), shRNA knockdown and overexpression in rat NP model\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-qPCR at specific locus, luciferase for upstream activator, in vivo phenotype; single lab\",\n      \"pmids\": [\"40485981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In tumor Treg cells, JMJD1C deletion enhances AKT signaling through its H3K9me2 demethylase activity and increases STAT3 signaling independently of H3K9me2 demethylase activity, collectively leading to robust IFN-γ production and Treg cell fragility. An oral JMJD1C inhibitor suppresses tumor growth by targeting intratumoral Treg cells.\",\n      \"method\": \"Treg-specific Jmjd1c knockout, ChIP for H3K9me2, STAT3 pathway analysis, pharmacological inhibition, tumor growth assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with mechanistic dissection of demethylase-dependent vs. independent STAT3 effects; multiple readouts; single lab\",\n      \"pmids\": [\"38356061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Jmjd1c depletion in 3T3-L1 preadipocytes impairs mitotic clonal expansion and increases H3K9me2 at promoters of key adipogenic transcription factors (C/EBPs and PPARγ), reducing their induction and impairing adipocyte differentiation, lipid droplet formation, and insulin-stimulated glucose/fatty acid uptake.\",\n      \"method\": \"shRNA knockdown in 3T3-L1, ChIP for H3K9me2 at C/EBP and PPARγ promoters, lipid staining, glucose/fatty acid uptake assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP at specific promoters links JMJD1C loss to H3K9me2 accumulation; defined adipogenic phenotype; single lab\",\n      \"pmids\": [\"28501567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JMJD1C interacts with FABP5 via its jumonji domain in MLL-rearranged AML cells, and FABP5 regulates JMJD1C mRNA and protein expression. JMJD1C regulates expression of lipid synthesis-associated genes FADS2 and SCD.\",\n      \"method\": \"Mass spectrometry interactome, co-immunoprecipitation (JMJD1C–FABP5), domain mapping, gene expression analysis, pharmacological rescue with lipids/recombinant FABP5\",\n      \"journal\": \"Leukemia & lymphoma\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP identifies binding partner; mechanistic follow-up is partial and rescue is indirect; single lab\",\n      \"pmids\": [\"35468015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Endothelial JMJD1C drives pathological ocular neovascularization by demethylating H3K9me2 at the Srebf2 locus to activate SREBF2-dependent cholesterol biosynthesis in endothelial cells. Endothelial-specific Jmjd1c deletion suppresses Srebf2 transcription, increases H3K9me2 at this locus, and markedly reduces pathological neovascularization in OIR and CNV mouse models.\",\n      \"method\": \"Endothelial-specific conditional Jmjd1c KO, ChIP-qPCR for H3K9me2 at Srebf2 locus, RNA-seq, in vitro angiogenesis assays, in vivo retinal flat-mount and CNV models\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with ChIP-qPCR at specific locus linking H3K9me2 demethylation to target gene activation; multiple in vitro and in vivo assays; single lab\",\n      \"pmids\": [\"41548765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JMJD1C promotes PCSK9 transcription in macrophages through H3K9 demethylation at the PCSK9 locus, driving foam cell formation and atherosclerosis progression. JMJD1C knockdown reduces plaque area and foam cell formation, effects reversed by PCSK9 overexpression.\",\n      \"method\": \"ChIP for H3K9 demethylation at PCSK9 promoter, shRNA knockdown in RAW264.7 cells and ApoE-/- mice, PCSK9 rescue overexpression\",\n      \"journal\": \"Journal of physiology and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ChIP at specific locus, rescue experiment; single lab with limited mechanistic depth\",\n      \"pmids\": [\"39511107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In PNH clones, elevated JMJD1C demethylates H3K36me3 at the CPS1 locus (reducing H3K36me3), suppressing CPS1 expression and promoting metabolic reprogramming that sustains clonal proliferation. JMJD1C knockdown in PIG-A KO K562 cells upregulates CPS1 and H3K36me3 and decreases proliferation.\",\n      \"method\": \"ChIP analysis of H3K36me3 at CPS1 locus, shRNA knockdown in K562 PIG-A KO cells, CPS1 expression and metabolic measurements, pharmacological inhibition with JIB-04\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ChIP links JMJD1C to H3K36me3 at specific locus; single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"38650379\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JMJD1C (KDM3C) is a JmjC domain-containing demethylase that removes mono- and di-methyl marks from histone H3K9 (and in some contexts H3K36) at specific gene loci to activate transcription, and also demethylates non-histone substrates including MDC1 (at K45, to regulate the RNF8–BRCA1 DNA damage response) and STAT3 (at K140, to restrain its phosphorylation and plasma cell differentiation); its activity is regulated post-translationally by mTOR-mediated phosphorylation at T505 (enabling USF-1 interaction for lipogenic gene activation) and by Deltex2-induced monoubiquitination (which inhibits its demethylase activity), and it acts as a transcriptional coactivator for nuclear receptors, RUNX1-RUNX1T1, HOXA9, and other transcription factors in contexts ranging from leukemic stem cell self-renewal and spermatogenesis to lipogenesis and immune cell differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"JMJD1C is a JmjC domain-containing lysine demethylase that removes mono- and di-methyl marks from histone H3K9 at specific gene promoters to activate transcription, functioning as a chromatin-based coactivator across diverse biological contexts including leukemia stem cell self-renewal, spermatogenesis, lipogenesis, adipogenesis, embryonic stem cell maintenance, and immune cell differentiation [PMID:20530532, PMID:26494788, PMID:26878175, PMID:32034158, PMID:24006281, PMID:28826851]. Beyond histone substrates, JMJD1C demethylates the non-histone proteins MDC1 at Lys45—enabling RNF8-dependent ubiquitylation and BRCA1 recruitment during the DNA damage response—and STAT3 at Lys140, which promotes PTPN6 phosphatase engagement to restrain STAT3 phosphorylation and plasma cell differentiation [PMID:24240613, PMID:35995859]. JMJD1C activity is regulated post-translationally by mTOR-mediated phosphorylation at Thr505, which licenses interaction with the transcription factor USF-1 at lipogenic promoters, and by Deltex2-induced monoubiquitination, which inhibits its catalytic demethylase function [PMID:32034158, PMID:28351977]. In leukemia, JMJD1C is recruited by RUNX1-RUNX1T1 and HOXA9 to sustain oncogenic gene expression programs, and its catalytic JmjC and zinc finger domains are essential for MLL-rearranged AML cell survival [PMID:26494788, PMID:26878175, PMID:31076406].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"The first functional characterization established that a splice variant of JMJD1C directly binds the androgen receptor and acts as a nuclear receptor coactivator, positioning it as a transcriptional regulator.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, and mammalian one-hybrid in cell lines\",\n      \"pmids\": [\"17353003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No demethylase activity was demonstrated in this study\",\n        \"Chromatin occupancy at AR target genes not tested\",\n        \"Physiological relevance of the AR interaction in vivo not addressed\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining JMJD1C as a bona fide H3K9me1/me2 demethylase resolved its catalytic identity and revealed its sequential promoter switch with the methyltransferase WHISTLE at steroidogenic genes.\",\n      \"evidence\": \"In vitro demethylation assay, TAP purification identifying WHISTLE and HSP90α, ChIP at p450c17 promoter in mouse testis\",\n      \"pmids\": [\"20530532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genome-wide target repertoire of JMJD1C not mapped\",\n        \"Whether HSP90α binding modulates catalytic activity was not tested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that JMJD1C demethylates the non-histone substrate MDC1 at Lys45 established a new paradigm in which its catalytic activity directly regulates the RNF8–BRCA1 DNA damage response pathway, broadening its function beyond chromatin.\",\n      \"evidence\": \"In vitro demethylation assay on MDC1, Co-IP of JMJD1C–RNF8–MDC1, laser-stripe DSB recruitment, site-specific mutagenesis\",\n      \"pmids\": [\"24240613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether JMJD1C demethylates MDC1 at DSBs in a cell-cycle-dependent manner was not addressed\",\n        \"In vivo physiological consequences of losing this DDR function not tested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that JMJD1C maintains undifferentiated spermatogonia and sustains miR-302 expression in human ESCs revealed its role in stem cell self-renewal through H3K9 demethylation at specific regulatory loci.\",\n      \"evidence\": \"Jmjd1c KO mouse testis phenotyping; shRNA knockdown in hESCs with ChIP at miR-302 promoter\",\n      \"pmids\": [\"24006281\", \"24318875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Genome-wide H3K9me2 changes in spermatogonia not characterized\",\n        \"Whether demethylase activity is required for the spermatogonial phenotype was not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of JMJD1C as a critical coactivator recruited by RUNX1-RUNX1T1 in AML—maintaining low H3K9me2 at leukemic target loci—established its oncogenic role and therapeutic relevance in leukemia.\",\n      \"evidence\": \"ChIP-seq, Co-IP, Jmjd1c KO mouse with RUNX1-RUNX1T1-driven proliferation assay\",\n      \"pmids\": [\"26494788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether H3K9 demethylase activity alone or a scaffolding function is responsible was not dissected\",\n        \"No structural basis for RUNX1-RUNX1T1 interaction determined\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A Rett syndrome-associated JMJD1C mutation was shown to impair its demethylase activity and MECP2 binding, providing initial evidence linking JMJD1C dysfunction to a neurodevelopmental disorder.\",\n      \"evidence\": \"Functional mutagenesis, in vitro MDC1 demethylation assay, Co-IP of JMJD1C–MECP2, neuronal knockdown\",\n      \"pmids\": [\"26181491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single patient mutation; causal relationship to Rett syndrome not genetically established\",\n        \"Neuronal H3K9me2 target loci not identified\",\n        \"Whether MECP2 binding is direct or bridged was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing JMJD1C as a direct HOXA9 partner required for leukemia stem cell self-renewal in MLL-rearranged AML clarified its oncogenic mechanism and showed therapeutic selectivity over normal HSCs.