{"gene":"JAZF1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2004,"finding":"JAZF1 (TIP27) physically interacts with the ligand-binding domain (LBD) of nuclear orphan receptor TAK1/TR4 through a defined TAK1-interaction domain (TID, residues Asp39–Lys79) on JAZF1, and the TAK1-LBD from helix 3 to the C-terminus is required for optimal interaction. This interaction represses DR1-dependent transcriptional activation by TAK1, without inhibiting TAK1 homodimerization or DNA binding, likely by affecting co-activator recruitment. JAZF1 and TAK1 co-localize in the nucleus.","method":"Yeast two-hybrid, mammalian two-hybrid, GST pull-down assay, confocal microscopy co-localization, transcriptional reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods including pull-down, two-hybrid, mutagenesis of interaction domains, and functional reporter assays in a single rigorous study","pmids":["15302918"],"is_preprint":false},{"year":2001,"finding":"A chromosomal translocation t(7;17)(p15;q21) fuses JAZF1 (chromosome 7p15) with JJAZ1/SUZ12 (chromosome 17q21) in endometrial stromal tumors, producing a JAZF1-JJAZ1 (JAZF1-SUZ12) fusion transcript detected by RT-PCR in tumor RNA.","method":"Cytogenetic analysis, RT-PCR of tumor RNA, breakpoint cloning","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — founding discovery, replicated across numerous independent labs with consistent results","pmids":["11371647"],"is_preprint":false},{"year":2017,"finding":"The JAZF1-SUZ12 fusion protein disrupts the PRC2 complex: it destabilizes EZH2 and EED components, reduces histone methyltransferase (HMT) activity of reconstituted PRC2 on nucleosome array substrates, decreases H3K27 trimethylation in ESS tissue harboring t(7;17) (but not H3K9 methylation), decreases PRC2 binding affinity to target chromatin loci, and fails to rescue neuronal differentiation in Suz12-/- ES cells while enhancing cell proliferation.","method":"Co-transfection assays, in vitro reconstituted PRC2 HMT assay with nucleosome arrays, chromatin binding assays, H3K27me3/H3K9me3 immunostaining in patient tissue, rescue experiments in Suz12-/- ES cells","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of PRC2 activity, multiple orthogonal functional assays, patient tissue validation, single lab","pmids":["27845897"],"is_preprint":false},{"year":2023,"finding":"Crystal structures of the TR4LBD–JAZF1 complex reveal that JAZF1 binds to an unidentified surface of the TR4 LBD (distinct from the classical AF-2 coactivator surface) and stabilizes an α13 helix not previously reported in the nuclear receptor family. This binding reinforces an autorepressed conformation of TR4 and suppresses coactivator (SRC-1, CREBBP) binding, thereby inhibiting TR4 transcriptional activation. Cancer-associated mutations at this interface impair these interactions and reduce TR4 transcriptional repression in vitro and in vivo.","method":"X-ray crystallography (high-resolution crystal structures of TR4DBD, TR4DBD-DNA, and TR4LBD-JAZF1 complexes), in vitro transcriptional activation assays, mutagenesis of cancer-associated residues","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional mutagenesis validation, single lab but multiple orthogonal methods","pmids":["36651297"],"is_preprint":false},{"year":2021,"finding":"JAZF1 is a member of the p400/TIP60/NuA4 chromatin-modifying complex, specifically associating with a p400 sub-complex containing MBTD1 but excluding ANP32E. JAZF1 depletion reduces H2A.Z acetylation levels at >1000 regulatory sites genome-wide (ChIP-seq) without affecting H2A.Z nucleosome positioning, and causes transcriptome changes including downregulation of ribosome biogenesis genes. JAZF1 associates with the histone acetyltransferase TIP60, whose depletion causes correlated H2A.Z deacetylation at JAZF1-targeted enhancer regions.","method":"Mass spectrometry identification of H2A.Z chaperone complexes, ChIP-seq (H2A.Z acetylation genome-wide), RNA-seq (transcriptome after JAZF1 depletion), Co-IP/complex association assays","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mass spectrometry complex identification, genome-wide ChIP-seq, transcriptomics, and functional depletion experiments; single lab with multiple orthogonal approaches","pmids":["33445503"],"is_preprint":false},{"year":2020,"finding":"JAZF1 is a transcriptional regulator of ribosome biogenesis. Genetic deletion of Jazf1 in mice causes global impairment of protein and insulin synthesis mediated by defects in ribosomal protein synthesis, ribosomal RNA processing, and aminoacyl-tRNA synthetase expression, leading to ER stress and increased β-cell susceptibility to apoptosis. JAZF1 is excluded from the nucleus under metabolic stress and its expression is reduced in diabetic islets.","method":"Jazf1 knockout mice, islet isolation, ribosome biogenesis assays, protein synthesis measurements, ER stress markers, subcellular fractionation/localization, gene expression profiling in murine T2D and human islets under metabolic stress","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO model with defined molecular phenotypes (ribosome biogenesis, ER stress), subcellular localization data, validation in human islets; single lab with multiple orthogonal methods","pmids":["32640216"],"is_preprint":false},{"year":2018,"finding":"JAZF1 suppresses hepatic SREBP-1c expression through inhibition of transcriptional activity at liver X receptor response elements (LXREs) in the SREBP-1c promoter, and increases AMPK phosphorylation in hepatocytes. Overexpression of JAZF1 in transgenic mice reduces lipogenesis gene expression and protects against HFD-induced hepatic steatosis; these effects are partially blocked by the AMPK inhibitor Compound C.","method":"JAZF1 transgenic mice (HFD model), hepatocyte overexpression/knockdown, LXRE luciferase reporter assay, AMPK phosphorylation western blot, gene expression analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model, reporter assay, signaling pathway analysis; single lab, multiple methods","pmids":["30154417"],"is_preprint":false},{"year":2015,"finding":"JAZF1 (TIP27) overexpression in transgenic mice and db/db mice reduces hepatic glucose production and improves insulin sensitivity through a PI3-kinase/Akt-dependent mechanism: overexpression increases phosphorylation of insulin receptor, IRS-1, AMPK, and Akt in liver, decreases expression of gluconeogenic enzymes PEPCK and G6Pase, and these effects are abolished by the PI3-kinase inhibitor LY294002.","method":"TIP27-Tg mice and adenovirus-mediated overexpression in db/db mice, hyperinsulinemic-euglycemic clamp, western blot for insulin signaling molecules, RT-qPCR, pharmacological inhibition with LY294002","journal":"International journal of obesity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic and adenoviral models, clamp studies, pathway inhibition; single lab","pmids":["25614086"],"is_preprint":false},{"year":2014,"finding":"JAZF1 overexpression inhibits hepatic cholesterol de novo synthesis by repressing HMGCR transcriptional activity through a CREB-dependent mechanism (inhibiting CRE activity in the HMGCR promoter), demonstrated by dual-luciferase reporter assay. In ApoE KO mice, JAZF1 overexpression decreases serum cholesterol and reduces atherosclerotic plaque area.","method":"Adenovirus-mediated JAZF1 overexpression in ApoE KO mice, dual-luciferase reporter assay for HMGCR promoter CREB activity, [14C]-acetate cholesterol synthesis measurement, hyperinsulinemic-euglycemic clamp, histological plaque quantification","journal":"International journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model, luciferase reporter for direct mechanistic step, isotope-labeling cholesterol synthesis; single lab","pmids":["25499349"],"is_preprint":false},{"year":2020,"finding":"Central (mediobasal hypothalamus) JAZF1 activation in HFD-fed rats reduces hepatic glucose production (HGP) by increasing hypothalamic insulin receptor (InsR)-PI3K-Akt signaling and decreasing AMPK phosphorylation. This effect requires intact KATP channels and the hepatic branch of the vagus nerve (disrupted by vagotomy), and is blocked by central AMPK activation (AICAR). JAZF1 also elevates InsR and Akt phosphorylation in SH-SY5Y neuronal cells upon insulin stimulation.","method":"MBH adenovirus-mediated JAZF1 overexpression in rats, pancreatic-euglycemic clamp to measure HGP, KATP channel inhibition, hepatic vagotomy, central AICAR