{"gene":"EGR1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1988,"finding":"EGR1 (Egr-1) is an immediate-early response gene encoding a nuclear protein with three zinc fingers that binds the consensus sequence CGCCCCCGC in a zinc-dependent manner and functions as a transcriptional regulator.","method":"cDNA cloning, sequence analysis, cell fractionation, immunocytochemistry, in vitro DNA binding assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — original characterization with multiple orthogonal methods (structural prediction, nuclear localization, zinc-dependent DNA binding in vitro), foundational paper with 1237 citations","pmids":["3127059"],"is_preprint":false},{"year":1990,"finding":"The EGR1 protein is an ~80 kDa short-lived, phosphorylated nuclear protein that binds with high affinity to the sequence CGCCCCCGC in a zinc-dependent manner; identified by anti-EGR1 antiserum in serum-stimulated fibroblasts and NGF-treated PC12 cells.","method":"Antisera generation, cell fractionation, immunocytochemistry, in vitro DNA binding assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical characterization of the protein (size, phosphorylation, nuclear location, DNA binding) with multiple orthogonal methods","pmids":["2109185"],"is_preprint":false},{"year":1995,"finding":"NAB1 is a corepressor that interacts with the R1 inhibitory domain of NGFI-A/EGR1 and represses EGR1-mediated transcription; identified by yeast two-hybrid screening and shown not to affect EGR3 or NGFI-G, demonstrating specificity.","method":"Yeast two-hybrid, transcriptional reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid plus functional repression assays, replicated and extended in subsequent NAB1/NAB2 studies, 240 citations","pmids":["7624335"],"is_preprint":false},{"year":1996,"finding":"NAB2, a second corepressor closely related to NAB1, interacts with the R1 domain of NGFI-A/EGR1 and Krox20 and represses their transcriptional activity; NAB2 expression is itself induced by the same stimuli (serum, NGF) that induce NGFI-A.","method":"Protein interaction assays, transcriptional reporter assays, expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional characterization with multiple assays, 328 citations","pmids":["8668170"],"is_preprint":false},{"year":1996,"finding":"EGR1 (NGFI-A) is required for luteinizing hormone beta (LH-β) transcription in pituitary gonadotropes; NGFI-A-deficient female mice are infertile due to LH-β deficiency, and a canonical NGFI-A binding site in the LH-β promoter is required for synergistic activation by NGFI-A and SF-1.","method":"Knockout mice (ES cell-derived), ovariectomy experiments, promoter-reporter assays, in situ hybridization","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function mouse model combined with promoter mutagenesis, 425 citations","pmids":["8703054"],"is_preprint":false},{"year":1998,"finding":"NAB1 repression of EGR1-mediated transcription is active (not passive blockade of DNA binding or nuclear localization); the repression function maps to the NCD2 domain in the C-terminal half of NAB1 and works on heterologous activation domains when NAB1 is tethered directly to DNA.","method":"Deletion and replacement mutagenesis, tethered-repressor assays, nuclear localization assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — structure-function mutagenesis with multiple domain-swap and tethering experiments, 97 citations","pmids":["9418898"],"is_preprint":false},{"year":1998,"finding":"EGR1 (Krox-24) deficiency in mice causes reduced body size and sterility in both sexes due to pituitary defects: somatotropes are reduced in number and GH content is decreased, while gonadotropes fail specifically to synthesize LH-β; additionally, ovarian LH receptor expression is prevented, implicating EGR1 at two levels of the pituitary-gonadal axis.","method":"Knockout mouse generation, histological analysis, RIA, immunohistochemistry, in situ hybridization","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 — independent Egr1 knockout allele with detailed in vivo phenotypic characterization, 232 citations","pmids":["9440815"],"is_preprint":false},{"year":1999,"finding":"EGR1 is a downstream effector of GnRH signaling via PKC activation; EGR1 directly interacts with both Ptx1 and SF-1 transcription factors, and these interactions synergistically enhance