{"gene":"EGR1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1993,"finding":"NGFI-A (EGR1) contains four transcriptional activation domains (acidic, proline/glutamine-rich, Krox-20 homology, and a novel domain) and an inhibitory domain whose removal causes a 15-fold increase in activity; competition and point-mutation experiments demonstrated the inhibitory domain interacts with a titratable cellular factor, and the I293F mutation in this domain abolishes the inhibitory interaction.","method":"GAL4-fusion cotransfection assay, deletion/point mutagenesis, competition experiments in mammalian and Drosophila cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro functional mutagenesis with multiple orthogonal assays (domain deletions, point mutations, competition) in a single rigorous study","pmids":["8413279"],"is_preprint":false},{"year":1995,"finding":"NAB1 is a nuclear corepressor that physically interacts with the inhibitory (R1) domain of NGFI-A (EGR1) and represses NGFI-A- and Krox20-mediated transcription, but does not repress Egr3 or NGFI-C, providing a mechanism for differential regulation of EGR family members. NAB1 does not block DNA binding or nuclear localization of NGFI-A.","method":"Yeast two-hybrid isolation, cotransfection repression assays, domain mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus functional cotransfection assays, replicated and extended by subsequent NAB1 mechanistic study (PMID:9418898)","pmids":["7624335","9418898"],"is_preprint":false},{"year":1996,"finding":"NAB2, a second corepressor highly related to NAB1, physically interacts with the R1 domain of NGFI-A (EGR1) through its first conserved domain and represses both NGFI-A and Krox20 transcriptional activity; NAB2 expression is induced by the same stimuli (serum, NGF) that induce NGFI-A.","method":"Domain interaction mapping, cotransfection repression assays, Northern blot expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal domain-mapping plus functional repression assays; finding independently corroborated by NAB1 studies","pmids":["8668170"],"is_preprint":false},{"year":1998,"finding":"Nab1 repression of EGR1 is not mediated by blocking DNA binding or nuclear localization; instead, Nab1 contains an active repression domain localized to the conserved NCD2 region in its carboxy terminus, and this domain can repress multiple types of activation domains when tethered directly to DNA, independent of promoter context or distance.","method":"GAL4-tethered repression assays, deletion/replacement mutagenesis, nuclear localization experiments, gel shift assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — extensive mutagenesis combined with functional tethered-repressor assays; multiple orthogonal approaches in single study","pmids":["9418898"],"is_preprint":false},{"year":1995,"finding":"EGR1 (NGFI-A) and related family members (NGFI-C, Egr3, Krox20) bind the consensus GC-rich sequence GCGGGGGCG; PCR-mediated random site selection revealed a broader consensus T-G-C-G-T/g-G/A-G-G-C/a/t-G-G/T and an optimal 10-nucleotide binding site. NGFI-C has >3-fold lower DNA binding affinity than NGFI-A/Egr3/Krox20 due to protein context outside the zinc fingers.","method":"PCR-based random site selection, gel shift assays, kinetic binding measurements","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical assays with multiple approaches (SELEX-like selection, EMSA, affinity measurements)","pmids":["7891721"],"is_preprint":false},{"year":1989,"finding":"The rat NGFI-A (EGR1) gene spans 3789 nt with a single intron; all three zinc-finger domains are encoded in the 3' exon. The 5' flanking region contains an NGF-responsive element (with serum response elements, CRE, Sp1 site, TATA box) demonstrated by CAT reporter transfection in PC12 cells.","method":"Gene cloning/sequencing, CAT reporter transfection assay, transcription start site mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter dissection in cellular transfection assay, single lab","pmids":["2492104"],"is_preprint":false},{"year":2008,"finding":"EGR1 is sumoylated in ECV304 cells upon EGF stimulation; SUMO-1/Ubc9 overexpression stabilizes ERK1/2 phosphorylation and increases EGR1 gene transcription, but simultaneously enhances EGR1 protein ubiquitination and proteasomal degradation, indicating that sumoylation promotes EGR1 turnover.","method":"Cotransfection of SUMO-1/Ubc9 constructs, immunoblotting, proteasome inhibitor (MG132) experiments, ubiquitination assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays in single lab demonstrating sumoylation-coupled ubiquitination/degradation","pmids":["21998680"],"is_preprint":false},{"year":2008,"finding":"EGR1 is phosphorylated by Akt at S350 and T309; this promotes interaction of EGR1 with ARF at K272 in its repressor domain, enabling ARF/Ubc9/SUMO-mediated sumoylation of EGR1, which is required for EGR1-dependent transcriptional induction of PTEN in vivo. ARF knockout mice show reduced EGR1 sumoylation and reduced PTEN.","method":"In vivo phosphorylation/sumoylation assays, co-immunoprecipitation, ARF-/- mouse analysis, site-directed mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, co-IP, knockout mouse validation) establishing a defined PTM cascade","pmids":["19057511"],"is_preprint":false},{"year":2021,"finding":"DNA-PKcs phosphorylates EGR1 at serine 301 in activated T cells; inhibition of DNA-PKcs or S301A CRISPR mutation increases proteasomal degradation of EGR1 and decreases EGR1-dependent IL-2 transcription, identifying DNA-PKcs as a kinase that stabilizes EGR1.","method":"Quantitative phosphoproteomics, DNA-PKcs inhibitor (NU7441), shRNA knockdown, CRISPR-Cas9 S301A mutation, proteasome inhibitor assays, luciferase/transcription assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — phosphoproteomics plus genetic validation (CRISPR mutation) plus functional transcription assay in single rigorous study","pmids":["34562454"],"is_preprint":false},{"year":2019,"finding":"EGR1 recruits the DNA demethylase TET1 to EGR1 binding sites during postnatal brain development, establishing hypomethylation specifically in neurons (not glia); Egr1-/- and Tet1-/- frontal cortices share strikingly similar gene expression and DNA methylation profiles.","method":"EGR1 ChIP-seq, WGBS methylation profiling, knockout mouse comparison (Egr1-/-, Tet1-/-), co-immunoprecipitation/recruitment assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP-seq, genome-wide methylation data, and parallel KO mouse comparison providing convergent mechanistic evidence","pmids":["31467272"],"is_preprint":false},{"year":2010,"finding":"EGR1 (and EGR2) directly bind and trans-activate the proximal promoter of Col1a1 in tendon cells; FGF4 (muscle-derived) activates Egr1 expression and downstream collagen expression in chick limbs; Egr1-/- mice show reduced Col1a1 transcripts and fewer collagen fibrils in embryonic tendons.","method":"ChIP assay (EGR1 recruitment to Col1a1 promoter), luciferase reporter trans-activation, chick misexpression, Egr1-/- mouse analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP, reporter assays, gain-of-function in vivo misexpression, and KO mouse with defined collagen phenotype","pmids":["21173153"],"is_preprint":false},{"year":2013,"finding":"EGR1 is recruited to Col1a1 and Col2a1 promoters in postnatal mouse tendons in vivo; EGR1-expressing MSCs promote tendon-like tissue formation and Achilles tendon repair; EGR1's pro-tenogenic effect is partially mediated by TGF-β2.","method":"ChIP assay (in vivo promoter recruitment), Egr1-/- mouse tendon analysis, MSC overexpression, rat Achilles tendon injury model, TGF-β2 neutralization","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo ChIP, KO mouse mechanical analysis, and in vivo rescue experiments with defined mediator","pmids":["23863709"],"is_preprint":false},{"year":2006,"finding":"EGR1 transcriptionally activates the TAp73 promoter (TP73 P1) through five distinct EGR1-binding sites; EGR1 induction of TAp73 by genotoxic stress was confirmed in vivo in mice; EGR1, p53, and TAp73 form an inter-regulating network with feedback loops sustaining apoptotic gene expression under stress.","method":"Promoter reporter assays, EGR1-binding site mutagenesis, ChIP, in vivo mouse genotoxic stress experiments","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — promoter mutagenesis, ChIP, and in vivo mouse validation","pmids":["16990849"],"is_preprint":false},{"year":2005,"finding":"EGR1 binds to the heparanase (HPSE) gene promoter in vivo in tumor cells; two functional EGR1 binding sites in a 280-bp critical promoter region were identified by site-directed mutagenesis and EMSA; EGR1 activates heparanase promoter in prostate, breast, and colon carcinoma but represses it in melanoma cells.","method":"ChIP (in vivo promoter binding), luciferase reporter assays, site-directed mutagenesis, EMSA, EGR1 overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP, EMSA, mutagenesis, and functional reporter assays across multiple cell lines","pmids":["16093249"],"is_preprint":false},{"year":2005,"finding":"Glucocorticoid receptor activation in hippocampus increases MAPK (ERK) pathway activity and leads to increased Egr-1 mRNA and protein; MAPK pathway inhibition within hippocampus abolishes glucocorticoid-induced enhancement of contextual fear conditioning, placing EGR1 downstream of GR/MAPK signaling in stress-related fear memory.","method":"Brain-specific GR knockout mice (GR(NesCre)), cell lines with constitutively active GR (DeltaGR), MAPK inhibitor intra-hippocampal injection, fear conditioning behavioral assay","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic GR KO combined with pharmacological MAPK inhibition and behavioral readout, replicated in vivo and in vitro","pmids":["15834420"],"is_preprint":false},{"year":2012,"finding":"NGFI-A (EGR1) binds to the exon 1(7) glucocorticoid receptor (GR) promoter in hippocampus in a manner dynamically regulated by maternal licking/grooming; serotonin (5-HT) induces NGFI-A-dependent GR transcription in hippocampal neurons; thyroid hormones and 5-HT mediate LG-induced NGFI-A binding to the GR promoter.","method":"ChIP (NGFI-A binding to GR promoter), hippocampal neuron reporter assay, NGFI-A overexpression, thyroid hormone/5-HT pharmacological manipulations","journal":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and