infusion, western blot for signaling molecules, cell line experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo stereotaxic viral delivery with clamp studies and multiple pharmacological/surgical interventions; single lab","pmids":["32275331"],"is_preprint":false},{"year":2022,"finding":"Deletion of Jazf1 in mice results in reduced plasma IGF-1, early growth retardation (shorter stature in young KO mice), and late-onset muscle insulin resistance exacerbated by HFD. Gene set enrichment analysis in KO liver identified decreased hepatocyte nuclear factor 4α (HNF4α), and JAZF1 knockdown in human hepatocytes inhibited GH-induced IGF-1 expression, placing JAZF1 upstream of the GH–IGF-1 axis and HNF4α in growth and metabolic regulation.","method":"Jazf1 knockout mice, 1H-NMR body composition, hyperinsulinemic-euglycemic clamp, IGF-1/GH plasma measurements, gene set enrichment analysis of liver transcriptome, JAZF1 knockdown in human hepatocytes with GH stimulation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse with clamp studies and human hepatocyte mechanistic validation; single lab","pmids":["36442127"],"is_preprint":false},{"year":2023,"finding":"JAZF1 safeguards human endometrial stromal cell (hESC) survival and decidualization by transcriptionally repressing G0S2. JAZF1 interacts with G0S2 transcriptional activator Purβ to restrict G0S2 expression; JAZF1 depletion in hESCs increases G0S2, causing apoptosis and defective decidualization. This mechanism was validated in decidual tissue from recurrent spontaneous abortion patients showing low JAZF1, high G0S2, and excess apoptosis.","method":"JAZF1 siRNA knockdown in hESCs, decidualization assays, apoptosis assays, Co-IP to demonstrate JAZF1–Purβ interaction, ChIP/reporter assays for G0S2 promoter, patient tissue validation (RSA vs. controls)","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein-protein interaction (Co-IP of JAZF1 with Purβ), functional KD with defined molecular mechanism, patient tissue corroboration; single lab","pmids":["37244968"],"is_preprint":false},{"year":2022,"finding":"JAZF1 (ZNF802) functions as a transcriptional repressor of the γ-globin (HBG) gene in adult erythroid cells. shRNA-mediated knockdown of ZNF802/JAZF1 in β0-thalassemia/HbE erythroblasts increased HBG transcription and translation, raising HbF levels to 35%, without affecting erythroblast proliferation or differentiation.","method":"Lentiviral shRNA knockdown of ZNF802/JAZF1 in β0-thalassemia/HbE erythroblasts, RT-qPCR for HBG mRNA, HPLC/western blot for HbF protein, flow cytometry for erythroblast differentiation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with defined transcriptional and translational outcomes; single lab, single method for the core claim","pmids":["35322124"],"is_preprint":false},{"year":2018,"finding":"Jazf1 promotes multiciliated cell (MCC) differentiation in mouse airway epithelium. Overexpression of Jazf1 in mouse embryonic tracheal explants promoted MCC differentiation, including cooperative effects with the canonical MCC transcription factor Foxj1. Knockdown of Jazf1 in adult mouse airway epithelial cultures impaired ciliated cell differentiation. Jazf1 likely functions downstream of IL-6 signaling and upstream of Foxj1 in the MCC differentiation pathway.","method":"Overexpression in mouse embryonic tracheal explants, siRNA knockdown in adult mouse airway epithelial cultures, Foxj1 co-expression epistasis experiments, IL-6 pathway genetic placement","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined cellular phenotype, epistasis placement; single lab","pmids":["29661797"],"is_preprint":false},{"year":2017,"finding":"Jazf1 promotes prostate cancer cell proliferation, colony formation, migration, and invasion via activation of the JNK/c-Jun phosphorylation pathway leading to upregulation of Slug and epithelial-mesenchymal transition (EMT; increased vimentin, decreased E-cadherin). In xenograft models, Jazf1-overexpressing tumors were larger and Jazf1-knockdown tumors were smaller.","method":"Jazf1 overexpression and knockdown in DU145 and LNCaP prostate cancer cell lines, transwell migration/invasion assays, microarray for Slug identification, western blot for JNK/c-Jun phosphorylation and EMT markers, xenograft mouse model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined pathway (JNK/Slug), in vivo validation; single lab","pmids":["29416651"],"is_preprint":false},{"year":2014,"finding":"JAZF1 promotes visfatin expression in adipocytes indirectly through upregulation of PPARα and PPARβ/δ, which then activate the visfatin promoter via PPRE elements. Luciferase reporter assays confirmed JAZF1 activates visfatin transcription; ChIP assays showed JAZF1 does not directly bind the visfatin PPRE. The visfatin induction was abolished by PPARα antagonist GW6471 and PPARβ/δ antagonist GSK3787, and confirmed with siRNA knockdown of PPARα and PPARβ/δ. JAZF1 simultaneously inhibits TAK1 and PPARγ expression.","method":"JAZF1 overexpression vector and siRNA in 3T3-L1 adipocytes, luciferase reporter assay for visfatin promoter, ChIP assay for JAZF1–visfatin PPRE binding, pharmacological antagonists and siRNA for PPARα/PPARβ/δ, western blot and RT-qPCR","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter, ChIP, and pharmacological/siRNA validation; single lab, multiple complementary methods","pmids":["24930994"],"is_preprint":false},{"year":2013,"finding":"rs1635852 in JAZF1 intron 1 displays allele-specific enhancer activity in pancreatic insulinoma cells: the T (risk) allele shows lower transcriptional activity than the C allele, and the T allele preferentially binds PDX1 (pancreatic master regulator) as part of a repressor complex identified by DNA affinity capture and mass spectrometry.","method":"Open chromatin mapping to prioritize variants, luciferase enhancer assays in 832/13 and MIN6 cells, DNA affinity capture with mass spectrometry to identify PDX1 as the T-allele-preferential binding factor","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — allele-specific reporter assay plus mass spectrometry protein identification; single lab, two orthogonal methods","pmids":["23328127"],"is_preprint":false},{"year":2021,"finding":"JAZF1 regulates β-cell differentiation and glucose homeostasis: Jazf1-KO iPSC-derived β-cells show reduced expression of β-cell specification/maturation genes and lower insulin/C-peptide secretion. Jazf1 heterozygous KO mice have lower serum insulin, reduced pancreatic insulin expression, smaller β-cell size, and impaired glucose homeostasis. JAZF1 modulates cyclin A2 levels in this context.","method":"Jazf1-KO iPSC differentiation to β-cells, MIN6 gain/loss-of-function, Jazf1+/- mice glucose tolerance and insulin measurements, teratoma assays for proliferation markers","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iPSC KO differentiation model and in vivo heterozygous KO mouse; single lab, multiple methods","pmids":["33555104"],"is_preprint":false},{"year":2019,"finding":"JAZF1 directly regulates vimentin and E-cadherin expression (EMT markers) in gastric cancer cells: JAZF1 was validated as a direct target of miR-1275 by luciferase assay, and overexpression of JAZF1 upregulated vimentin and downregulated E-cadherin, promoting migration and invasion in vitro and in vivo. ChIP analysis confirmed JAZF1 directly regulates vimentin transcription.","method":"Luciferase reporter assay (miR-1275 targeting of JAZF1), western blot, RT-qPCR, transwell migration/invasion, xenograft, ChIP assay for JAZF1 at vimentin promoter","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase and ChIP validation, in vivo model; single lab","pmids":["31357957"],"is_preprint":false},{"year":2019,"finding":"JAZF1 overexpression suppresses cell proliferation, induces G0/G1 arrest, and promotes apoptosis in papillary thyroid carcinoma BCPAP cells by suppressing the TAK1/NF-κB signaling pathway: JAZF1 overexpression decreased TAK1 and NF-κB p-p65 protein levels and decreased Bcl-2 while increasing Bax, without affecting NF-κB p65 mRNA/protein expression levels.","method":"Adenovirus-mediated JAZF1 overexpression in BCPAP cells, cell proliferation/colony assays, cell cycle analysis, apoptosis flow cytometry, western blot for TAK1, NF-κB p65, p-p65, Bcl-2, Bax","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single cell line, single lab, overexpression only with western blot pathway readout; no mechanistic