LH-β promoter transcription.","method":"Co-immunoprecipitation, GST pulldown, promoter-reporter assays, PKC inhibitor experiments","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — direct protein-protein interaction demonstrated by pulldown plus functional synergy in reporter assays, 225 citations","pmids":["10082522"],"is_preprint":false},{"year":1999,"finding":"EGR1 regulates transcription of multiple vascular biology genes and is induced by hemodynamic forces and growth factors in vascular smooth muscle and endothelial cells, placing EGR1 as a convergence point for vascular stress signaling.","method":"Promoter-reporter assays, EMSA, in vivo vascular injury models (review synthesizing primary experimental data)","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 3 — synthesis of experimental data from multiple studies, pathway placement in vascular biology","pmids":["10079243"],"is_preprint":false},{"year":1995,"finding":"EGR1 protects cells against UV-induced damage; NIH3T3 cells constitutively expressing antisense Egr-1 (unable to produce Egr-1 response) grow significantly slower after UV irradiation; the Egr-1 response to UV is dependent on tyrosine kinase, protein kinase C activities, and c-Ha-Ras, and is mediated by oxidative stress rather than direct DNA damage.","method":"Antisense oligonucleotides, kinase inhibitors, cell growth assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined phenotypic readout and pathway dissection, single lab","pmids":["7845671"],"is_preprint":false},{"year":2001,"finding":"EGR1 is required for progression of prostate cancer from PIN to invasive carcinoma; Egr1-deficient mice in two transgenic prostate cancer models show significantly delayed progression to invasive carcinoma without affecting tumor initiation or growth rate.","method":"Egr1 knockout crossed with CR2-T-Ag and TRAMP transgenic prostate cancer models; MRI, histopathology, survival analysis","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — two independent mouse models with in vivo loss-of-function, defined phenotypic transition point, 150 citations","pmids":["11135623"],"is_preprint":false},{"year":2003,"finding":"EGR1 directly regulates transcription of cyclin D2, p19INK4d, and Fas/CD95 in prostate cancer cells; EGR1-mediated inhibition of Fas expression contributes to resistance to FasL-induced apoptosis.","method":"Affymetrix microarray, real-time PCR, immunoblot, chromatin immunoprecipitation (ChIP), antisense oligonucleotides","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP validates direct promoter binding, loss-of-function with antisense confirms target regulation, 133 citations","pmids":["12556466"],"is_preprint":false},{"year":2003,"finding":"EGR1 supports FGF-dependent angiogenesis; EGR1 DNAzymes inhibit microvascular endothelial cell replication, migration, and tube formation, block Matrigel angiogenesis in mice, and suppress endothelial FGF-2 (but not VEGF) expression; Egr1-deficient mice also show impaired angiogenesis.","method":"DNAzyme knockdown, Matrigel plug assays, Egr1 knockout mice, endothelial cell functional assays (proliferation, migration, tube formation)","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — two independent methods (DNAzyme and knockout), multiple in vitro and in vivo readouts, 322 citations","pmids":["12872165"],"is_preprint":false},{"year":2003,"finding":"EGR1 mediates inhibition of 4E-BP1 expression downstream of ERK and p38 MAPK activation; a dominant-negative EGR mutant (ZnEgr) blocks PMA-induced and GM-CSF-induced repression of the 4e-bp1 promoter, showing EGR1 directly represses 4E-BP1 transcription.","method":"Dominant-negative EGR mutant, promoter-reporter assays, MAPK inhibitors, Western blotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — dominant-negative approach plus promoter assays, single lab, 52 citations","pmids":["12618431"],"is_preprint":false},{"year":2003,"finding":"HGF induces cell scattering through a MAPK/EGR1/Snail pathway; EGR1 is required for HGF-induced upregulation of Snail, which in turn represses E-cadherin and claudin-3; Snail also binds the EGR1 promoter establishing a negative feedback loop.","method":"shRNA knockdown, promoter-reporter assays, ChIP, EMSA, invasion assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — pathway epistasis established by shRNA knockdown with defined