overexpression in neurons, single lab","pmids":["22826348"],"is_preprint":false},{"year":2014,"finding":"MBD2 (methyl-CpG binding domain protein-2) collaborates with NGFI-A (EGR1) to activate the methylated exon 17 GR promoter; MBD2 knockdown abolishes exon 17 GR promoter activation; site-directed mutagenesis of the NGFI-A response element within the methylated promoter confirmed that NGFI-A binding is required.","method":"MBD2 knockdown in hippocampal primary culture, ectopic co-expression in HEK293 cells, site-directed mutagenesis of NGFI-A response element, luciferase reporter assay","journal":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown and mutagenesis in two cell systems, single lab","pmids":["25135974"],"is_preprint":false},{"year":2008,"finding":"UV irradiation activates EGF receptor, induces EGR1, and EGR1 then binds to 288 gene promoters (ChIP-on-chip); a major subgroup of bound targets is the EGFR signal-transduction pathway (24 genes); EGR1 binding impacts target gene expression, and siRNA depletion of EGR1 abolishes UV-induced apoptosis in prostate M12 cells, identifying FasL, MAX, and RRAS2 as novel EGR1 targets.","method":"ChIP-on-chip (genome-wide promoter binding), conventional ChIP-qPCR validation, siRNA knockdown, UV-induced apoptosis assay","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide ChIP-on-chip with siRNA functional validation and multiple orthogonal methods","pmids":["19032775"],"is_preprint":false},{"year":2010,"finding":"SMAD3 and EGR1 physically interact via the SMAD3 MH2 domain and the EGR1 DNA-binding domain; SMAD3 inhibits EGR1-induced human LHB promoter activity but potentiates EGR1-induced murine Lhb promoter activity; this species-specific difference depends on SMAD-binding elements (SBEs) present in the murine but not human promoter.","method":"Co-immunoprecipitation, domain mapping, promoter reporter assays, SBE site-directed mutagenesis, ChIP","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-IP for physical interaction plus mutagenesis of binding elements to establish functional mechanism","pmids":["20149866"],"is_preprint":false},{"year":2011,"finding":"EGR1 directly binds to the heparanase gene promoter via two functional EGR1 sites and activates its expression in cancer cells; EGR1-driven chromatin remodeling and transactivation of HPSE is potentiated by p300-mediated activation (in the hnRNPU/p300/EGR1/HPSE axis).","method":"ChIP assay, luciferase reporter, co-IP (EGR1–p300/CBP interaction verified)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and co-IP in single lab; p300 interaction aspect from PMID:29511351","pmids":["29511351"],"is_preprint":false},{"year":2023,"finding":"EGR1 physically interacts with p300/CBP (verified by co-IP) and together transcriptionally activates SNAI2 (Slug) promoter, driving EMT and invasion in pancreatic cancer; EGR1 binding to the SNAI2 promoter was confirmed by ChIP-qPCR.","method":"Co-IP (EGR1–p300/CBP), ChIP-qPCR (EGR1 at SNAI2 promoter), dual-luciferase reporter, Transwell invasion assay, in vivo liver metastasis model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus reporter, single lab","pmids":["36932397"],"is_preprint":false},{"year":2015,"finding":"EGR1 directly binds the proximal promoter of Per1 to activate its transcription; EGR1 is itself transactivated by the CLOCK/BMAL1 heterodimer through a conserved E-box; in Egr1-/- mice the amplitude (but not phase) of hepatic clock genes including Bmal1, Per1, Per2, Rev-erbα/β is reduced.","method":"ChIP (EGR1 at Per1 promoter), luciferase reporter assay (E-box CLOCK/BMAL1 transactivation), Egr1-/- mouse circadian gene expression analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP, reporter assay, and KO mouse with quantified amplitude phenotype","pmids":["26471974"],"is_preprint":false},{"year":2021,"finding":"In differentiating macrophages, EGR1 binds inflammatory enhancers (many without its canonical motif) and represses inflammatory genes through the NuRD corepressor complex; in monocytes, EGR1 binds enhancers regulating developmental genes like CSF1R.","method":"EGR1 ChIP-seq (monocytes vs macrophages), ATAC-seq, NuRD complex co-immunoprecipitation, EGR1 knockdown with inflammatory gene expression readout","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide ChIP-seq, chromatin accessibility profiling, co-IP of NuRD complex, and functional knockdown","pmids":["33523892"],"is_preprint":false},{"year":2009,"finding":"Mutant EGFR (delE746_A750) constitutively upregulates EGR1 expression through the ERK (MEK/ERK) pathway, not through PI3K; MEK inhibitor U0126 blocks EGR1 expression in mutant EGFR cells, while PI3K inhibitor LY294002 does not.","method":"Gene expression profiling, RT-PCR/immunoblotting, MEK inhibitor (U0126), PI3K inhibitor (LY294002), EGFR-TKI treatment","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection in transfected cells, single lab","pmids":["19414352"],"is_preprint":false},{"year":2021,"finding":"EGR1 is a downstream effector of B-cell receptor/JAK1 signaling in DLBCL; EGR1 upregulates MYC and E2F pathway genes through the CBP/p300/H3K27ac/BRD4 axis and represses type I IFN pathway genes by interacting with corepressor NAB2.","method":"EGR1 ChIP-seq, H3K27ac ChIP-seq, co-IP (EGR1–NAB2, EGR1–CBP/p300), EGR1 knockdown/knockout, xenograft mouse models","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP-seq, co-IP for complex identification, genetic knockdown with in vivo xenograft validation","pmids":["33980611"],"is_preprint":false},{"year":2018,"finding":"EGR1 acts as a transcriptional activator of KLK7 through direct binding to the EBS in the KLK7 proximal promoter in response to IL-13; ERK1/2 MAPK pathway is required for IL-13-induced EGR1-dependent KLK7 transcription; Egr1-/- mice lack IL-13/DNCB-induced KLK7 expression in AD-like skin lesions.","method":"Promoter reporter assay (EBS point mutation), ChIP (EGR1 at KLK7 promoter), EGR1 shRNA knockdown, Egr1-/- mice, ERK1/2 inhibitor experiments","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP, promoter mutagenesis, shRNA, and KO mouse validation","pmids":["33276948"],"is_preprint":false},{"year":2019,"finding":"EGR1 is a direct transcriptional activator of leptin gene expression in breast cancer cells; the EGR1-binding motif in the proximal leptin promoter is required for TNF-α-induced leptin transcription (shown by point mutation); EGR1 overexpression activates leptin promoter and EGR1 knockdown reduces TNF-α-induced leptin accumulation; ERK1/2 pathway mediates this response.","method":"Promoter reporter assay (EBS point mutation), EGR1 overexpression, EGR1 siRNA knockdown, ERK1/2 pathway inhibition","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis and siRNA in single lab","pmids":["30417207"],"is_preprint":false},{"year":2022,"finding":"EGR1 directly binds the Sox9 gene promoter and activates SOX9 expression in renal tubular cells; EGR1-induced SOX9 promotes tubular cell proliferation through the Wnt/β-catenin pathway; genetic Egr1 knockout aggravates AKI severity in mouse models.","method":"ChIP assay (EGR1 at Sox9 promoter), dual-luciferase reporter, Egr1-/- mice with IRI and nephrotoxic AKI models, RNA sequencing","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP, reporter assay, and KO mouse with two AKI models","pmids":["35910788"],"is_preprint":false},{"year":2019,"finding":"EGR1 directly binds the METTL3 promoter (confirmed by ChIP) to transcriptionally activate METTL3 expression; METTL3-mediated m6A modification of VIM mRNA downregulates VIM expression, thereby protecting hippocampal neurons from injury in epilepsy.","method":"ChIP assay (EGR1 at METTL3 promoter), EGR1/METTL3/VIM knockdown in epilepsy cell and mouse models, m6A modification assay","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional loss-of-function, single lab","pmids":["37268752"],"is_preprint":false},{"year":2024,"finding":"EGR1 directly binds the PFKL (phosphofructokinase-1, liver type) promoter and represses PFKL gene expression, thereby inhibiting aerobic glycolysis and suppressing hepatocellular carcinoma growth; EGR1 overexpression in mouse HCC models and human hepatoma organoids validated this tumor-suppressive mechanism.","method":"ChIP (EGR1 at PFKL promoter), EGR1 overexpression/knockdown in vitro and in vivo, xenograft tumor model, human hepatoma organoid, glycolysis assays","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional in vivo models, single lab","pmids":["38287371"],"is_preprint":false},{"year":2015,"finding":"EGR1 regulates ATGL (adipose triglyceride lipase) expression and fat storage in adipocytes; EGR1 protein expression is predominantly regulated via the mTORC1/4E-BP translational axis rather than transcriptionally; 4E-BP1/2 knockout cells translate Egr1 mRNA more efficiently, express less ATGL, and accumulate more fat.","method":"35S-labeling (translational efficiency), MEK inhibitor/mTORC1 inhibitor pharmacology, 4E-BP1/2-null and TSC2-null MEFs, ATGL expression and fat accumulation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO MEFs, metabolic labeling, pharmacological pathway dissection; single lab","pmids":["25814662"],"is_preprint":false},{"year":2019,"finding":"EGR1 transcriptionally activates TFEB expression by directly binding the TFEB promoter; in the absence of EGR1, the TFEB-mediated transcriptional response to starvation is impaired; pharmacological inhibition of EGR1 (via MEK1/2 inhibitor Trametinib) reduces proliferation of cells with constitutive TFEB activation.","method":"EGR1 ChIP-seq (EGR1 at TFEB promoter), EGR1 genetic knockout, MEK1/2 inhibitor (Trametinib), 3D culture proliferation assay, BHD patient-derived cells","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP-seq, genetic KO, pharmacological inhibition, and patient-derived model validation","pmids":["36888606"],"is_preprint":false},{"year":2018,"finding":"EGR1 interacts with TBX2 (co-immunoprecipitation); TBX2 binding inhibits EGR1-dependent transcription of target genes including p21 (CDKN1A), PTEN, NDRG1, and CST6; EGR1 overexpression in ARMS cells reduces proliferation and induces apoptosis via the intrinsic pathway (BAX activation, BAD dephosphorylation).","method":"Co-immunoprecipitation (EGR1-TBX2), EGR1 overexpression, reporter gene assays, apoptosis flow cytometry, western