dissection of direct vs. indirect regulation","pmids":["31819531"],"is_preprint":false},{"year":2018,"finding":"miRNA-31-5p targets JAZF1 directly (validated by dual-luciferase assay) in human spermatogonial stem cells (SSCs); JAZF1 silencing reduces SSC proliferation, DNA synthesis, and increases apoptosis, and decreases cyclin A2 but not cyclin D1 or cyclin E1 levels, placing JAZF1 in a PAK1–JAZF1–cyclin A2 pathway controlling SSC fate.","method":"Dual-luciferase reporter assay for miR-31-5p targeting of JAZF1, CCK-8/EDU proliferation assays, Annexin V/PI apoptosis, JAZF1 siRNA knockdown, western blot for cyclins","journal":"Molecular therapy. Nucleic acids","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase validation of miRNA target plus functional KD; single lab, limited pathway mechanistic resolution","pmids":["30583099"],"is_preprint":false},{"year":2015,"finding":"JAZF1 overexpression in C2C12 myoblasts promotes cell proliferation and transcriptionally represses MEF2C and MRF4 (and their downstream genes including AMPD1), thereby retarding myogenic differentiation. JAZF1-mediated repression of Ampd1 acts through MEF2-binding sites and E-box elements in the Ampd1 proximal regulatory region rather than through TR4/JAZF1 complex binding sites. JAZF1 overexpression and AMPD1 overexpression or JAZF1 downregulation both impaired AMPK phosphorylation.","method":"JAZF1 overexpression in C2C12 cells, gene array analysis, promoter activity assays with MEF2-site and E-box mutations, RT-qPCR, western blot for AMPK phosphorylation","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — promoter mutagenesis and functional assays, but single lab and limited direct binding evidence","pmids":["26101156"],"is_preprint":false},{"year":2021,"finding":"RNA-driven formation of the JAZF1-SUZ12 fusion gene can be induced in human endometrial stromal cells by expressing designed antisense (but not sense) chimeric RNAs in a sequence-dependent manner; this process is inhibited by estrogen or progesterone. The induced fusion gene was validated at both RNA and genomic DNA levels.","method":"Transfection of designed chimeric RNAs in human endometrial stromal cells, RT-PCR and genomic PCR validation of JAZF1-SUZ12 fusion, sense vs. antisense chimeric RNA comparison, hormone inhibition experiments","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequence-dependent and strand-specific mechanism with RNA and DNA validation; single lab, novel mechanistic claim","pmids":["34928964"],"is_preprint":false}],"current_model":"JAZF1 is a zinc finger transcriptional co-repressor that directly binds the ligand-binding domain of nuclear orphan receptor TR4/TAK1 (stabilizing an autorepressed TR4 conformation via a novel α13 helix as shown by crystal structure), and is also a subunit of the p400/TIP60/NuA4 chromatin-modifying complex where it promotes H2A.Z acetylation at regulatory regions; together, these activities regulate ribosome biogenesis, gluconeogenesis, lipid metabolism (via SREBP-1c/LXRE and HMGCR/CREB axes), β-cell differentiation and insulin translation, growth (GH–IGF-1–HNF4α axis), γ-globin repression in erythroid cells, and endometrial stromal cell survival (via G0S2/Purβ repression), while its oncogenic JAZF1-SUZ12 fusion disrupts PRC2 complex integrity and H3K27 trimethylation in endometrial stromal sarcomas."},"narrative":{"mechanistic_narrative":"JAZF1 is a zinc-finger transcriptional co-repressor that couples nuclear-receptor regulation to chromatin modification, governing metabolic, developmental, and proliferative programs [PMID:15302918, PMID:33445503]. It directly binds the ligand-binding domain of the orphan nuclear receptor TR4/TAK1 through a defined interaction domain, and crystallography shows it engages a non-canonical surface of the TR4 LBD—stabilizing a previously unobserved α13 helix that reinforces an autorepressed TR4 conformation and excludes coactivators such as SRC-1 and CREBBP, thereby blunting TR4-driven transcription [PMID:15302918, PMID:36651297]. Independently, JAZF1 is a subunit of a p400/TIP60/NuA4 sub-complex (containing MBTD1, excluding ANP32E) that promotes H2A.Z acetylation at over a thousand regulatory sites and sustains expression of ribosome-biogenesis genes [PMID:33445503]. Through these activities it acts as a master metabolic regulator: it drives ribosomal protein and rRNA synthesis required for insulin translation and β-cell survival [PMID:32640216, PMID:33555104], represses hepatic lipogenesis and cholesterol synthesis via SREBP-1c/LXRE, HMGCR/CREB, and AMPK axes [PMID:30154417, PMID:25499349], suppresses gluconeogenesis through PI3K/Akt signaling both hepatically and via central hypothalamic circuits [PMID:25614086, PMID:32275331], and sits upstream of the GH–IGF-1–HNF4α growth axis [PMID:36442127]. In other lineages JAZF1 represses γ-globin (HBG) in adult erythroid cells [PMID:35322124] and safeguards endometrial stromal cell survival and decidualization by interacting with Purβ to repress G0S2 [PMID:37244968]. The recurrent t(7;17) JAZF1-SUZ12 fusion in endometrial stromal sarcoma destabilizes EZH2 and EED, reduces PRC2 histone-methyltransferase activity and H3K27 trimethylation, and enhances proliferation [PMID:11371647, PMID:27845897].","teleology":[{"year":2001,"claim":"Established JAZF1 as a recurrent fusion partner in endometrial stromal tumors, defining its first disease link before any functional role was known.","evidence":"Cytogenetics and RT-PCR of tumor RNA identifying the t(7;17) JAZF1-SUZ12 fusion transcript","pmids":["11371647"],"confidence":"High","gaps":["Did not define the normal function of JAZF1","Did not explain how the fusion drives tumorigenesis"]},{"year":2004,"claim":"Identified the first molecular activity of JAZF1—repression of the nuclear receptor TR4/TAK1—answering what the protein does biochemically.","evidence":"Yeast/mammalian two-hybrid, GST pull-down, mutagenesis of the TID, and reporter assays in mammalian cells","pmids":["15302918"],"confidence":"High","gaps":["Structural basis of the interaction unresolved","Did not identify target genes downstream of TR4 repression"]},{"year":2013,"claim":"Connected a JAZF1 diabetes-risk variant to allele-specific enhancer activity and PDX1 binding, linking genetic association to β-cell regulatory function.","evidence":"Open chromatin mapping, luciferase enhancer assays in insulinoma cells, and DNA affinity capture-mass spectrometry","pmids":["23328127"],"confidence":"Medium","gaps":["Effect of the variant on endogenous JAZF1 expression in human islets not shown","Mechanism of PDX1 repressor complex assembly unresolved"]},{"year":2014,"claim":"Demonstrated JAZF1 controls lipid metabolism through both direct (HMGCR/CREB) and indirect (PPAR-mediated) transcriptional mechanisms.","evidence":"Adenoviral overexpression in ApoE-KO and 3T3-L1 systems, dual-luciferase reporters, ChIP, and pharmacological/siRNA dissection of PPARα/βδ","pmids":["25499349","24930994"],"confidence":"Medium","gaps":["Whether JAZF1 acts directly or via cofactors at the HMGCR promoter not fully resolved","ChIP showed no direct JAZF1 binding at the visfatin PPRE"]},{"year":2015,"claim":"Showed JAZF1 improves systemic glucose handling by suppressing hepatic glucose production through PI3K/Akt and gluconeogenic enzyme repression.","evidence":"Transgenic and adenoviral overexpression in db/db mice, hyperinsulinemic-euglycemic clamps, and LY294002 inhibition","pmids":["25614086"],"confidence":"Medium","gaps":["Direct transcriptional targets at PEPCK/G6Pase promoters not mapped","Relationship to TR4 repression in this context unclear"]},{"year":2018,"claim":"Extended JAZF1's hepatic role to lipogenesis suppression via SREBP-1c/LXRE and AMPK, positioning it as a protector against steatosis.","evidence":"Transgenic HFD mice, LXRE luciferase reporters, AMPK phospho-blots, and Compound C rescue","pmids":["30154417"],"confidence":"Medium","gaps":["Direct vs. indirect action at the LXRE not definitively separated","Upstream activator of AMPK by JAZF1 unidentified"]},{"year":2020,"claim":"Defined a unifying nuclear function—JAZF1 drives ribosome biogenesis—linking its metabolic phenotypes to a defect in the protein-synthesis machinery, and added a hypothalamic axis for glucose control.","evidence":"Jazf1-KO mice with ribosome-biogenesis and ER-stress assays, human islet validation, and MBH viral overexpression with clamps and