EMT phenotype, promoter binding confirmed by ChIP/EMSA, 293 citations","pmids":["16858414"],"is_preprint":false},{"year":2005,"finding":"EGR1 directly binds the heparanase gene promoter in vivo and activates heparanase transcription in multiple tumor cell lines (prostate, breast, colon adenocarcinomas) through two functional EGR1 sites; EGR1 can also repress heparanase promoter activity in melanoma cells, demonstrating cell-type-dependent dual regulation.","method":"ChIP, EMSA, site-directed mutagenesis, transactivation reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vivo ChIP combined with EMSA and mutagenesis of binding sites in multiple cell lines, 76 citations","pmids":["16093249"],"is_preprint":false},{"year":2005,"finding":"EGR1 is required for behavioral responses to persistent inflammatory pain but not acute pain; Egr1 knockout mice show significantly reduced nociceptive responses to peripheral inflammation, and inflammation triggers EGR1 upregulation in the anterior cingulate cortex; synaptic potentiation by theta-burst stimulation in ACC is reduced in Egr1 knockout mice.","method":"Egr1 knockout mice, behavioral pain assays, LTP electrophysiology in ACC slices","journal":"The journal of pain","confidence":"High","confidence_rationale":"Tier 2 — knockout mouse with specific behavioral and electrophysiological phenotypes, 51 citations","pmids":["15629414"],"is_preprint":false},{"year":2005,"finding":"The MAPK pathway and EGR1 mediate stress-related behavioral effects of glucocorticoids; glucocorticoid receptor activation increases MAPK pathway protein activity and EGR1 mRNA/protein in hippocampus; MAPK inhibition within hippocampus abolishes glucocorticoid-induced enhancement of contextual fear conditioning.","method":"Brain-specific GR knockout mice, cell lines with inducible GR, MAPK activity assays, hippocampal drug infusions, behavioral fear conditioning","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological dissection of pathway in vivo with behavioral readout, 195 citations","pmids":["15834420"],"is_preprint":false},{"year":2003,"finding":"EGR1 is induced via PI3K/ERK signaling downstream of the EP4 (but not EP2) prostaglandin receptor; PGE2 stimulation of EP4 leads to phosphorylation of ERKs through PI3K and subsequent functional EGR1 protein expression.","method":"Selective EP receptor agonists, PI3K inhibitors, ERK phosphorylation assays, Western blotting for EGR1","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological dissection of receptor-specific pathway, single lab, 261 citations","pmids":["12566441"],"is_preprint":false},{"year":2006,"finding":"EGR1 transactivates the TP73 P1 promoter (but not P2) through five distinct EGR1-binding sites, upregulating TAp73; induction of TAp73 by genotoxic stress requires EGR1 in vivo; EGR1, p53, and p73 form an inter-regulating network with non-consensus p53-binding sites in each other's promoters creating feedback loops for sustained apoptotic signaling.","method":"Promoter-reporter assays, EMSA, ChIP, in vivo stress models (EGR1-deficient mice)","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — multiple promoter binding sites characterized by EMSA and ChIP, validated in vivo with EGR1-deficient mice, 87 citations","pmids":["16990849"],"is_preprint":false},{"year":2006,"finding":"AMPK activation induces EGR1 expression, which directly binds the DUSP4 promoter to activate DUSP4 transcription; EGR1 and DUSP4 together mediate AMPK-dependent inhibition of hepatic gluconeogenesis (repressing PEPCK and G6Pase promoter activity and expression).","method":"Transcriptional profiling, reporter assays, ChIP, siRNA knockdown, glucose production assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP confirms direct binding to DUSP4 promoter; siRNA epistasis places EGR1 upstream of DUSP4 in gluconeogenesis inhibition, 68 citations","pmids":["16849326"],"is_preprint":false},{"year":2008,"finding":"EGR1 is phosphorylated by Akt at S350 and T309; this phosphorylation promotes interaction of EGR1 with ARF, leading to ARF/Ubc9/SUMO-mediated sumoylation of EGR1 at K272 in its repressor domain; sumoylated EGR1 is required for PTEN transactivation in vivo—defining an Akt-EGR1-ARF-PTEN axis.","method":"Site-directed mutagenesis, co-IP, sumoylation assays, ARF knockout mice, in vivo PTEN expression analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — specific phosphorylation sites and sumoylation site identified by mutagenesis, validated in knockout mice, 115 citations","pmids":["19057511"],"is_preprint":false},{"year":2008,"finding":"EGR1 directly binds the calsequestrin 2 (CSQ2) promoter and acts as a transcriptional repressor; overexpression of Egr-1 reduces CSQ expression and abolishes calcium release from CSQ-dependent ryanodine-sensitive stores, while leaving calreticulin-dependent IP3-sensitive stores unaffected; EGR1 forms a complex with NFAT3 at the CSQ2 promoter.","method":"Adenoviral overexpression, immunoblot, in vivo and in vitro ChIP, calcium imaging (fura-2), co-IP, site-directed mutagenesis (I293F)","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1 — ChIP confirms direct promoter binding, mutagenesis defines functional domain, calcium imaging links repression to functional consequence, 27 citations","pmids":["19103607"],"is_preprint":false},{"year":2008,"finding":"Upon induction, EGR1 occupies its own gene promoter without competing with Sp1; phosphorylation of ELK1 and CREB via MEK1/2 and p38 kinases is required for EGR1 gene induction; NAB1 and NAB2 bind the EGR1 promoter to terminate transcription; histone acetylation changes accompany activation.","method":"ChIP, pharmacological kinase inhibition, quantitative promoter occupancy mapping","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative ChIP mapping of factor binding kinetics at EGR1 promoter, single lab, 32 citations","pmids":["20582451"],"is_preprint":false},{"year":2008,"finding":"Egr-1 directly binds the LC3B autophagy gene promoter (with E2F-4) and activates LC3B expression in response to cigarette smoke extract (CSE); Egr-1 also activates Atg4B; Egr1-deficient mice resist cigarette smoke-induced autophagy, apoptosis, and emphysema.","method":"ChIP, siRNA knockdown, Egr1 knockout mice, HDAC activity assays, electron microscopy","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — ChIP confirms direct LC3B promoter binding, validated in vivo with Egr1 knockout mice showing protection from emphysema, 389 citations","pmids":["18836406"],"is_preprint":false},{"year":2009,"finding":"The transcription factors Egr1 and Egr2 have opposing roles in adipocyte differentiation: Egr1 inhibits adipogenesis (overexpression blocks, knockdown potentiates differentiation), while Egr2 promotes it; pro-adipogenic effects of IBMX involve suppression of Egr1's inhibitory influence.","method":"Ectopic expression, siRNA knockdown, 3T3-L1 adipocyte differentiation assays, promoter-reporter assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with quantitative differentiation readout, single lab, 82 citations","pmids":["19229250"],"is_preprint":false},{"year":2010,"finding":"miR-183 directly targets and downregulates EGR1 mRNA in multiple tumor types (synovial sarcoma, rhabdomyosarcoma, colon cancer); miR-183 knockdown derepresses EGR1, activating a miR-183-EGR1-PTEN tumor suppressor network; EGR1 mediates the effect of miR-183 on cell migration.","method":"miRNA overexpression/knockdown, luciferase reporter assays (3′UTR), integrative genomic analysis, migration assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3′UTR targeting validated by luciferase assay, functional rescue experiments, 249 citations","pmids":["21118966"],"is_preprint":false},{"year":2010,"finding":"SMAD3 physically interacts with EGR1 via the SMAD3 MH2 domain and the EGR1 DNA-binding domain; SMAD3 modulates EGR1 occupancy at the LHB promoter in a species-specific manner: SMAD3 inhibits EGR1-driven human LHB transcription and reduces EGR1 promoter recruitment, while potentiating EGR1-driven murine Lhb transcription when SMAD-binding elements (SBEs) are present.","method":"Co-IP, GST pulldown, ChIP, domain-mapping mutagenesis, promoter-reporter assays with SBE swap mutants","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 — direct interaction mapped to specific domains by pulldown and mutagenesis, functional consequence demonstrated with ChIP and promoter-swap experiments, 19 citations","pmids":["20149866"],"is_preprint":false},{"year":2013,"finding":"Genome-wide EGR1 ChIP-seq in APP23 Alzheimer's disease model mouse brains identifies EGR1 binding near genes for synaptic plasticity (Arc, Grin1, Syn2, Vamp2, Stx6) and AD-related genes (Picalm, Psen2, App); EGR1 