blot","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional overexpression, single lab","pmids":["29719592"],"is_preprint":false},{"year":2022,"finding":"EGR1 controls TET2 recruitment to the MIF promoter through protein-protein interaction; TET2 downregulation disrupts this interaction with EGR1 and histone deacetylases at the MIF promoter, leading to enhanced EGR1-driven MIF transcription and MIF secretion in resting monocytes.","method":"ChIP (TET2, EGR1 at MIF promoter), co-IP (TET2-EGR1-HDAC complex), TET2 knockdown in mouse and human cells, MIF secretion ELISA","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and co-IP, replicated in mouse and human cells, single lab","pmids":["35115654"],"is_preprint":false},{"year":2022,"finding":"Egr1 is required for dopaminergic signaling during social behavior in zebrafish; egr1 mutant fish show reduced social approach and tyrosine hydroxylase (TH) expression is markedly decreased in TH-positive neurons of the anterior parvocellular preoptic nucleus; chemogenetic ablation of ~30% of these TH+ neurons phenocopies the egr1 social behavior deficit.","method":"Egr1 zebrafish mutant (loss-of-function), in situ hybridization for TH, chemogenetic neuronal ablation, behavioral assays","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with neurochemical and behavioral readout, plus chemogenetic epistasis; single lab","pmids":["35346959"],"is_preprint":false},{"year":2024,"finding":"Egr1 regulates regenerative senescence in the adult mouse heart; in cardiac fibroblasts, Egr1 is activated by the integrin-FAK-ERK-Akt1 signaling axis in response to agrin; Egr1 facilitates angiogenesis and cardiomyocyte proliferation in neonatal hearts and is required for agrin-induced senescence-mediated cardiac repair in adult mice.","method":"Proteomics, single-cell RNA sequencing, Egr1 conditional KO in cardiac fibroblasts, agrin-treatment mouse model, pathway inhibition (FAK-ERK-Akt1)","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multi-omics profiling, conditional KO, mechanistic pathway inhibition, and two in vivo cardiac models","pmids":["39196027"],"is_preprint":false},{"year":2019,"finding":"EGR1 binds the viral genome upstream of the CMV UL138 latency gene and is sufficient to promote UL138 expression; disruption of EGR1 binding upstream of UL138 prevents the establishment of CMV latency in CD34+ hematopoietic progenitor cells; EGR1 is induced downstream of EGFR/MEK/ERK signaling in HPCs.","method":"EGR1 ChIP on viral genome, EGR1 overexpression (sufficient for UL138 induction), mutation of EGR1 binding site in viral genome, CMV latency assay in CD34+ HPCs","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP, gain-of-function, and viral genome site-directed mutagenesis with functional latency readout","pmids":["31725811"],"is_preprint":false},{"year":2019,"finding":"EGR1 transcriptionally activates GnRH-responsive AMH receptor type 2 (AMHR2) expression in gonadotrope cells; EGR1 mediates both basal and GnRH-dependent AMHR2 promoter activity through a proximal -53/-37 bp binding site; FOXO1 acts as a negative regulator of EGR1-dependent AMHR2 expression.","method":"Promoter deletion constructs, site-directed mutagenesis of Egr1 motif, siRNA knockdown of Egr1, constitutively active FOXO1 mutant, perifusion of LβT2 gonadotrope cells","journal":"Neuroendocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis plus siRNA knockdown; single lab","pmids":["30368511"],"is_preprint":false},{"year":2020,"finding":"EGR1 directly activates CCND1 (cyclin D1) promoter transcription (confirmed by ChIP assay with EGF stimulation); EGR1 silencing inhibits glioma cell proliferation and induces G1 phase arrest, establishing EGR1-CCND1 as a proliferative axis in glioma.","method":"ChIP assay (EGR1 at CCND1 promoter), siRNA EGR1 knockdown, cell cycle analysis, proliferation assays in U251/U87 cells and in vivo xenograft","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional knockdown, single lab","pmids":["29246166"],"is_preprint":false},{"year":1998,"finding":"Targeted disruption of Egr-1 (Krox-24) in mice causes sterility and reduced body size; specifically, Egr-1 null gonadotropes fail to synthesize the LHβ subunit and somatotropes are reduced in number, indicating EGR1 is required for LHβ transcription in gonadotropes and for somatotrope proliferation/survival.","method":"Gene targeting (null allele), histopathology, immunohistochemistry, hormone measurement in Egr1-/- mice","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined genetic KO with specific endocrine cell-lineage phenotypes; replicated across two independent Egr1 null allele reports","pmids":["9440815"],"is_preprint":false},{"year":2019,"finding":"EGR1 directly upregulates p53 transcription by binding the p53 promoter; EGR1 promotes p53-dependent apoptosis in retinal vascular endothelial cells under high-glucose conditions; downregulation of Egr1 reduces apoptosis and tube formation in vivo through p53 reduction.","method":"EGR1 shRNA knockdown, p53 overexpression rescue, in vivo sh-Egr1 delivery in diabetic rats, apoptosis/tube formation assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown with rescue experiment and in vivo validation, single lab","pmids":["30887692"],"is_preprint":false},{"year":2019,"finding":"EGR1 identified as a novel splicing isoform: a shorter EGR1 protein lacking part of the N-terminal activation domain can enter the nucleus but cannot fully activate transcription compared to canonical EGR1.","method":"RT-PCR cloning of novel transcript, nuclear localization assay, transcriptional activation reporter assay","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited functional characterization; no mutagenesis or binding studies","pmids":["30925677"],"is_preprint":false},{"year":2022,"finding":"EGR1 promotes hepatoprotection in acetaminophen-induced liver injury by transcriptionally upregulating Acaa2 (a key gene for mitochondrial fatty acid β-oxidation); liver-specific Egr1 knockout worsens AILI while adenoviral EGR1 overexpression ameliorates it; Acaa2 knockdown abolishes EGR1's protective effect.","method":"Liver-specific Egr1-KO mice, adenoviral EGR1 overexpression, ChIP-seq (EGR1 at Acaa2 locus), RNA-seq, Seahorse metabolic assay, Acaa2 siRNA knockdown","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — conditional KO, ChIP-seq, rescue by Acaa2 knockdown, and metabolic assays","pmids":["35813467"],"is_preprint":false},{"year":2020,"finding":"RUNX2 and EGR1 co-occupy Htra1 enhancers in osteoblasts (validated by Re-ChIP assay) and together co-repress Htra1 while promoting expression of osterix, osteocalcin, and osteoprotegerin; co-knockdown of RUNX2 and EGR1 reduces osteoblast calcification and ALP activity.","method":"RUNX2 ChIP-seq, RNA-seq (Runx2 heterozygous mice), dual-luciferase enhancer assays, Re-ChIP (RUNX2+EGR1 co-occupancy), siRNA double knockdown, Alizarin red/ALP staining","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Re-ChIP for co-occupancy plus functional co-knockdown; single lab","pmids":["32324256"],"is_preprint":false}],"current_model":"EGR1 is a zinc-finger transcription factor that binds GC-rich promoter/enhancer elements (consensus ~GCGGGGGCG) to activate or repress a wide array of target genes (including PTEN, p53/p73, LHβ, Col1a1, HPSE, Per1, TFEB, CCND1, PFKL, Acaa2, and others); its activity is regulated post-translationally by Akt-mediated phosphorylation (S350/T309) that enables sumoylation via ARF/Ubc9, by DNA-PKcs phosphorylation at S301 that stabilizes the protein against proteasomal degradation, and by coupled sumoylation/ubiquitination that can enhance turnover; EGR1 recruits corepressors NAB1/NAB2 (binding its R1 inhibitory domain) and the NuRD complex to repress inflammatory genes, while it cooperates with coactivators p300/CBP, TET1 (for DNA demethylation), and SMAD3 in a context-dependent manner to activate transcription; upstream, EGR1 expression and activity are induced primarily through the EGFR–MEK–ERK pathway, and by GR/glucocorticoid–MAPK signaling, placing it as a convergence node coupling extracellular growth factor, stress, and hormonal signals to nuclear gene programs governing tendon differentiation, synaptic plasticity, memory, cardiac regeneration, reproductive function, circadian rhythm amplitude, and tumor progression."},"narrative":{"mechanistic_narrative":"EGR1 is an immediate-early zinc-finger transcription factor that converts extracellular growth factor, stress, and hormonal cues into nuclear gene programs by binding GC-rich promoter and enhancer elements (consensus GCGGGGGCG) through its zinc fingers [PMID:7891721]. Its protein contains four distinct activation domains and a discrete inhibitory (R1) domain whose deletion sharply increases activity by relieving a titratable cellular repressor [PMID:8413279]; this domain is the docking site for the corepressors NAB1 and NAB2, which repress EGR1- and Krox20-directed transcription without blocking DNA binding or nuclear import, NAB1 acting through an active repression domain (NCD2) in its carboxy terminus [PMID:7624335, PMID:9418898, PMID:8668170]. EGR1 expression and protein output are driven principally through EGFR–MEK–ERK signaling [PMID:19414352, PMID:31725811], with GR/glucocorticoid–MAPK input in the hippocampus [PMID:15834420] and additional control by the mTORC1/4E-BP translational axis [PMID:25814662]; its stability and activity are further tuned post-translationally, with Akt phosphorylation at S350/T309 promoting ARF/Ubc9-dependent sumoylation required for PTEN induction [PMID:19057511], DNA-PKcs phosphorylation at S301 protecting EGR1 from proteasomal degradation to sustain IL-2 transcription [PMID:34562454], and sumoylation-coupled ubiquitination promoting turnover [PMID:21998680]. As a transcriptional node EGR1 activates or represses context-specific targets—activating Col1a1/Col2a1 in tendon differentiation [PMID:21173153, PMID:23863709], TAp73 and p53 in stress apoptosis [PMID:16990849, PMID:30887692], Per1 within the circadian feedback loop [PMID:26471974], TFEB [PMID:36888606], CCND1 [PMID:29246166], and SNAI2 in cancer [PMID:36932397], while repressing PFKL to limit glycolysis [PMID:38287371] and inflammatory enhancer genes via the NuRD complex [PMID:33523892]. It cooperates with coactivators p300/CBP [PMID:36932397, PMID:33980611], recruits TET1 for neuronal