vagotomy","pmids":["32640216","32275331"],"confidence":"High","gaps":["Direct genomic targets among ribosomal/rRNA processing genes not enumerated","How metabolic stress excludes JAZF1 from the nucleus is unknown"]},{"year":2021,"claim":"Placed JAZF1 within the p400/TIP60/NuA4 complex as an H2A.Z acetylation regulator, providing the chromatin-level mechanism underlying its ribosome-biogenesis transcriptional control.","evidence":"Mass spectrometry of H2A.Z chaperone complexes, genome-wide H2A.Z-acetyl ChIP-seq, and RNA-seq after JAZF1 depletion","pmids":["33445503"],"confidence":"High","gaps":["How JAZF1 targets the complex to specific enhancers is unresolved","Relationship between this complex and TR4 corepression not addressed"]},{"year":2021,"claim":"Tied JAZF1 to β-cell specification and proliferation through cyclin A2, integrating its diabetes-associated role into cell differentiation.","evidence":"Jazf1-KO iPSC β-cell differentiation, MIN6 gain/loss-of-function, and Jazf1+/- mouse glucose-homeostasis studies","pmids":["33555104"],"confidence":"Medium","gaps":["Direct transcriptional targets governing β-cell maturation not mapped","Mechanism of cyclin A2 modulation unresolved"]},{"year":2022,"claim":"Identified JAZF1 as an upstream regulator of the GH–IGF-1–HNF4α growth axis, broadening its role from glucose/lipid metabolism to organismal growth.","evidence":"Jazf1-KO mice with body composition, clamps, plasma IGF-1, liver transcriptome GSEA, and GH-stimulated human hepatocyte knockdown","pmids":["36442127"],"confidence":"Medium","gaps":["Whether JAZF1 directly regulates HNF4α transcription not established","Mechanistic step linking JAZF1 to GH-induced IGF-1 unknown"]},{"year":2022,"claim":"Mechanistically dissected the oncogenic fusion: JAZF1-SUZ12 disrupts PRC2 integrity and H3K27me3, and the fusion itself can be RNA-induced, illuminating both its activity and origin.","evidence":"Reconstituted PRC2 HMT assays on nucleosome arrays, patient-tissue immunostaining, Suz12-/- rescue, plus chimeric-RNA induction with hormone inhibition","pmids":["27845897","34928964"],"confidence":"Medium","gaps":["Genome-wide target genes derepressed by the fusion not catalogued","In vivo relevance of RNA-driven fusion formation unconfirmed"]},{"year":2023,"claim":"Resolved the structural basis of JAZF1-mediated repression, showing it stabilizes a novel α13 helix to lock TR4 in an autorepressed, coactivator-excluding state.","evidence":"X-ray crystallography of TR4LBD-JAZF1 complex with cancer-mutation mutagenesis and transcription assays","pmids":["36651297"],"confidence":"High","gaps":["Structure of full-length JAZF1 and its zinc fingers not determined","How this mode relates to JAZF1's chromatin-complex activity unknown"]},{"year":2023,"claim":"Showed JAZF1 protects endometrial stromal cells via Purβ-dependent G0S2 repression, defining a survival/decidualization function with disease relevance to recurrent abortion.","evidence":"siRNA knockdown in hESCs, decidualization and apoptosis assays, JAZF1-Purβ Co-IP, G0S2 promoter ChIP/reporter, and patient tissue","pmids":["37244968"],"confidence":"Medium","gaps":["Whether JAZF1 binds the G0S2 promoter directly or only via Purβ not resolved","Reciprocal interaction validation beyond single Co-IP not shown"]},{"year":null,"claim":"How JAZF1's two characterized activities—TR4 LBD corepression and p400/TIP60-mediated H2A.Z acetylation—are coordinated at specific loci to produce its tissue-specific metabolic, developmental, and oncogenic outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating nuclear-receptor corepression with chromatin-modifying complex membership","Direct genome-wide JAZF1 binding map across tissues not established","Determinants of context-specific activation versus repression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,6,8,11,12,15,18,21]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[18,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,4,6,8]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,7,8,9,10]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2]}],"complexes":["p400/TIP60/NuA4 complex","PRC2 (via JAZF1-SUZ12 fusion)"],"partners":["TR4/TAK1","TIP60","MBTD1","SUZ12","PURΒ","PDX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86VZ6","full_name":"Juxtaposed with another zinc finger protein 1","aliases":["TAK1-interacting protein 27","Zinc finger protein 802"],"length_aa":243,"mass_kda":27.1,"function":"Acts as a transcriptional corepressor of orphan nuclear receptor NR2C2 (PubMed:15302918). Inhibits expression of the gluconeogenesis enzyme PCK2 through inhibition of NR2C2 activity (By similarity). Also involved in transcriptional activation of NAMPT by promoting expression of PPARA and PPARD (By similarity). Plays a role in lipid metabolism by suppressing lipogenesis, increasing lipolysis and decreasing lipid accumulation in adipose tissue (By similarity). 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sarcomas.","date":"2022","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/34843125","citation_count":5,"is_preprint":false},{"pmid":"35245575","id":"PMC_35245575","title":"Preparation of a JAZF1 protein polyclonal antibody and its potential role in broiler ascites syndrome.","date":"2022","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35245575","citation_count":5,"is_preprint":false},{"pmid":"27142911","id":"PMC_27142911","title":"[Endometrial stromal sarcoma: morphologic features and detection of JAZF1-SUZ12 and YWHAE FAM22 fusion genes].","date":"2016","source":"Zhonghua bing li xue za zhi = Chinese journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27142911","citation_count":5,"is_preprint":false},{"pmid":"24750188","id":"PMC_24750188","title":"Colonic low-grade endometrial stromal sarcoma and orthotopic endometrial stromal tumor with limited infiltration sharing the JAZF1-SUZ12 gene fusion.","date":"2014","source":"Pathology international","url":"https://pubmed.ncbi.nlm.nih.gov/24750188","citation_count":5,"is_preprint":false},{"pmid":"22870092","id":"PMC_22870092","title":"Absence of the JAZF1/SUZ12 chimeric transcript in the immortalized non-neoplastic endometrial stromal cell line T HESCs.","date":"2010","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/22870092","citation_count":5,"is_preprint":false},{"pmid":"35838627","id":"PMC_35838627","title":"An Unusual Benign Uterine Stromal Spindle Cell Tumor Harboring JAZF1::BCORL1.","date":"2022","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/35838627","citation_count":4,"is_preprint":false},{"pmid":"27570842","id":"PMC_27570842","title":"Prostate Cancer Related JAZF1 Gene is Associated with Schizophrenia.","date":"2014","source":"Journal of schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/27570842","citation_count":4,"is_preprint":false},{"pmid":"34978128","id":"PMC_34978128","title":"Cis-regulation of antisense non-coding RNA at the JAZF1 locus in type 2 diabetes.","date":"2022","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34978128","citation_count":3,"is_preprint":false},{"pmid":"25596907","id":"PMC_25596907","title":"Association between KIAA0319L, PXK and JAZF1 gene polymorphisms and unexplained recurrent pregnancy loss in Chinese Han couples.","date":"2014","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/25596907","citation_count":3,"is_preprint":false},{"pmid":"34074959","id":"PMC_34074959","title":"Low-grade Endometrial Stromal Sarcoma With Sex Cord-like Differentiation and PHF1-JAZF1 Fusion With Deletions: A Diagnostic Pitfall of JAZF1 FISH.","date":"2021","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/34074959","citation_count":3,"is_preprint":false},{"pmid":"37377600","id":"PMC_37377600","title":"Variants in JAZF1 are associated with asthma, type 2 diabetes, and height in the United Kingdom biobank population.