\",\n      \"evidence\": \"In vivo shRNA screen, conditional KO, Co-IP of JMJD1C–HOXA9, serial transplantation\",\n      \"pmids\": [\"26878175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific gene targets co-regulated by JMJD1C and HOXA9 were not fully delineated\",\n        \"Catalytic versus scaffolding contribution not separated\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that Deltex2 inhibits JMJD1C by promoting its monoubiquitination revealed the first post-translational mechanism controlling JMJD1C catalytic activity, with functional consequences for MyoD expression and myogenesis.\",\n      \"evidence\": \"Co-IP, in vitro demethylase assay, monoubiquitination-site mutagenesis, ChIP at MyoD locus, muscle stem cell rescue experiments\",\n      \"pmids\": [\"28351977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The E3 ligase catalyzing monoubiquitination was not identified\",\n        \"Whether monoubiquitination regulates JMJD1C in non-muscle contexts was not tested\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Work in mESCs and preadipocytes extended the H3K9 demethylation paradigm to pluripotency (miR-200/miR-290 family loci via KLF4) and adipogenesis (C/EBP and PPARγ promoters), broadening the physiological scope of JMJD1C function.\",\n      \"evidence\": \"shRNA in mESCs with ChIP and MEK inhibitor rescue; shRNA in 3T3-L1 with ChIP at adipogenic promoters\",\n      \"pmids\": [\"28826851\", \"28501567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether KLF4 directly recruits JMJD1C was not tested biochemically\",\n        \"In vivo adipogenesis phenotype not confirmed in KO mice\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Domain-resolution CRISPR screening in MLL-rearranged AML showed that both the JmjC catalytic domain and zinc finger domain are essential for leukemia survival, and identified H3K36 methylation as a potential JMJD1C activity mark, expanding its substrate range beyond H3K9.\",\n      \"evidence\": \"CRISPR/Cas9 domain-specific negative-selection screen, ChIP for H3K36me, single-cell transcriptomics, RAS epistasis\",\n      \"pmids\": [\"31076406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct H3K36 demethylation by JMJD1C not demonstrated in vitro in this study\",\n        \"Whether H3K36 and H3K9 demethylation are context-dependent was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of mTOR-mediated Thr505 phosphorylation as a nutrient-responsive switch enabling JMJD1C–USF-1 interaction at lipogenic promoters established a signaling-to-chromatin mechanism for feeding-induced lipogenesis.\",\n      \"evidence\": \"In vivo phosphorylation mapping, T505A mutagenesis, Co-IP with USF-1, ChIP at FASN/GPAT, hepatic triglyceride measurements in mice\",\n      \"pmids\": [\"32034158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional kinases regulate JMJD1C was not explored\",\n        \"Structural basis of USF-1 recognition of phospho-T505 not determined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that JMJD1C demethylates STAT3 at Lys140 to enable PTPN6 phosphatase docking established a second non-histone demethylation event with direct signaling consequences, explaining how JMJD1C restrains plasma cell differentiation.\",\n      \"evidence\": \"B cell-specific Jmjd1c KO, in vitro STAT3 demethylation assay, K140R mutagenesis, Co-IP of STAT3–PTPN6, flow cytometry\",\n      \"pmids\": [\"35995859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether JMJD1C demethylates STAT3 in non-B cell contexts was not tested\",\n        \"Full set of non-histone substrates remains unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Treg-specific deletion revealed a dual mechanism in tumor immunity: JMJD1C loss enhances AKT signaling via H3K9me2 demethylase activity and boosts STAT3 signaling through a demethylase-independent mechanism, inducing Treg fragility and anti-tumor immunity.\",\n      \"evidence\": \"Treg-specific Jmjd1c KO, ChIP for H3K9me2, STAT3 pathway dissection, oral JMJD1C inhibitor in tumor models\",\n      \"pmids\": [\"38356061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The demethylase-independent mechanism of STAT3 regulation in Tregs is undefined\",\n        \"Selectivity and pharmacology of the oral JMJD1C inhibitor not deeply characterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the complete catalog of JMJD1C non-histone substrates, the structural basis for its interactions with transcription factors and regulation by post-translational modifications, and whether its H3K36 demethylase activity is physiologically significant.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of JMJD1C or its complexes exists\",\n        \"Full non-histone substrate repertoire uncharacterized\",\n        \"H3K36 demethylation not validated by direct in vitro assay\",\n        \"Relative contributions of catalytic versus scaffolding functions unresolved in most contexts\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 8]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 2, 4, 8, 16]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2, 4, 7, 8, 9, 16]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 4, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MDC1\",\n      \"RNF8\",\n      \"HOXA9\",\n      \"RUNX1\",\n      \"USF1\",\n      \"STAT3\",\n      \"HSP90AA1\",\n      \"DTX2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}