DNA demethylation [PMID:31467272], and partners with SMAD3, TBX2, RUNX2, and TET2 to set target-gene output in a context-dependent manner [PMID:20149866, PMID:29719592, PMID:32324256, PMID:35115654]. Genetic loss of Egr1 in mice causes sterility, failed LHβ synthesis in gonadotropes, and somatotrope deficits [PMID:9440815], underscoring its requirement across reproductive, tendon, cardiac, circadian, and metabolic processes.","teleology":[{"year":1989,"claim":"Establishing the EGR1 gene's structure and inducibility defined it as an NGF/serum-responsive immediate-early gene with its DNA-contacting zinc fingers encoded in a single 3' exon.","evidence":"Gene cloning/sequencing and CAT reporter transfection of the 5' flanking region in PC12 cells","pmids":["2492104"],"confidence":"Medium","gaps":["Did not define the DNA target sequence recognized by the protein","Promoter dissection in a single cell type"]},{"year":1993,"claim":"Dissecting the EGR1 protein into functional domains showed it carries multiple activation domains plus an inhibitory domain that binds a titratable cellular factor, explaining why its intrinsic activity is held in check.","evidence":"GAL4-fusion cotransfection, deletion/point mutagenesis (I293F), and competition assays in mammalian and Drosophila cells","pmids":["8413279"],"confidence":"High","gaps":["Identity of the titratable inhibitory factor not established in this study","No DNA-binding or in vivo target validation"]},{"year":1995,"claim":"Identifying the consensus GC-rich binding site and the NAB1 corepressor explained how EGR1 selects targets and how its activity is silenced without affecting DNA binding or localization.","evidence":"PCR-based random site selection with EMSA/affinity measurements, and yeast two-hybrid plus cotransfection repression assays","pmids":["7891721","7624335","9418898"],"confidence":"High","gaps":["Mechanism by which NAB1 represses once bound not yet defined","Family selectivity (no repression of Egr3/NGFI-C) mechanism unclear"]},{"year":1996,"claim":"NAB2, a co-induced paralog of NAB1, was shown to bind the same R1 domain and repress EGR1, establishing a feedback corepressor module coupled to EGR1 induction.","evidence":"Domain interaction mapping, cotransfection repression, and Northern blot expression analysis","pmids":["8668170"],"confidence":"High","gaps":["Repression mechanism downstream of binding not defined here","Physiological context of NAB2 feedback not tested in vivo"]},{"year":1998,"claim":"Genetic ablation and mapping of an active NAB1 repression domain (NCD2) resolved how EGR1 silencing works and demonstrated EGR1's developmental necessity for endocrine cell lineages.","evidence":"GAL4-tethered repression/mutagenesis assays and Egr1 null mouse histopathology/hormone analysis","pmids":["9418898","9440815"],"confidence":"High","gaps":["Corepressor machinery recruited by NCD2 not identified","Cell-autonomy of somatotrope/gonadotrope defects not fully resolved"]},{"year":2006,"claim":"Defining EGR1 activation of TAp73 (and later p53) placed EGR1 within a stress-responsive apoptotic transcriptional network with feedback amplification.","evidence":"Promoter reporter assays, binding-site mutagenesis, ChIP, and in vivo mouse genotoxic stress experiments","pmids":["16990849"],"confidence":"High","gaps":["Stress-specific signaling that activates EGR1 in this network not defined","Cofactor requirements for TAp73 induction unspecified"]},{"year":2008,"claim":"Mapping Akt-driven phosphorylation/ARF-dependent sumoylation versus sumoylation-coupled ubiquitination revealed that PTMs both license target induction (PTEN) and control EGR1 turnover.","evidence":"In vivo phosphorylation/sumoylation assays, co-IP, site-directed mutagenesis, ARF-/- mice (PTEN axis), and SUMO-1/Ubc9 cotransfection with MG132 ubiquitination assays","pmids":["19057511","21998680"],"confidence":"High","gaps":["How sumoylation can both activate and destabilize EGR1 reconciled only partially","Physiological stimuli balancing these PTMs unclear"]},{"year":2009,"claim":"Pharmacological pathway dissection established that EGFR signaling induces EGR1 specifically through MEK/ERK rather than PI3K, defining the dominant upstream route.","evidence":"Expression profiling with MEK (U0126) versus PI3K (LY294002) inhibitors in mutant-EGFR cells","pmids":["19414352"],"confidence":"Medium","gaps":["Single cell-line pharmacology","Transcription factors mediating ERK-to-EGR1 induction not identified"]},{"year":2013,"claim":"In vivo ChIP and rescue experiments established EGR1 as a direct activator of collagen genes driving tendon differentiation and repair via TGF-β2.","evidence":"In vivo ChIP at Col1a1/Col2a1, Egr1-/- tendon analysis, MSC overexpression, and a rat Achilles tendon injury model with TGF-β2 neutralization","pmids":["21173153","23863709"],"confidence":"High","gaps":["Cofactors enabling tenogenic versus other programs not defined","Extent of TGF-β2-independent contribution unresolved"]},{"year":2008,"claim":"Genome-wide promoter mapping after UV/EGFR activation showed EGR1 binds hundreds of promoters, including EGFR-pathway and pro-apoptotic genes, defining it as a broad signal-responsive regulatory hub.","evidence":"ChIP-on-chip with ChIP-qPCR validation, siRNA knockdown, and UV-induced apoptosis assays","pmids":["19032775"],"confidence":"High","gaps":["Functional contribution of most bound promoters untested","Determinants of activation versus repression at each site unclear"]},{"year":2019,"claim":"Discovery that EGR1 recruits TET1 for neuron-specific demethylation and activates TFEB defined EGR1 as a writer of chromatin/epigenetic state coupling to lysosomal/metabolic programs.","evidence":"EGR1 ChIP-seq, WGBS, parallel Egr1-/-/Tet1-/- cortex comparison; and EGR1 ChIP-seq with KO and Trametinib in TFEB study","pmids":["31467272","36888606"],"confidence":"High","gaps":["Direct EGR1–TET1 contact interface not mapped","Selectivity for neuronal versus glial recruitment mechanistically unexplained"]},{"year":2021,"claim":"Genome-wide profiling in myeloid cells demonstrated EGR1 represses inflammatory enhancers through the NuRD corepressor complex, defining a direct repressive mechanism complementary to its activator role.","evidence":"EGR1 ChIP-seq, ATAC-seq, NuRD co-IP, and EGR1 knockdown with inflammatory gene readout; plus DNA-PKcs-stabilized EGR1 sustaining IL-2","pmids":["33523892","34562454"],"confidence":"High","gaps":["How EGR1 binds non-canonical (motif-less) enhancers unclear","Switch between NAB/NuRD repression and p300 activation not defined"]},{"year":2024,"claim":"Conditional-KO and multi-omics studies extended EGR1 to cardiac regeneration, hepatoprotective β-oxidation, and tumor-suppressive glycolytic control, broadening its physiological reach.","evidence":"Conditional Egr1 KO with proteomics/scRNA-seq (cardiac agrin model), liver-specific KO with ChIP-seq/Seahorse (Acaa2), and ChIP with organoid/xenograft models (PFKL)","pmids":["39196027","35813467","38287371"],"confidence":"High","gaps":["Tissue-specific cofactors directing opposite (activating vs repressing) outputs not resolved","Whether shared upstream ERK/Akt input distinguishes these programs unclear"]},{"year":null,"claim":"It remains unresolved what molecular logic dictates whether EGR1 acts as an activator (with p300/CBP, TET1) or a repressor (with NAB1/2, NuRD, TET2/HDAC) at a given locus.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or rule-based model linking partner choice to gene-specific outcome","Crosstalk between phosphorylation/sumoylation PTM state and cofactor recruitment not integrated","Determinants of binding at non-canonical enhancers undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,10,12,13,21,22,24,29,31,38]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,5]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,3,41]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,10,12,21,22,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,23,35,36]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,22,24,33]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,40]}],"complexes":["NuRD complex"],"partners":["NAB1","NAB2","TET1","EP300","SMAD3","TBX2","RUNX2","TET2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P18146","full_name":"Early growth response protein 1","aliases":["AT225","Nerve growth factor-induced protein A","NGFI-A","Transcription factor ETR103","Transcription factor Zif268","Zinc finger protein 225","Zinc finger protein Krox-24"],"length_aa":543,"mass_kda":57.5,"function":"Transcriptional regulator (PubMed:20121949). Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3'(EGR-site) in the promoter region of target genes (By similarity). Binds double-stranded target DNA, irrespective of the cytosine methylation status (PubMed:25258363, PubMed:25999311). Regulates the transcription of numerous target genes, and thereby plays an important role in regulating the response to growth factors, DNA damage, and ischemia. Plays a role in the regulation of cell survival, proliferation and cell death. Activates expression of p53/TP53 and TGFB1, and thereby helps prevent tumor formation. Required for normal progress through mitosis and normal proliferation of hepatocytes after partial hepatectomy. Mediates responses to ischemia and hypoxia; regulates the expression of proteins such as IL1B and CXCL2 that are involved in inflammatory processes and development of tissue damage after ischemia. Regulates biosynthesis of luteinizing hormone (LHB) in the pituitary (By similarity). Regulates the amplitude of the expression rhythms of clock genes: BMAL1, PER2 and NR1D1 in the liver via the activation of PER1 (clock repressor) transcription. Regulates the rhythmic expression of core-clock gene BMAL1 in the suprachiasmatic nucleus (SCN) (By similarity)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P18146/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EGR1","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EGR1","total_profiled":1310},"omim":[{"mim_id":"618303","title":"CAVEOLAE-ASSOCIATED PROTEIN 3; CAVIN3","url":"https://www.omim.org/entry/618303"},{"mim_id":"614969","title":"PONTOCEREBELLAR HYPOPLASIA, TYPE 7; PCH7","url":"https://www.omim.org/entry/614969"},{"mim_id":"613991","title":"CDC42-BINDING PROTEIN KINASE, GAMMA; CDC42BPG","url":"https://www.omim.org/entry/613991"},{"mim_id":"613931","title":"TARGET OF EGR1; TOE1","url":"https://www.omim.org/entry/613931"},{"mim_id":"613858","title":"PROTEASE, SERINE, 56; PRSS56","url":"https://www.omim.org/entry/613858"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EGR1"},"hgnc":{"alias_symbol":["225","TIS8","AT225","G0S30","NGFI-A","ZIF268","KROX-24","ZIF-268"],"prev_symbol":[]},"alphafold":{"accession":"P18146","domains":[{"cath_id":"3.30.160.60","chopping":"365-393","consensus_level":"medium","plddt":89.6166,"start":365,"end":393},{"cath_id":"3.30.160.60","chopping":"395-429","consensus_level":"medium","plddt":81.6123,"start":395,"end":429}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P18146","model_url":"https://alphafold.ebi.ac.uk/files/AF-P18146-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P18146-F1-predicted_aligned_error_v6.png","plddt_mean":49.