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37377600","citation_count":3,"is_preprint":false},{"pmid":"27788707","id":"PMC_27788707","title":"[Effect of JAZF1 over-expression on high-fat diet-induced non-alcoholic fatty liver disease].","date":"2016","source":"Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/27788707","citation_count":3,"is_preprint":false},{"pmid":"33425511","id":"PMC_33425511","title":"Association of the JAZF1 Variant in Adults With a Parental History of Type 2 Diabetes Mellitus In Pakistan.","date":"2020","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/33425511","citation_count":3,"is_preprint":false},{"pmid":"39455528","id":"PMC_39455528","title":"Identification of JAZF1, KNOP1, and PLEKHA1 as causally associated genes and drug targets for Alzheimer's disease: a summary data-based Mendelian randomization study.","date":"2024","source":"Inflammopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39455528","citation_count":2,"is_preprint":false},{"pmid":"36166196","id":"PMC_36166196","title":"JAZF1: A Metabolic Regulator of Sensitivity to a Polyamine-Targeted Therapy.","date":"2023","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/36166196","citation_count":2,"is_preprint":false},{"pmid":"26739470","id":"PMC_26739470","title":"[Effects of JAZF1 overexpression on proinflammatory cytokines in hepatocytes induced by palmitic acid].","date":"2015","source":"Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/26739470","citation_count":2,"is_preprint":false},{"pmid":"39873241","id":"PMC_39873241","title":"Spindle Cell Sarcoma With Novel JAZF1::NUDT5 Gene Fusion: Report of a Previously Undescribed Neoplasm.","date":"2025","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39873241","citation_count":1,"is_preprint":false},{"pmid":"29136690","id":"PMC_29136690","title":"[Values of JAZF1 gene rearrangement detected by fluorescence in-situ hybridization in diagnosis of endometrial stromal tumours].","date":"2017","source":"Zhonghua bing li xue za zhi = Chinese journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29136690","citation_count":1,"is_preprint":false},{"pmid":"40866818","id":"PMC_40866818","title":"The study of JAZF1-mediated apoptosis of decidual stromal cells by activating the NF-κB signaling pathway in spontaneous preterm birth.","date":"2025","source":"BMC pregnancy and childbirth","url":"https://pubmed.ncbi.nlm.nih.gov/40866818","citation_count":0,"is_preprint":false},{"pmid":"38358587","id":"PMC_38358587","title":"CircRNA ITCH Inhibits Epithelial-Mesenchymal Transformation and Promotes Apoptosis in Papillary Thyroid Carcinoma via miR-106a-5p/JAZF1 Axis.","date":"2024","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38358587","citation_count":0,"is_preprint":false},{"pmid":"40767152","id":"PMC_40767152","title":"Incidentally Discovered Intra-Abdominal Low-Grade Endometrioid Stromal Sarcoma Confirmed by JAZF1 Rearrangement Study.","date":"2025","source":"International journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40767152","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.17.24312688","title":"Causal associations between plasma proteins and prostate cancer: a Proteome-Wide Mendelian Randomization","date":"2024-09-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.17.24312688","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51454,"output_tokens":7027,"usd":0.129884,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16306,"output_tokens":4737,"usd":0.099977,"stage2_stop_reason":"end_turn"},"total_usd":0.229861,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"JAZF1 (TIP27) physically interacts with the ligand-binding domain (LBD) of nuclear orphan receptor TAK1/TR4 through a defined TAK1-interaction domain (TID, residues Asp39–Lys79) on JAZF1, and the TAK1-LBD from helix 3 to the C-terminus is required for optimal interaction. This interaction represses DR1-dependent transcriptional activation by TAK1, without inhibiting TAK1 homodimerization or DNA binding, likely by affecting co-activator recruitment. JAZF1 and TAK1 co-localize in the nucleus.\",\n      \"method\": \"Yeast two-hybrid, mammalian two-hybrid, GST pull-down assay, confocal microscopy co-localization, transcriptional reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods including pull-down, two-hybrid, mutagenesis of interaction domains, and functional reporter assays in a single rigorous study\",\n      \"pmids\": [\"15302918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"A chromosomal translocation t(7;17)(p15;q21) fuses JAZF1 (chromosome 7p15) with JJAZ1/SUZ12 (chromosome 17q21) in endometrial stromal tumors, producing a JAZF1-JJAZ1 (JAZF1-SUZ12) fusion transcript detected by RT-PCR in tumor RNA.\",\n      \"method\": \"Cytogenetic analysis, RT-PCR of tumor RNA, breakpoint cloning\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — founding discovery, replicated across numerous independent labs with consistent results\",\n      \"pmids\": [\"11371647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The JAZF1-SUZ12 fusion protein disrupts the PRC2 complex: it destabilizes EZH2 and EED components, reduces histone methyltransferase (HMT) activity of reconstituted PRC2 on nucleosome array substrates, decreases H3K27 trimethylation in ESS tissue harboring t(7;17) (but not H3K9 methylation), decreases PRC2 binding affinity to target chromatin loci, and fails to rescue neuronal differentiation in Suz12-/- ES cells while enhancing cell proliferation.\",\n      \"method\": \"Co-transfection assays, in vitro reconstituted PRC2 HMT assay with nucleosome arrays, chromatin binding assays, H3K27me3/H3K9me3 immunostaining in patient tissue, rescue experiments in Suz12-/- ES cells\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of PRC2 activity, multiple orthogonal functional assays, patient tissue validation, single lab\",\n      \"pmids\": [\"27845897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal structures of the TR4LBD–JAZF1 complex reveal that JAZF1 binds to an unidentified surface of the TR4 LBD (distinct from the classical AF-2 coactivator surface) and stabilizes an α13 helix not previously reported in the nuclear receptor family. This binding reinforces an autorepressed conformation of TR4 and suppresses coactivator (SRC-1, CREBBP) binding, thereby inhibiting TR4 transcriptional activation. Cancer-associated mutations at this interface impair these interactions and reduce TR4 transcriptional repression in vitro and in vivo.\",\n      \"method\": \"X-ray crystallography (high-resolution crystal structures of TR4DBD, TR4DBD-DNA, and TR4LBD-JAZF1 complexes), in vitro transcriptional activation assays, mutagenesis of cancer-associated residues\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional mutagenesis validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36651297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JAZF1 is a member of the p400/TIP60/NuA4 chromatin-modifying complex, specifically associating with a p400 sub-complex containing MBTD1 but excluding ANP32E. JAZF1 depletion reduces H2A.Z acetylation levels at >1000 regulatory sites genome-wide (ChIP-seq) without affecting H2A.Z nucleosome positioning, and causes transcriptome changes including downregulation of ribosome biogenesis genes. JAZF1 associates with the histone acetyltransferase TIP60, whose depletion causes correlated H2A.Z deacetylation at JAZF1-targeted enhancer regions.\",\n      \"method\": \"Mass spectrometry identification of H2A.Z chaperone complexes, ChIP-seq (H2A.Z acetylation genome-wide), RNA-seq (transcriptome after JAZF1 depletion), Co-IP/complex association assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mass spectrometry complex identification, genome-wide ChIP-seq, transcriptomics, and functional depletion experiments; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"33445503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JAZF1 is a transcriptional regulator of ribosome biogenesis. Genetic deletion of Jazf1 in mice causes global impairment of protein and insulin synthesis mediated by defects in ribosomal protein synthesis, ribosomal RNA processing, and aminoacyl-tRNA synthetase expression, leading to ER stress and increased β-cell susceptibility to apoptosis. JAZF1 is excluded from the nucleus under metabolic stress and its expression is reduced in diabetic islets.\",\n      \"method\": \"Jazf1 knockout mice, islet isolation, ribosome biogenesis assays, protein synthesis measurements, ER stress markers, subcellular fractionation/localization, gene expression profiling in murine T2D and human islets under metabolic stress\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model with defined molecular phenotypes (ribosome biogenesis, ER stress), subcellular localization data, validation in human islets; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32640216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JAZF1 suppresses hepatic SREBP-1c expression through inhibition of transcriptional activity at liver X receptor response elements (LXREs) in the SREBP-1c promoter, and increases AMPK phosphorylation in hepatocytes. Overexpression of JAZF1 in transgenic mice reduces lipogenesis gene expression and protects against HFD-induced hepatic steatosis; these effects are partially blocked by the AMPK inhibitor Compound C.