binding correlates with activating chromatin marks; conditions that upregulate Egr1 (spatial memory task) also increase expression of these targets.","method":"ChIP-seq, quantitative ChIP-PCR, behavioral testing, protein expression analysis in APP23 vs. wild-type mice","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 — genome-wide binding mapped and validated, in vivo correlation with EGR1 induction, 67 citations","pmids":["24269917"],"is_preprint":false},{"year":2015,"finding":"EGR1 directly binds the proximal Per1 promoter to activate its transcription; EGR1 is itself transcriptionally activated by the CLOCK/BMAL1 heterodimer through a conserved E-box element; EGR1 regulates the amplitude of multiple core clock genes (Bmal1, Per1, Per2, Rev-erbα, Rev-erbβ) in hepatocytes.","method":"ChIP, E-box reporter assays, Egr1 knockout mice with light/feeding phase experiments, qRT-PCR","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — ChIP confirms direct Per1 promoter binding, validated in Egr1 knockout mice with circadian phenotype, 35 citations","pmids":["26471974"],"is_preprint":false},{"year":2015,"finding":"EGR1 functions as a potent repressor of MEF2 transcriptional activity; EGR1 physically interacts with MEF2A, and costamere gene expression in cardiomyocytes is dependent on EGR1 transcriptional activity.","method":"Co-IP, transcription reporter assays, siRNA knockdown of EGR1 in cardiomyocytes, bioinformatic promoter analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — physical interaction and functional repression demonstrated, single lab, 15 citations","pmids":["26011708"],"is_preprint":false},{"year":2015,"finding":"EGR1 translation is regulated by the mTORC1/4E-BP axis; 4E-BP1/2-null cells translate EGR1 mRNA more efficiently despite lower mRNA levels; mTORC1 inhibitors (rapamycin, PP242) suppress EGR1 protein without increasing mRNA; EGR1-dependent repression of adipose triglyceride lipase (ATGL) promotes fat storage.","method":"35S-methionine labeling (translation assay), 4E-BP1/2 and TSC2 genetic knockout MEFs, mTORC1 inhibitors, siRNA, adipocyte lipid accumulation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct translation assay with isotope labeling confirms post-transcriptional regulation; multiple genetic models, 25 citations","pmids":["25814662"],"is_preprint":false},{"year":2016,"finding":"EGR1 expression is mechanosensitive in tendon cells; EGR1 directly responds to mechanical signals and overexpression of EGR1 prevents downregulation of tendon-specific genes (e.g., Scx, Col1) when tension is released from 3D-engineered tendons or during tendon healing under reduced mechanical load.","method":"3D tendon organoid culture with tension release, in vivo tendon healing with reduced load, ultrasound/microbubble-mediated EGR1 overexpression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo gain-of-function with mechanically controlled conditions, single lab, 52 citations","pmids":["27820865"],"is_preprint":false},{"year":2016,"finding":"Egr-1 deficiency protects mice from renal inflammation and fibrosis; Egr1-/- mice on an adenine-rich diet show attenuated NF-κB activity, reduced cytokine/chemokine expression, and reduced TGFβ signaling and fibrotic area; in vitro, Egr-1 deficiency blunts primary tubular epithelial cell responses to TNFα and TGFβ.","method":"Egr1 knockout mice, adenine-induced TIN model, primary tubular epithelial cell cultures with cytokine treatment, NF-κB activity assays","journal":"Journal of molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — in vivo knockout model with mechanistic in vitro validation, multiple signaling pathway readouts, 81 citations","pmids":["26960759"],"is_preprint":false},{"year":2018,"finding":"ER stress activates EGR1 transcription via a SRC-RAS-RAF-MEK-ERK cascade leading to ELK1 phosphorylation; ELK1 and SRF are constitutively bound to the EGR1 promoter, but phospho-ELK1 abundance increases upon ER stress; ELK1 knockdown completely blocks ER stress-induced EGR1 mRNA increase.","method":"siRNA knockdown of ELK1 and SRF, ERK pathway inhibitors, ChIP for promoter occupancy of phospho-ELK1 and phospho-SRF, kinase cascade inhibitors","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms promoter occupancy changes, siRNA epistasis identifies ELK1 as required mediator, single lab","pmids":["30290239"],"is_preprint":false},{"year":2019,"finding":"EGR1 