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EGR1","jax_strain_url":"https://www.jax.org/strain/search?query=EGR1"},"sequence":{"accession":"P18146","fasta_url":"https://rest.uniprot.org/uniprotkb/P18146.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P18146/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P18146"}},"corpus_meta":[{"pmid":"8668170","id":"PMC_8668170","title":"NAB2, 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NAB1 does not block DNA binding or nuclear localization of NGFI-A.\",\n      \"method\": \"Yeast two-hybrid isolation, cotransfection repression assays, domain mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus functional cotransfection assays, replicated and extended by subsequent NAB1 mechanistic study (PMID:9418898)\",\n      \"pmids\": [\"7624335\", \"9418898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NAB2, a second corepressor highly related to NAB1, physically interacts with the R1 domain of NGFI-A (EGR1) through its first conserved domain and represses both NGFI-A and Krox20 transcriptional activity; NAB2 expression is induced by the same stimuli (serum, NGF) that induce NGFI-A.\",\n      \"method\": \"Domain interaction mapping, cotransfection repression assays, Northern blot expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal domain-mapping plus functional repression assays; finding independently corroborated by NAB1 studies\",\n      \"pmids\": [\"8668170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Nab1 repression of EGR1 is not mediated by blocking DNA binding or nuclear localization; instead, Nab1 contains an active repression domain localized to the conserved NCD2 region in its carboxy terminus, and this domain can repress multiple types of activation domains when tethered directly to DNA, independent of promoter context or distance.\",\n      \"method\": \"GAL4-tethered repression assays, deletion/replacement mutagenesis, nuclear localization experiments, gel shift assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — extensive mutagenesis combined with functional tethered-repressor assays; multiple orthogonal approaches in single study\",\n      \"pmids\": [\"9418898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"EGR1 (NGFI-A) and related family members (NGFI-C, Egr3, Krox20) bind the consensus GC-rich sequence GCGGGGGCG; PCR-mediated random site selection revealed a broader consensus T-G-C-G-T/g-G/A-G-G-C/a/t-G-G/T and an optimal 10-nucleotide binding site. NGFI-C has >3-fold lower DNA binding affinity than NGFI-A/Egr3/Krox20 due to protein context outside the zinc fingers.\",\n      \"method\": \"PCR-based random site selection, gel shift assays, kinetic binding measurements\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical assays with multiple approaches (SELEX-like selection, EMSA, affinity measurements)\",\n      \"pmids\": [\"7891721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"The rat NGFI-A (EGR1) gene spans 3789 nt with a single intron; all three zinc-finger domains are encoded in the 3' exon. The 5' flanking region contains an NGF-responsive element (with serum response elements, CRE, Sp1 site, TATA box) demonstrated by CAT reporter transfection in PC12 cells.\",\n      \"method\": \"Gene cloning/sequencing, CAT reporter transfection assay, transcription start site mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter dissection in cellular transfection assay, single lab\",\n      \"pmids\": [\"2492104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EGR1 is sumoylated in ECV304 cells upon EGF stimulation; SUMO-1/Ubc9 overexpression stabilizes ERK1/2 phosphorylation and increases EGR1 gene transcription, but simultaneously enhances EGR1 protein ubiquitination and proteasomal degradation, indicating that sumoylation promotes EGR1 turnover.\",\n      \"method\": \"Cotransfection of SUMO-1/Ubc9 constructs, immunoblotting, proteasome inhibitor (MG132) experiments, ubiquitination assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays in single lab demonstrating sumoylation-coupled ubiquitination/degradation\",\n      \"pmids\": [\"21998680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EGR1 is phosphorylated by Akt at S350 and T309; this promotes interaction of EGR1 with ARF at K272 in its repressor domain, enabling ARF/Ubc9/SUMO-mediated sumoylation of EGR1, which is required for EGR1-dependent transcriptional induction of PTEN in vivo. ARF knockout mice show reduced EGR1 sumoylation and reduced PTEN.\",\n      \"method\": \"In vivo phosphorylation/sumoylation assays, co-immunoprecipitation, ARF-/- mouse analysis, site-directed mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, co-IP, knockout mouse validation) establishing a defined PTM cascade\",\n      \"pmids\": [\"19057511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DNA-PKcs phosphorylates EGR1 at serine 301 in activated T cells; inhibition of DNA-PKcs or S301A CRISPR mutation increases proteasomal degradation of EGR1 and decreases EGR1-dependent IL-2 transcription, identifying DNA-PKcs as a kinase that stabilizes EGR1.\",\n      \"method\": \"Quantitative phosphoproteomics, DNA-PKcs inhibitor (NU7441), shRNA knockdown, CRISPR-Cas9 S301A mutation, proteasome inhibitor assays, luciferase/transcription assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — phosphoproteomics plus genetic validation (CRISPR mutation) plus functional transcription assay in single rigorous study\",\n      \"pmids\": [\"34562454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 recruits the DNA demethylase TET1 to EGR1 binding sites during postnatal brain development, establishing hypomethylation specifically in neurons (not glia); Egr1-/- and Tet1-/- frontal cortices share strikingly similar gene expression and DNA methylation profiles.\",\n      \"method\": \"EGR1 ChIP-seq, WGBS methylation profiling, knockout mouse comparison (Egr1-/-, Tet1-/-), co-immunoprecipitation/recruitment assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP-seq, genome-wide methylation data, and parallel KO mouse comparison providing convergent mechanistic evidence\",\n      \"pmids\": [\"31467272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EGR1 (and EGR2) directly bind and trans-activate the proximal promoter of Col1a1 in tendon cells; FGF4 (muscle-derived) activates Egr1 expression and downstream collagen expression in chick limbs; Egr1-/- mice show reduced Col1a1 transcripts and fewer collagen fibrils in embryonic tendons.\",\n      \"method\": \"ChIP assay (EGR1 recruitment to Col1a1 promoter), luciferase reporter trans-activation, chick misexpression, Egr1-/- mouse analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP, reporter assays, gain-of-function in vivo misexpression, and KO mouse with defined collagen phenotype\",\n      \"pmids\": [\"21173153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EGR1 is recruited to Col1a1 and Col2a1 promoters in postnatal mouse tendons in vivo; EGR1-expressing MSCs promote tendon-like tissue formation and Achilles tendon repair; EGR1's pro-tenogenic effect is partially mediated by TGF-β2.\",\n      \"method\": \"ChIP assay (in vivo promoter recruitment), Egr1-/- mouse tendon analysis, MSC overexpression, rat Achilles tendon injury model, TGF-β2 neutralization\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo ChIP, KO mouse mechanical analysis, and in vivo rescue experiments with defined mediator\",\n      \"pmids\": [\"23863709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EGR1 transcriptionally activates the TAp73 promoter (TP73 P1) through five distinct EGR1-binding sites; EGR1 induction of TAp73 by genotoxic stress was confirmed in vivo in mice; EGR1, p53, and TAp73 form an inter-regulating network with feedback loops sustaining apoptotic gene expression under stress.\",\n      \"method\": \"Promoter reporter assays, EGR1-binding site mutagenesis, ChIP, in vivo mouse genotoxic stress experiments\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — promoter mutagenesis, ChIP, and in vivo mouse validation\",\n      \"pmids\": [\"16990849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EGR1 binds to the heparanase (HPSE) gene promoter in vivo in tumor cells; two functional EGR1 binding sites in a 280-bp critical promoter region were identified by site-directed mutagenesis and EMSA; EGR1 activates heparanase promoter in prostate, breast, and colon carcinoma but represses it in melanoma cells.\",\n      \"method\": \"ChIP (in vivo promoter binding), luciferase reporter assays, site-directed mutagenesis, EMSA, EGR1 overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP, EMSA, mutagenesis, and functional reporter assays across multiple cell lines\",\n      \"pmids\": [\"16093249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Glucocorticoid receptor activation in hippocampus increases MAPK (ERK) pathway activity and leads to increased Egr-1 mRNA and protein; MAPK pathway inhibition within hippocampus abolishes glucocorticoid-induced enhancement of contextual fear conditioning, placing EGR1 downstream of GR/MAPK signaling in stress-related fear memory.