\",\n      \"method\": \"JAZF1 transgenic mice (HFD model), hepatocyte overexpression/knockdown, LXRE luciferase reporter assay, AMPK phosphorylation western blot, gene expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model, reporter assay, signaling pathway analysis; single lab, multiple methods\",\n      \"pmids\": [\"30154417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JAZF1 (TIP27) overexpression in transgenic mice and db/db mice reduces hepatic glucose production and improves insulin sensitivity through a PI3-kinase/Akt-dependent mechanism: overexpression increases phosphorylation of insulin receptor, IRS-1, AMPK, and Akt in liver, decreases expression of gluconeogenic enzymes PEPCK and G6Pase, and these effects are abolished by the PI3-kinase inhibitor LY294002.\",\n      \"method\": \"TIP27-Tg mice and adenovirus-mediated overexpression in db/db mice, hyperinsulinemic-euglycemic clamp, western blot for insulin signaling molecules, RT-qPCR, pharmacological inhibition with LY294002\",\n      \"journal\": \"International journal of obesity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic and adenoviral models, clamp studies, pathway inhibition; single lab\",\n      \"pmids\": [\"25614086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JAZF1 overexpression inhibits hepatic cholesterol de novo synthesis by repressing HMGCR transcriptional activity through a CREB-dependent mechanism (inhibiting CRE activity in the HMGCR promoter), demonstrated by dual-luciferase reporter assay. In ApoE KO mice, JAZF1 overexpression decreases serum cholesterol and reduces atherosclerotic plaque area.\",\n      \"method\": \"Adenovirus-mediated JAZF1 overexpression in ApoE KO mice, dual-luciferase reporter assay for HMGCR promoter CREB activity, [14C]-acetate cholesterol synthesis measurement, hyperinsulinemic-euglycemic clamp, histological plaque quantification\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model, luciferase reporter for direct mechanistic step, isotope-labeling cholesterol synthesis; single lab\",\n      \"pmids\": [\"25499349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Central (mediobasal hypothalamus) JAZF1 activation in HFD-fed rats reduces hepatic glucose production (HGP) by increasing hypothalamic insulin receptor (InsR)-PI3K-Akt signaling and decreasing AMPK phosphorylation. This effect requires intact KATP channels and the hepatic branch of the vagus nerve (disrupted by vagotomy), and is blocked by central AMPK activation (AICAR). JAZF1 also elevates InsR and Akt phosphorylation in SH-SY5Y neuronal cells upon insulin stimulation.\",\n      \"method\": \"MBH adenovirus-mediated JAZF1 overexpression in rats, pancreatic-euglycemic clamp to measure HGP, KATP channel inhibition, hepatic vagotomy, central AICAR infusion, western blot for signaling molecules, cell line experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo stereotaxic viral delivery with clamp studies and multiple pharmacological/surgical interventions; single lab\",\n      \"pmids\": [\"32275331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Deletion of Jazf1 in mice results in reduced plasma IGF-1, early growth retardation (shorter stature in young KO mice), and late-onset muscle insulin resistance exacerbated by HFD. Gene set enrichment analysis in KO liver identified decreased hepatocyte nuclear factor 4α (HNF4α), and JAZF1 knockdown in human hepatocytes inhibited GH-induced IGF-1 expression, placing JAZF1 upstream of the GH–IGF-1 axis and HNF4α in growth and metabolic regulation.\",\n      \"method\": \"Jazf1 knockout mice, 1H-NMR body composition, hyperinsulinemic-euglycemic clamp, IGF-1/GH plasma measurements, gene set enrichment analysis of liver transcriptome, JAZF1 knockdown in human hepatocytes with GH stimulation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse with clamp studies and human hepatocyte mechanistic validation; single lab\",\n      \"pmids\": [\"36442127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"JAZF1 safeguards human endometrial stromal cell (hESC) survival and decidualization by transcriptionally repressing G0S2. JAZF1 interacts with G0S2 transcriptional activator Purβ to restrict G0S2 expression; JAZF1 depletion in hESCs increases G0S2, causing apoptosis and defective decidualization. This mechanism was validated in decidual tissue from recurrent spontaneous abortion patients showing low JAZF1, high G0S2, and excess apoptosis.\",\n      \"method\": \"JAZF1 siRNA knockdown in hESCs, decidualization assays, apoptosis assays, Co-IP to demonstrate JAZF1–Purβ interaction, ChIP/reporter assays for G0S2 promoter, patient tissue validation (RSA vs. controls)\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein-protein interaction (Co-IP of JAZF1 with Purβ), functional KD with defined molecular mechanism, patient tissue corroboration; single lab\",\n      \"pmids\": [\"37244968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAZF1 (ZNF802) functions as a transcriptional repressor of the γ-globin (HBG) gene in adult erythroid cells. shRNA-mediated knockdown of ZNF802/JAZF1 in β0-thalassemia/HbE erythroblasts increased HBG transcription and translation, raising HbF levels to 35%, without affecting erythroblast proliferation or differentiation.\",\n      \"method\": \"Lentiviral shRNA knockdown of ZNF802/JAZF1 in β0-thalassemia/HbE erythroblasts, RT-qPCR for HBG mRNA, HPLC/western blot for HbF protein, flow cytometry for erythroblast differentiation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with defined transcriptional and translational outcomes; single lab, single method for the core claim\",\n      \"pmids\": [\"35322124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Jazf1 promotes multiciliated cell (MCC) differentiation in mouse airway epithelium. Overexpression of Jazf1 in mouse embryonic tracheal explants promoted MCC differentiation, including cooperative effects with the canonical MCC transcription factor Foxj1. Knockdown of Jazf1 in adult mouse airway epithelial cultures impaired ciliated cell differentiation. Jazf1 likely functions downstream of IL-6 signaling and upstream of Foxj1 in the MCC differentiation pathway.\",\n      \"method\": \"Overexpression in mouse embryonic tracheal explants, siRNA knockdown in adult mouse airway epithelial cultures, Foxj1 co-expression epistasis experiments, IL-6 pathway genetic placement\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined cellular phenotype, epistasis placement; single lab\",\n      \"pmids\": [\"29661797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Jazf1 promotes prostate cancer cell proliferation, colony formation, migration, and invasion via activation of the JNK/c-Jun phosphorylation pathway leading to upregulation of Slug and epithelial-mesenchymal transition (EMT; increased vimentin, decreased E-cadherin). In xenograft models, Jazf1-overexpressing tumors were larger and Jazf1-knockdown tumors were smaller.\",\n      \"method\": \"Jazf1 overexpression and knockdown in DU145 and LNCaP prostate cancer cell lines, transwell migration/invasion assays, microarray for Slug identification, western blot for JNK/c-Jun phosphorylation and EMT markers, xenograft mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined pathway (JNK/Slug), in vivo validation; single lab\",\n      \"pmids\": [\"29416651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JAZF1 promotes visfatin expression in adipocytes indirectly through upregulation of PPARα and PPARβ/δ, which then activate the visfatin promoter via PPRE elements. Luciferase reporter assays confirmed JAZF1 activates visfatin transcription; ChIP assays showed JAZF1 does not directly bind the visfatin PPRE. The visfatin induction was abolished by PPARα antagonist GW6471 and PPARβ/δ antagonist GSK3787, and confirmed with siRNA knockdown of PPARα and PPARβ/δ. JAZF1 simultaneously inhibits TAK1 and PPARγ expression.