\",\n      \"method\": \"Brain-specific GR knockout mice (GR(NesCre)), cell lines with constitutively active GR (DeltaGR), MAPK inhibitor intra-hippocampal injection, fear conditioning behavioral assay\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic GR KO combined with pharmacological MAPK inhibition and behavioral readout, replicated in vivo and in vitro\",\n      \"pmids\": [\"15834420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NGFI-A (EGR1) binds to the exon 1(7) glucocorticoid receptor (GR) promoter in hippocampus in a manner dynamically regulated by maternal licking/grooming; serotonin (5-HT) induces NGFI-A-dependent GR transcription in hippocampal neurons; thyroid hormones and 5-HT mediate LG-induced NGFI-A binding to the GR promoter.\",\n      \"method\": \"ChIP (NGFI-A binding to GR promoter), hippocampal neuron reporter assay, NGFI-A overexpression, thyroid hormone/5-HT pharmacological manipulations\",\n      \"journal\": \"Philosophical transactions of the Royal Society of London. Series B, Biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and overexpression in neurons, single lab\",\n      \"pmids\": [\"22826348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MBD2 (methyl-CpG binding domain protein-2) collaborates with NGFI-A (EGR1) to activate the methylated exon 17 GR promoter; MBD2 knockdown abolishes exon 17 GR promoter activation; site-directed mutagenesis of the NGFI-A response element within the methylated promoter confirmed that NGFI-A binding is required.\",\n      \"method\": \"MBD2 knockdown in hippocampal primary culture, ectopic co-expression in HEK293 cells, site-directed mutagenesis of NGFI-A response element, luciferase reporter assay\",\n      \"journal\": \"Philosophical transactions of the Royal Society of London. Series B, Biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown and mutagenesis in two cell systems, single lab\",\n      \"pmids\": [\"25135974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"UV irradiation activates EGF receptor, induces EGR1, and EGR1 then binds to 288 gene promoters (ChIP-on-chip); a major subgroup of bound targets is the EGFR signal-transduction pathway (24 genes); EGR1 binding impacts target gene expression, and siRNA depletion of EGR1 abolishes UV-induced apoptosis in prostate M12 cells, identifying FasL, MAX, and RRAS2 as novel EGR1 targets.\",\n      \"method\": \"ChIP-on-chip (genome-wide promoter binding), conventional ChIP-qPCR validation, siRNA knockdown, UV-induced apoptosis assay\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide ChIP-on-chip with siRNA functional validation and multiple orthogonal methods\",\n      \"pmids\": [\"19032775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SMAD3 and EGR1 physically interact via the SMAD3 MH2 domain and the EGR1 DNA-binding domain; SMAD3 inhibits EGR1-induced human LHB promoter activity but potentiates EGR1-induced murine Lhb promoter activity; this species-specific difference depends on SMAD-binding elements (SBEs) present in the murine but not human promoter.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, promoter reporter assays, SBE site-directed mutagenesis, ChIP\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-IP for physical interaction plus mutagenesis of binding elements to establish functional mechanism\",\n      \"pmids\": [\"20149866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EGR1 directly binds to the heparanase gene promoter via two functional EGR1 sites and activates its expression in cancer cells; EGR1-driven chromatin remodeling and transactivation of HPSE is potentiated by p300-mediated activation (in the hnRNPU/p300/EGR1/HPSE axis).\",\n      \"method\": \"ChIP assay, luciferase reporter, co-IP (EGR1–p300/CBP interaction verified)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and co-IP in single lab; p300 interaction aspect from PMID:29511351\",\n      \"pmids\": [\"29511351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EGR1 physically interacts with p300/CBP (verified by co-IP) and together transcriptionally activates SNAI2 (Slug) promoter, driving EMT and invasion in pancreatic cancer; EGR1 binding to the SNAI2 promoter was confirmed by ChIP-qPCR.\",\n      \"method\": \"Co-IP (EGR1–p300/CBP), ChIP-qPCR (EGR1 at SNAI2 promoter), dual-luciferase reporter, Transwell invasion assay, in vivo liver metastasis model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus reporter, single lab\",\n      \"pmids\": [\"36932397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EGR1 directly binds the proximal promoter of Per1 to activate its transcription; EGR1 is itself transactivated by the CLOCK/BMAL1 heterodimer through a conserved E-box; in Egr1-/- mice the amplitude (but not phase) of hepatic clock genes including Bmal1, Per1, Per2, Rev-erbα/β is reduced.\",\n      \"method\": \"ChIP (EGR1 at Per1 promoter), luciferase reporter assay (E-box CLOCK/BMAL1 transactivation), Egr1-/- mouse circadian gene expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP, reporter assay, and KO mouse with quantified amplitude phenotype\",\n      \"pmids\": [\"26471974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In differentiating macrophages, EGR1 binds inflammatory enhancers (many without its canonical motif) and represses inflammatory genes through the NuRD corepressor complex; in monocytes, EGR1 binds enhancers regulating developmental genes like CSF1R.\",\n      \"method\": \"EGR1 ChIP-seq (monocytes vs macrophages), ATAC-seq, NuRD complex co-immunoprecipitation, EGR1 knockdown with inflammatory gene expression readout\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide ChIP-seq, chromatin accessibility profiling, co-IP of NuRD complex, and functional knockdown\",\n      \"pmids\": [\"33523892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mutant EGFR (delE746_A750) constitutively upregulates EGR1 expression through the ERK (MEK/ERK) pathway, not through PI3K; MEK inhibitor U0126 blocks EGR1 expression in mutant EGFR cells, while PI3K inhibitor LY294002 does not.\",\n      \"method\": \"Gene expression profiling, RT-PCR/immunoblotting, MEK inhibitor (U0126), PI3K inhibitor (LY294002), EGFR-TKI treatment\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection in transfected cells, single lab\",\n      \"pmids\": [\"19414352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGR1 is a downstream effector of B-cell receptor/JAK1 signaling in DLBCL; EGR1 upregulates MYC and E2F pathway genes through the CBP/p300/H3K27ac/BRD4 axis and represses type I IFN pathway genes by interacting with corepressor NAB2.\",\n      \"method\": \"EGR1 ChIP-seq, H3K27ac ChIP-seq, co-IP (EGR1–NAB2, EGR1–CBP/p300), EGR1 knockdown/knockout, xenograft mouse models\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP-seq, co-IP for complex identification, genetic knockdown with in vivo xenograft validation\",\n      \"pmids\": [\"33980611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EGR1 acts as a transcriptional activator of KLK7 through direct binding to the EBS in the KLK7 proximal promoter in response to IL-13; ERK1/2 MAPK pathway is required for IL-13-induced EGR1-dependent KLK7 transcription; Egr1-/- mice lack IL-13/DNCB-induced KLK7 expression in AD-like skin lesions.\",\n      \"method\": \"Promoter reporter assay (EBS point mutation), ChIP (EGR1 at KLK7 promoter), EGR1 shRNA knockdown, Egr1-/- mice, ERK1/2 inhibitor experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP, promoter mutagenesis, shRNA, and KO mouse validation\",\n      \"pmids\": [\"33276948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 is a direct transcriptional activator of leptin gene expression in breast cancer cells; the EGR1-binding motif in the proximal leptin promoter is required for TNF-α-induced leptin transcription (shown by point mutation); EGR1 overexpression activates leptin promoter and EGR1 knockdown reduces TNF-α-induced leptin accumulation; ERK1/2 pathway mediates this response.\",\n      \"method\": \"Promoter reporter assay (EBS point mutation), EGR1 overexpression, EGR1 siRNA knockdown, ERK1/2 pathway inhibition\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis and siRNA in single lab\",\n      \"pmids\": [\"30417207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EGR1 directly binds the Sox9 gene promoter and activates SOX9 expression in renal tubular cells; EGR1-induced SOX9 promotes tubular cell proliferation through the Wnt/β-catenin pathway; genetic Egr1 knockout aggravates AKI severity in mouse models.\",\n      \"method\": \"ChIP assay (EGR1 at Sox9 promoter), dual-luciferase reporter, Egr1-/- mice with IRI and nephrotoxic AKI models, RNA sequencing\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP, reporter assay, and KO mouse with two AKI models\",\n      \"pmids\": [\"35910788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 directly binds the METTL3 promoter (confirmed by ChIP) to transcriptionally activate METTL3 expression; METTL3-mediated m6A modification of VIM mRNA downregulates VIM expression, thereby protecting hippocampal neurons from injury in epilepsy.\",\n      \"method\": \"ChIP assay (EGR1 at METTL3 promoter), EGR1/METTL3/VIM knockdown in epilepsy cell and mouse models, m6A modification assay\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional loss-of-function, single lab\",\n      \"pmids\": [\"37268752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EGR1 directly binds the PFKL (phosphofructokinase-1, liver type) promoter and represses PFKL gene expression, thereby inhibiting aerobic glycolysis and suppressing hepatocellular carcinoma growth; EGR1 overexpression in mouse HCC models and human hepatoma organoids validated this tumor-suppressive mechanism.\",\n      \"method\": \"ChIP (EGR1 at PFKL promoter), EGR1 overexpression/knockdown in vitro and in vivo, xenograft tumor model, human hepatoma organoid, glycolysis assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional in vivo models, single lab\",\n      \"pmids\": [\"38287371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EGR1 regulates ATGL (adipose triglyceride lipase) expression and fat storage in adipocytes; EGR1 protein expression is predominantly regulated via the mTORC1/4E-BP translational axis rather than transcriptionally; 4E-BP1/2 knockout cells translate Egr1 mRNA more efficiently, express less ATGL, and accumulate more fat.\",\n      \"method\": \"35S-labeling (translational efficiency), MEK inhibitor/mTORC1 inhibitor pharmacology, 4E-BP1/2-null and TSC2-null MEFs, ATGL expression and fat accumulation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO MEFs, metabolic labeling, pharmacological pathway dissection; single lab\",\n      \"pmids\": [\"25814662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 transcriptionally activates TFEB expression by directly binding the TFEB promoter; in the absence of EGR1, the TFEB-mediated transcriptional response to starvation is impaired; pharmacological inhibition of EGR1 (via MEK1/2 inhibitor Trametinib) reduces proliferation of cells with constitutive TFEB activation.\",\n      \"method\": \"EGR1 ChIP-seq (EGR1 at TFEB promoter), EGR1 genetic knockout, MEK1/2 inhibitor (Trametinib), 3D culture proliferation assay, BHD patient-derived cells\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP-seq, genetic KO, pharmacological inhibition, and patient-derived model validation\",\n      \"pmids\": [\"36888606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EGR1 interacts with TBX2 (co-immunoprecipitation); TBX2 binding inhibits EGR1-dependent transcription of target genes including p21 (CDKN1A), PTEN, NDRG1, and CST6; EGR1 overexpression in ARMS cells reduces proliferation and induces apoptosis via the intrinsic pathway (BAX activation, BAD dephosphorylation).\",\n      \"method\": \"Co-immunoprecipitation (EGR1-TBX2), EGR1 overexpression, reporter gene assays, apoptosis flow cytometry, western blot\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional overexpression, single lab\",\n      \"pmids\": [\"29719592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EGR1 controls TET2 recruitment to the MIF promoter through protein-protein interaction; TET2 downregulation disrupts this interaction with EGR1 and histone deacetylases at the MIF promoter, leading to enhanced EGR1-driven MIF transcription and MIF secretion in resting monocytes.\",\n      \"method\": \"ChIP (TET2, EGR1 at MIF promoter), co-IP (TET2-EGR1-HDAC complex), TET2 knockdown in mouse and human cells, MIF secretion ELISA\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and co-IP, replicated in mouse and human cells, single lab\",\n      \"pmids\": [\"35115654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Egr1 is required for dopaminergic signaling during social behavior in zebrafish; egr1 mutant fish show reduced social approach and tyrosine hydroxylase (TH) expression is markedly decreased in TH-positive neurons of the anterior parvocellular preoptic nucleus; chemogenetic ablation of ~30% of these TH+ neurons phenocopies the egr1 social behavior deficit.\",\n      \"method\": \"Egr1 zebrafish mutant (loss-of-function), in situ hybridization for TH, chemogenetic neuronal ablation, behavioral assays\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with neurochemical and behavioral readout, plus chemogenetic epistasis; single lab\",\n      \"pmids\": [\"35346959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Egr1 regulates regenerative senescence in the adult mouse heart; in cardiac fibroblasts, Egr1 is activated by the integrin-FAK-ERK-Akt1 signaling axis in response to agrin; Egr1 facilitates angiogenesis and cardiomyocyte proliferation in neonatal hearts and is required for agrin-induced senescence-mediated cardiac repair in adult mice.\",\n      \"method\": \"Proteomics, single-cell RNA sequencing, Egr1 conditional KO in cardiac fibroblasts, agrin-treatment mouse model, pathway inhibition (FAK-ERK-Akt1)\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multi-omics profiling, conditional KO, mechanistic pathway inhibition, and two in vivo cardiac models\",\n      \"pmids\": [\"39196027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 binds the viral genome upstream of the CMV UL138 latency gene and is sufficient to promote UL138 expression; disruption of EGR1 binding upstream of UL138 prevents the establishment of CMV latency in CD34+ hematopoietic progenitor cells; EGR1 is induced downstream of EGFR/MEK/ERK signaling in HPCs.\",\n      \"method\": \"EGR1 ChIP on viral genome, EGR1 overexpression (sufficient for UL138 induction), mutation of EGR1 binding site in viral genome, CMV latency assay in CD34+ HPCs\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP, gain-of-function, and viral genome site-directed mutagenesis with functional latency readout\",\n      \"pmids\": [\"31725811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 transcriptionally activates GnRH-responsive AMH receptor type 2 (AMHR2) expression in gonadotrope cells; EGR1 mediates both basal and GnRH-dependent AMHR2 promoter activity through a proximal -53/-37 bp binding site; FOXO1 acts as a negative regulator of EGR1-dependent AMHR2 expression.\",\n      \"method\": \"Promoter deletion constructs, site-directed mutagenesis of Egr1 motif, siRNA knockdown of Egr1, constitutively active FOXO1 mutant, perifusion of LβT2 gonadotrope cells\",\n      \"journal\": \"Neuroendocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis plus siRNA knockdown; single lab\",\n      \"pmids\": [\"30368511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EGR1 directly activates CCND1 (cyclin D1) promoter transcription (confirmed by ChIP assay with EGF stimulation); EGR1 silencing inhibits glioma cell proliferation and induces G1 phase arrest, establishing EGR1-CCND1 as a proliferative axis in glioma.\",\n      \"method\": \"ChIP assay (EGR1 at CCND1 promoter), siRNA EGR1 knockdown, cell cycle analysis, proliferation assays in U251/U87 cells and in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional knockdown, single lab\",\n      \"pmids\": [\"29246166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Targeted disruption of Egr-1 (Krox-24) in mice causes sterility and reduced body size; specifically, Egr-1 null gonadotropes fail to synthesize the LHβ subunit and somatotropes are reduced in number, indicating EGR1 is required for LHβ transcription in gonadotropes and for somatotrope proliferation/survival.\",\n      \"method\": \"Gene targeting (null allele), histopathology, immunohistochemistry, hormone measurement in Egr1-/- mice\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined genetic KO with specific endocrine cell-lineage phenotypes; replicated across two independent Egr1 null allele reports\",\n      \"pmids\": [\"9440815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 directly upregulates p53 transcription by binding the p53 promoter; EGR1 promotes p53-dependent apoptosis in retinal vascular endothelial cells under high-glucose conditions; downregulation of Egr1 reduces apoptosis and tube formation in vivo through p53 reduction.\",\n      \"method\": \"EGR1 shRNA knockdown, p53 overexpression rescue, in vivo sh-Egr1 delivery in diabetic rats, apoptosis/tube formation assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown with rescue experiment and in vivo validation, single lab\",\n      \"pmids\": [\"30887692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 identified as a novel splicing isoform: a shorter EGR1 protein lacking part of the N-terminal activation domain can enter the nucleus but cannot fully activate transcription compared to canonical EGR1.\",\n      \"method\": \"RT-PCR cloning of novel transcript, nuclear localization assay, transcriptional activation reporter assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited functional characterization; no mutagenesis or binding studies\",\n      \"pmids\": [\"30925677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EGR1 promotes hepatoprotection in acetaminophen-induced liver injury by transcriptionally upregulating Acaa2 (a key gene for mitochondrial fatty acid β-oxidation); liver-specific Egr1 knockout worsens AILI while adenoviral EGR1 overexpression ameliorates it; Acaa2 knockdown abolishes EGR1's protective effect.\",\n      \"method\": \"Liver-specific Egr1-KO mice, adenoviral EGR1 overexpression, ChIP-seq (EGR1 at Acaa2 locus), RNA-seq, Seahorse metabolic assay, Acaa2 siRNA knockdown\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — conditional KO, ChIP-seq, rescue by Acaa2 knockdown, and metabolic assays\",\n      \"pmids\": [\"35813467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RUNX2 and EGR1 co-occupy Htra1 enhancers in osteoblasts (validated by Re-ChIP assay) and together co-repress Htra1 while promoting expression of osterix, osteocalcin, and osteoprotegerin; co-knockdown of RUNX2 and EGR1 reduces osteoblast calcification and ALP activity.\",\n      \"method\": \"RUNX2 ChIP-seq, RNA-seq (Runx2 heterozygous mice), dual-luciferase enhancer assays, Re-ChIP (RUNX2+EGR1 co-occupancy), siRNA double knockdown, Alizarin red/ALP staining\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Re-ChIP for co-occupancy plus functional co-knockdown; single lab\",\n      \"pmids\": [\"32324256\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EGR1 is a zinc-finger transcription factor that binds GC-rich promoter/enhancer elements (consensus ~GCGGGGGCG) to activate or repress a wide array of target genes (including PTEN, p53/p73, LHβ, Col1a1, HPSE, Per1, TFEB, CCND1, PFKL, Acaa2, and others); its activity is regulated post-translationally by Akt-mediated phosphorylation (S350/T309) that enables sumoylation via ARF/Ubc9, by DNA-PKcs phosphorylation at S301 that stabilizes the protein against proteasomal degradation, and by coupled sumoylation/ubiquitination that can enhance turnover; EGR1 recruits corepressors NAB1/NAB2 (binding its R1 inhibitory domain) and the NuRD complex to repress inflammatory genes, while it cooperates with coactivators p300/CBP, TET1 (for DNA demethylation), and SMAD3 in a context-dependent manner to activate transcription; upstream, EGR1 expression and activity are induced primarily through the EGFR–MEK–ERK pathway, and by GR/glucocorticoid–MAPK signaling, placing it as a convergence node coupling extracellular growth factor, stress, and hormonal signals to nuclear gene programs governing tendon differentiation, synaptic plasticity, memory, cardiac regeneration, reproductive function, circadian rhythm amplitude, and tumor progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EGR1 is an immediate-early zinc-finger transcription factor that converts extracellular growth factor, stress, and hormonal cues into nuclear gene programs by binding GC-rich promoter and enhancer elements (consensus GCGGGGGCG) through its zinc fingers [#4]. Its protein contains four distinct activation domains and a discrete inhibitory (R1) domain whose deletion sharply increases activity by relieving a titratable cellular repressor [#0]; this