\",\n      \"method\": \"JAZF1 overexpression vector and siRNA in 3T3-L1 adipocytes, luciferase reporter assay for visfatin promoter, ChIP assay for JAZF1–visfatin PPRE binding, pharmacological antagonists and siRNA for PPARα/PPARβ/δ, western blot and RT-qPCR\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter, ChIP, and pharmacological/siRNA validation; single lab, multiple complementary methods\",\n      \"pmids\": [\"24930994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"rs1635852 in JAZF1 intron 1 displays allele-specific enhancer activity in pancreatic insulinoma cells: the T (risk) allele shows lower transcriptional activity than the C allele, and the T allele preferentially binds PDX1 (pancreatic master regulator) as part of a repressor complex identified by DNA affinity capture and mass spectrometry.\",\n      \"method\": \"Open chromatin mapping to prioritize variants, luciferase enhancer assays in 832/13 and MIN6 cells, DNA affinity capture with mass spectrometry to identify PDX1 as the T-allele-preferential binding factor\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — allele-specific reporter assay plus mass spectrometry protein identification; single lab, two orthogonal methods\",\n      \"pmids\": [\"23328127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JAZF1 regulates β-cell differentiation and glucose homeostasis: Jazf1-KO iPSC-derived β-cells show reduced expression of β-cell specification/maturation genes and lower insulin/C-peptide secretion. Jazf1 heterozygous KO mice have lower serum insulin, reduced pancreatic insulin expression, smaller β-cell size, and impaired glucose homeostasis. JAZF1 modulates cyclin A2 levels in this context.\",\n      \"method\": \"Jazf1-KO iPSC differentiation to β-cells, MIN6 gain/loss-of-function, Jazf1+/- mice glucose tolerance and insulin measurements, teratoma assays for proliferation markers\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPSC KO differentiation model and in vivo heterozygous KO mouse; single lab, multiple methods\",\n      \"pmids\": [\"33555104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JAZF1 directly regulates vimentin and E-cadherin expression (EMT markers) in gastric cancer cells: JAZF1 was validated as a direct target of miR-1275 by luciferase assay, and overexpression of JAZF1 upregulated vimentin and downregulated E-cadherin, promoting migration and invasion in vitro and in vivo. ChIP analysis confirmed JAZF1 directly regulates vimentin transcription.\",\n      \"method\": \"Luciferase reporter assay (miR-1275 targeting of JAZF1), western blot, RT-qPCR, transwell migration/invasion, xenograft, ChIP assay for JAZF1 at vimentin promoter\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase and ChIP validation, in vivo model; single lab\",\n      \"pmids\": [\"31357957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JAZF1 overexpression suppresses cell proliferation, induces G0/G1 arrest, and promotes apoptosis in papillary thyroid carcinoma BCPAP cells by suppressing the TAK1/NF-κB signaling pathway: JAZF1 overexpression decreased TAK1 and NF-κB p-p65 protein levels and decreased Bcl-2 while increasing Bax, without affecting NF-κB p65 mRNA/protein expression levels.\",\n      \"method\": \"Adenovirus-mediated JAZF1 overexpression in BCPAP cells, cell proliferation/colony assays, cell cycle analysis, apoptosis flow cytometry, western blot for TAK1, NF-κB p65, p-p65, Bcl-2, Bax\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single cell line, single lab, overexpression only with western blot pathway readout; no mechanistic dissection of direct vs. indirect regulation\",\n      \"pmids\": [\"31819531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miRNA-31-5p targets JAZF1 directly (validated by dual-luciferase assay) in human spermatogonial stem cells (SSCs); JAZF1 silencing reduces SSC proliferation, DNA synthesis, and increases apoptosis, and decreases cyclin A2 but not cyclin D1 or cyclin E1 levels, placing JAZF1 in a PAK1–JAZF1–cyclin A2 pathway controlling SSC fate.\",\n      \"method\": \"Dual-luciferase reporter assay for miR-31-5p targeting of JAZF1, CCK-8/EDU proliferation assays, Annexin V/PI apoptosis, JAZF1 siRNA knockdown, western blot for cyclins\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase validation of miRNA target plus functional KD; single lab, limited pathway mechanistic resolution\",\n      \"pmids\": [\"30583099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JAZF1 overexpression in C2C12 myoblasts promotes cell proliferation and transcriptionally represses MEF2C and MRF4 (and their downstream genes including AMPD1), thereby retarding myogenic differentiation. JAZF1-mediated repression of Ampd1 acts through MEF2-binding sites and E-box elements in the Ampd1 proximal regulatory region rather than through TR4/JAZF1 complex binding sites. JAZF1 overexpression and AMPD1 overexpression or JAZF1 downregulation both impaired AMPK phosphorylation.\",\n      \"method\": \"JAZF1 overexpression in C2C12 cells, gene array analysis, promoter activity assays with MEF2-site and E-box mutations, RT-qPCR, western blot for AMPK phosphorylation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — promoter mutagenesis and functional assays, but single lab and limited direct binding evidence\",\n      \"pmids\": [\"26101156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNA-driven formation of the JAZF1-SUZ12 fusion gene can be induced in human endometrial stromal cells by expressing designed antisense (but not sense) chimeric RNAs in a sequence-dependent manner; this process is inhibited by estrogen or progesterone. The induced fusion gene was validated at both RNA and genomic DNA levels.\",\n      \"method\": \"Transfection of designed chimeric RNAs in human endometrial stromal cells, RT-PCR and genomic PCR validation of JAZF1-SUZ12 fusion, sense vs. antisense chimeric RNA comparison, hormone inhibition experiments\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequence-dependent and strand-specific mechanism with RNA and DNA validation; single lab, novel mechanistic claim\",\n      \"pmids\": [\"34928964\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JAZF1 is a zinc finger transcriptional co-repressor that directly binds the ligand-binding domain of nuclear orphan receptor TR4/TAK1 (stabilizing an autorepressed TR4 conformation via a novel α13 helix as shown by crystal structure), and is also a subunit of the p400/TIP60/NuA4 chromatin-modifying complex where it promotes H2A.Z acetylation at regulatory regions; together, these activities regulate ribosome biogenesis, gluconeogenesis, lipid metabolism (via SREBP-1c/LXRE and HMGCR/CREB axes), β-cell differentiation and insulin translation, growth (GH–IGF-1–HNF4α axis), γ-globin repression in erythroid cells, and endometrial stromal cell survival (via G0S2/Purβ repression), while its oncogenic JAZF1-SUZ12 fusion disrupts PRC2 complex integrity and H3K27 trimethylation in endometrial stromal sarcomas.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"JAZF1 is a zinc-finger transcriptional co-repressor that couples nuclear-receptor regulation to chromatin modification, governing metabolic, developmental, and proliferative programs [#0, #4]. It directly binds the ligand-binding domain of the orphan nuclear receptor TR4/TAK1 through a defined interaction domain, and crystallography shows it engages a non-canonical surface of the TR4 LBD—stabilizing a previously unobserved \\u03b113 helix that reinforces an autorepressed TR4 conformation and excludes coactivators such as SRC-1 and CREBBP, thereby blunting TR4-driven transcription [#0, #3]. Independently, JAZF1 is a subunit of a p400/TIP60/NuA4 sub-complex (containing MBTD1, excluding ANP32E) that promotes H2A.Z acetylation at over a thousand regulatory sites and sustains expression of ribosome-biogenesis genes [#4]. Through these activities it acts as a master metabolic regulator: it drives ribosomal protein and rRNA synthesis required for insulin translation and \\u03b2-cell survival [#5, #17], represses hepatic lipogenesis and cholesterol synthesis via SREBP-1c/LXRE, HMGCR/CREB, and AMPK axes [#6, #8], suppresses gluconeogenesis through PI3K/Akt signaling both hepatically and via central hypothalamic circuits [#7, #9], and sits upstream of the GH\\u2013IGF-1\\u2013HNF4\\u03b1 growth axis [#10]. In other lineages JAZF1 represses \\u03b3-globin (HBG) in adult erythroid cells [#12] and safeguards endometrial stromal cell survival and decidualization by interacting with Pur\\u03b2 to repress G0S2 [#11]. The recurrent t(7;17) JAZF1-SUZ12 fusion in endometrial stromal sarcoma destabilizes EZH2 and EED, reduces PRC2 histone-methyltransferase activity and H3K27 trimethylation, and enhances proliferation [#1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established JAZF1 as a recurrent fusion partner in endometrial stromal tumors, defining its first disease link before any functional role was known.