domain is the docking site for the corepressors NAB1 and NAB2, which repress EGR1- and Krox20-directed transcription without blocking DNA binding or nuclear import, NAB1 acting through an active repression domain (NCD2) in its carboxy terminus [#1, #2, #3]. EGR1 expression and protein output are driven principally through EGFR\\u2013MEK\\u2013ERK signaling [#23, #36], with GR/glucocorticoid\\u2013MAPK input in the hippocampus [#14] and additional control by the mTORC1/4E-BP translational axis [#30]; its stability and activity are further tuned post-translationally, with Akt phosphorylation at S350/T309 promoting ARF/Ubc9-dependent sumoylation required for PTEN induction [#7], DNA-PKcs phosphorylation at S301 protecting EGR1 from proteasomal degradation to sustain IL-2 transcription [#8], and sumoylation-coupled ubiquitination promoting turnover [#6]. As a transcriptional node EGR1 activates or represses context-specific targets\\u2014activating Col1a1/Col2a1 in tendon differentiation [#10, #11], TAp73 and p53 in stress apoptosis [#12, #40], Per1 within the circadian feedback loop [#21], TFEB [#31], CCND1 [#38], and SNAI2 in cancer [#20], while repressing PFKL to limit glycolysis [#29] and inflammatory enhancer genes via the NuRD complex [#22]. It cooperates with coactivators p300/CBP [#20, #24], recruits TET1 for neuronal DNA demethylation [#9], and partners with SMAD3, TBX2, RUNX2, and TET2 to set target-gene output in a context-dependent manner [#18, #32, #43, #33]. Genetic loss of Egr1 in mice causes sterility, failed LH\\u03b2 synthesis in gonadotropes, and somatotrope deficits [#39], underscoring its requirement across reproductive, tendon, cardiac, circadian, and metabolic processes.\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing the EGR1 gene's structure and inducibility defined it as an NGF/serum-responsive immediate-early gene with its DNA-contacting zinc fingers encoded in a single 3' exon.\",\n      \"evidence\": \"Gene cloning/sequencing and CAT reporter transfection of the 5' flanking region in PC12 cells\",\n      \"pmids\": [\"2492104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the DNA target sequence recognized by the protein\", \"Promoter dissection in a single cell type\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Dissecting the EGR1 protein into functional domains showed it carries multiple activation domains plus an inhibitory domain that binds a titratable cellular factor, explaining why its intrinsic activity is held in check.\",\n      \"evidence\": \"GAL4-fusion cotransfection, deletion/point mutagenesis (I293F), and competition assays in mammalian and Drosophila cells\",\n      \"pmids\": [\"8413279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the titratable inhibitory factor not established in this study\", \"No DNA-binding or in vivo target validation\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying the consensus GC-rich binding site and the NAB1 corepressor explained how EGR1 selects targets and how its activity is silenced without affecting DNA binding or localization.\",\n      \"evidence\": \"PCR-based random site selection with EMSA/affinity measurements, and yeast two-hybrid plus cotransfection repression assays\",\n      \"pmids\": [\"7891721\", \"7624335\", \"9418898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which NAB1 represses once bound not yet defined\", \"Family selectivity (no repression of Egr3/NGFI-C) mechanism unclear\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"NAB2, a co-induced paralog of NAB1, was shown to bind the same R1 domain and repress EGR1, establishing a feedback corepressor module coupled to EGR1 induction.\",\n      \"evidence\": \"Domain interaction mapping, cotransfection repression, and Northern blot expression analysis\",\n      \"pmids\": [\"8668170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Repression mechanism downstream of binding not defined here\", \"Physiological context of NAB2 feedback not tested in vivo\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Genetic ablation and mapping of an active NAB1 repression domain (NCD2) resolved how EGR1 silencing works and demonstrated EGR1's developmental necessity for endocrine cell lineages.\",\n      \"evidence\": \"GAL4-tethered repression/mutagenesis assays and Egr1 null mouse histopathology/hormone analysis\",\n      \"pmids\": [\"9418898\", \"9440815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Corepressor machinery recruited by NCD2 not identified\", \"Cell-autonomy of somatotrope/gonadotrope defects not fully resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining EGR1 activation of TAp73 (and later p53) placed EGR1 within a stress-responsive apoptotic transcriptional network with feedback amplification.\",\n      \"evidence\": \"Promoter reporter assays, binding-site mutagenesis, ChIP, and in vivo mouse genotoxic stress experiments\",\n      \"pmids\": [\"16990849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stress-specific signaling that activates EGR1 in this network not defined\", \"Cofactor requirements for TAp73 induction unspecified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping Akt-driven phosphorylation/ARF-dependent sumoylation versus sumoylation-coupled ubiquitination revealed that PTMs both license target induction (PTEN) and control EGR1 turnover.\",\n      \"evidence\": \"In vivo phosphorylation/sumoylation assays, co-IP, site-directed mutagenesis, ARF-/- mice (PTEN axis), and SUMO-1/Ubc9 cotransfection with MG132 ubiquitination assays\",\n      \"pmids\": [\"19057511\", \"21998680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How sumoylation can both activate and destabilize EGR1 reconciled only partially\", \"Physiological stimuli balancing these PTMs unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Pharmacological pathway dissection established that EGFR signaling induces EGR1 specifically through MEK/ERK rather than PI3K, defining the dominant upstream route.\",\n      \"evidence\": \"Expression profiling with MEK (U0126) versus PI3K (LY294002) inhibitors in mutant-EGFR cells\",\n      \"pmids\": [\"19414352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell-line pharmacology\", \"Transcription factors mediating ERK-to-EGR1 induction not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"In vivo ChIP and rescue experiments established EGR1 as a direct activator of collagen genes driving tendon differentiation and repair via TGF-\\u03b22.\",\n      \"evidence\": \"In vivo ChIP at Col1a1/Col2a1, Egr1-/- tendon analysis, MSC overexpression, and a rat Achilles tendon injury model with TGF-\\u03b22 neutralization\",\n      \"pmids\": [\"21173153\", \"23863709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors enabling tenogenic versus other programs not defined\", \"Extent of TGF-\\u03b22-independent contribution unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genome-wide promoter mapping after UV/EGFR activation showed EGR1 binds hundreds of promoters, including EGFR-pathway and pro-apoptotic genes, defining it as a broad signal-responsive regulatory hub.\",\n      \"evidence\": \"ChIP-on-chip with ChIP-qPCR validation, siRNA knockdown, and UV-induced apoptosis assays\",\n      \"pmids\": [\"19032775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contribution of most bound promoters untested\", \"Determinants of activation versus repression at each site unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that EGR1 recruits TET1 for neuron-specific demethylation and activates TFEB defined EGR1 as a writer of chromatin/epigenetic state coupling to lysosomal/metabolic programs.\",\n      \"evidence\": \"EGR1 ChIP-seq, WGBS, parallel Egr1-/-/Tet1-/- cortex comparison; and EGR1 ChIP-seq with KO and Trametinib in TFEB study\",\n      \"pmids\": [\"31467272\", \"36888606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct EGR1\\u2013TET1 contact interface not mapped\", \"Selectivity for neuronal versus glial recruitment mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genome-wide profiling in myeloid cells demonstrated EGR1 represses inflammatory enhancers through the NuRD corepressor complex, defining a direct repressive mechanism complementary to its activator role.\",\n      \"evidence\": \"EGR1 ChIP-seq, ATAC-seq, NuRD co-IP, and EGR1 knockdown with inflammatory gene readout; plus DNA-PKcs-stabilized EGR1 sustaining IL-2\",\n      \"pmids\": [\"33523892\", \"34562454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EGR1 binds non-canonical (motif-less) enhancers unclear\", \"Switch between NAB/NuRD repression and p300 activation not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Conditional-KO and multi-omics studies extended EGR1 to cardiac regeneration, hepatoprotective \\u03b2-oxidation, and tumor-suppressive glycolytic control, broadening its physiological reach.\",\n      \"evidence\": \"Conditional Egr1 KO with proteomics/scRNA-seq (cardiac agrin model), liver-specific KO with ChIP-seq/Seahorse (Acaa2), and ChIP with organoid/xenograft models (PFKL)\",\n      \"pmids\": [\"39196027\", \"35813467\", \"38287371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific cofactors directing opposite (activating vs repressing) outputs not resolved\", \"Whether shared upstream ERK/Akt input distinguishes these programs unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what molecular logic dictates whether EGR1 acts as an activator (with p300/CBP, TET1) or a repressor (with NAB1/2, NuRD, TET2/HDAC) at a given locus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or rule-based model linking partner choice to gene-specific outcome\", \"Crosstalk between phosphorylation/sumoylation PTM state and cofactor recruitment not integrated\", \"Determinants of binding at non-canonical enhancers undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 10, 12, 13, 21, 22, 24, 29, 31, 38]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 10, 12, 21, 22, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 23, 35, 36]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 22, 24, 33]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 40]}\n    ],\n    \"complexes\": [\"NuRD complex\"],\n    \"partners\": [\"NAB1\", \"NAB2\", \"TET1\", \"EP300\", \"SMAD3\", \"TBX2\", \"RUNX2\", \"TET2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}