\",\n      \"evidence\": \"Cytogenetics and RT-PCR of tumor RNA identifying the t(7;17) JAZF1-SUZ12 fusion transcript\",\n      \"pmids\": [\"11371647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the normal function of JAZF1\", \"Did not explain how the fusion drives tumorigenesis\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the first molecular activity of JAZF1—repression of the nuclear receptor TR4/TAK1—answering what the protein does biochemically.\",\n      \"evidence\": \"Yeast/mammalian two-hybrid, GST pull-down, mutagenesis of the TID, and reporter assays in mammalian cells\",\n      \"pmids\": [\"15302918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the interaction unresolved\", \"Did not identify target genes downstream of TR4 repression\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected a JAZF1 diabetes-risk variant to allele-specific enhancer activity and PDX1 binding, linking genetic association to \\u03b2-cell regulatory function.\",\n      \"evidence\": \"Open chromatin mapping, luciferase enhancer assays in insulinoma cells, and DNA affinity capture-mass spectrometry\",\n      \"pmids\": [\"23328127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect of the variant on endogenous JAZF1 expression in human islets not shown\", \"Mechanism of PDX1 repressor complex assembly unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated JAZF1 controls lipid metabolism through both direct (HMGCR/CREB) and indirect (PPAR-mediated) transcriptional mechanisms.\",\n      \"evidence\": \"Adenoviral overexpression in ApoE-KO and 3T3-L1 systems, dual-luciferase reporters, ChIP, and pharmacological/siRNA dissection of PPAR\\u03b1/\\u03b2\\u03b4\",\n      \"pmids\": [\"25499349\", \"24930994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JAZF1 acts directly or via cofactors at the HMGCR promoter not fully resolved\", \"ChIP showed no direct JAZF1 binding at the visfatin PPRE\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed JAZF1 improves systemic glucose handling by suppressing hepatic glucose production through PI3K/Akt and gluconeogenic enzyme repression.\",\n      \"evidence\": \"Transgenic and adenoviral overexpression in db/db mice, hyperinsulinemic-euglycemic clamps, and LY294002 inhibition\",\n      \"pmids\": [\"25614086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets at PEPCK/G6Pase promoters not mapped\", \"Relationship to TR4 repression in this context unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended JAZF1's hepatic role to lipogenesis suppression via SREBP-1c/LXRE and AMPK, positioning it as a protector against steatosis.\",\n      \"evidence\": \"Transgenic HFD mice, LXRE luciferase reporters, AMPK phospho-blots, and Compound C rescue\",\n      \"pmids\": [\"30154417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect action at the LXRE not definitively separated\", \"Upstream activator of AMPK by JAZF1 unidentified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a unifying nuclear function—JAZF1 drives ribosome biogenesis—linking its metabolic phenotypes to a defect in the protein-synthesis machinery, and added a hypothalamic axis for glucose control.\",\n      \"evidence\": \"Jazf1-KO mice with ribosome-biogenesis and ER-stress assays, human islet validation, and MBH viral overexpression with clamps and vagotomy\",\n      \"pmids\": [\"32640216\", \"32275331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct genomic targets among ribosomal/rRNA processing genes not enumerated\", \"How metabolic stress excludes JAZF1 from the nucleus is unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed JAZF1 within the p400/TIP60/NuA4 complex as an H2A.Z acetylation regulator, providing the chromatin-level mechanism underlying its ribosome-biogenesis transcriptional control.\",\n      \"evidence\": \"Mass spectrometry of H2A.Z chaperone complexes, genome-wide H2A.Z-acetyl ChIP-seq, and RNA-seq after JAZF1 depletion\",\n      \"pmids\": [\"33445503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How JAZF1 targets the complex to specific enhancers is unresolved\", \"Relationship between this complex and TR4 corepression not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tied JAZF1 to \\u03b2-cell specification and proliferation through cyclin A2, integrating its diabetes-associated role into cell differentiation.\",\n      \"evidence\": \"Jazf1-KO iPSC \\u03b2-cell differentiation, MIN6 gain/loss-of-function, and Jazf1+/- mouse glucose-homeostasis studies\",\n      \"pmids\": [\"33555104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets governing \\u03b2-cell maturation not mapped\", \"Mechanism of cyclin A2 modulation unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified JAZF1 as an upstream regulator of the GH\\u2013IGF-1\\u2013HNF4\\u03b1 growth axis, broadening its role from glucose/lipid metabolism to organismal growth.\",\n      \"evidence\": \"Jazf1-KO mice with body composition, clamps, plasma IGF-1, liver transcriptome GSEA, and GH-stimulated human hepatocyte knockdown\",\n      \"pmids\": [\"36442127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JAZF1 directly regulates HNF4\\u03b1 transcription not established\", \"Mechanistic step linking JAZF1 to GH-induced IGF-1 unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mechanistically dissected the oncogenic fusion: JAZF1-SUZ12 disrupts PRC2 integrity and H3K27me3, and the fusion itself can be RNA-induced, illuminating both its activity and origin.\",\n      \"evidence\": \"Reconstituted PRC2 HMT assays on nucleosome arrays, patient-tissue immunostaining, Suz12-/- rescue, plus chimeric-RNA induction with hormone inhibition\",\n      \"pmids\": [\"27845897\", \"34928964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide target genes derepressed by the fusion not catalogued\", \"In vivo relevance of RNA-driven fusion formation unconfirmed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the structural basis of JAZF1-mediated repression, showing it stabilizes a novel \\u03b113 helix to lock TR4 in an autorepressed, coactivator-excluding state.\",\n      \"evidence\": \"X-ray crystallography of TR4LBD-JAZF1 complex with cancer-mutation mutagenesis and transcription assays\",\n      \"pmids\": [\"36651297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length JAZF1 and its zinc fingers not determined\", \"How this mode relates to JAZF1's chromatin-complex activity unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed JAZF1 protects endometrial stromal cells via Pur\\u03b2-dependent G0S2 repression, defining a survival/decidualization function with disease relevance to recurrent abortion.\",\n      \"evidence\": \"siRNA knockdown in hESCs, decidualization and apoptosis assays, JAZF1-Pur\\u03b2 Co-IP, G0S2 promoter ChIP/reporter, and patient tissue\",\n      \"pmids\": [\"37244968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JAZF1 binds the G0S2 promoter directly or only via Pur\\u03b2 not resolved\", \"Reciprocal interaction validation beyond single Co-IP not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How JAZF1's two characterized activities—TR4 LBD corepression and p400/TIP60-mediated H2A.Z acetylation—are coordinated at specific loci to produce its tissue-specific metabolic, developmental, and oncogenic outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating nuclear-receptor corepression with chromatin-modifying complex membership\", \"Direct genome-wide JAZF1 binding map across tissues not established\", \"Determinants of context-specific activation versus repression unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 6, 8, 11, 12, 15, 18, 21]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [18, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 4, 6, 8]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 7, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"p400/TIP60/NuA4 complex\",\n      \"PRC2 (via JAZF1-SUZ12 fusion)\"\n    ],\n    \"partners\": [\n      \"TR4/TAK1\",\n      \"TIP60\",\n      \"MBTD1\",\n      \"SUZ12\",\n      \"Pur\\u03b2\",\n      \"PDX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}