recruits TET1 to specific genomic loci to mediate DNA demethylation during postnatal brain development; EGR1 ChIP-seq shows thousands of binding sites that become hypomethylated in mature neurons; frontal cortices from Egr1 or Tet1 knockout mice share highly similar gene expression and methylation profiles.","method":"EGR1 ChIP-seq, whole-genome bisulfite sequencing, Egr1 and Tet1 knockout mice, RNA-seq, co-IP","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — genome-wide binding and methylation data, validated in two independent knockout models with parallel methylome and transcriptome analysis, 116 citations","pmids":["31467272"],"is_preprint":false},{"year":2019,"finding":"EGR1 regulates angiogenic and osteoclastogenic factors (PDGFA, TGFB1, SPP1, IL6, IL8, TGFA) in prostate cancer metastases; FN14 (TNFRSF12A) ligation drives NF-κB-independent, MEK-dependent EGR1 expression; EGR1 depletion reduces metastasis number/size, blood vessel density in metastases, and osteolytic bone lesion area.","method":"EGR1 knockdown in metastasis model (DU145/RasB1), intracardiac injection metastasis assays, histology for vascularization and osteoclasts, MEK inhibitor experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function in defined metastasis model with multiple in vivo readouts and pathway placement (MEK-dependent), 125 citations","pmids":["31312026"],"is_preprint":false},{"year":2019,"finding":"EGR1 binds the CMV viral genome upstream of the UL138 latency gene and is sufficient to promote UL138 expression; disruption of EGR1 binding upstream of UL138 prevents establishment of CMV latency in CD34+ hematopoietic progenitor cells; EGR1 is induced via MEK/ERK downstream of EGFR signaling and is important for hematopoietic stemness.","method":"EGR1 ChIP on viral genome, site-directed mutagenesis of EGR1 binding sites, CD34+ HPC infection/latency assays, MEK/ERK/PI3K inhibition","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — direct ChIP on viral genome plus functional mutagenesis of binding site with defined latency phenotype, 60 citations","pmids":["31725811"],"is_preprint":false},{"year":2019,"finding":"MIR2052HG lncRNA interacts with EGR1 protein and facilitates EGR1 recruitment to the LMTK3 promoter; EGR1 is required for LMTK3 transcription, which sustains ERα levels in breast cancer cells.","method":"RNA-binding protein immunoprecipitation (RIP), ChIP, RNA-DNA dual FISH, luciferase reporter assays","journal":"Breast cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — RIP and ChIP confirm EGR1-RNA interaction and promoter occupancy, single lab","pmids":["30944027"],"is_preprint":false},{"year":2019,"finding":"Fasting and glucose restriction activate EGR1 via regulation of PKA and AMPK pathways; EGR1 functions as the mammalian ortholog of yeast Msn2/4 stress-resistance transcription factors; EGR1 activates cardioprotective peptides ANP and BNP, contributing to protection against doxorubicin toxicity.","method":"Fasting/glucose restriction experiments in mice, PKA and AMPK pharmacological manipulation, cardiac gene expression analysis, doxorubicin toxicity assays","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 — pathway placement via pharmacological manipulation and dietary intervention, functional phenotype (cardioprotection), single lab","pmids":["28358805"],"is_preprint":false},{"year":2021,"finding":"DNA-PKcs phosphorylates EGR1 at serine 301; this phosphorylation stabilizes EGR1 by preventing proteasomal degradation; S301A mutation (via CRISPR-Cas9) reduces EGR1 protein levels and decreases EGR1-dependent IL-2 transcription in activated T cells.","method":"Quantitative phosphoproteomic screen in T cells, DNA-PKcs inhibitor (NU7441) and shRNA knockdown, CRISPR-Cas9 S301A knockin, proteasome inhibitor rescue, IL-2 reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — phosphosite identified by mass spectrometry, validated by CRISPR knockin mutagenesis, functional consequence on protein stability and target gene transcription, 18 citations","pmids":["34562454"],"is_preprint":false},{"year":2019,"finding":"RAF-induced oncogenic signaling activates EGR1 transcription via the MEK-ERK MAPK pathway; EGR1 in turn regulates p15 (CDKN2B) and p21 (CDKN1A) expression, which are redundantly required for B-RAF-V600E-induced proliferative arrest (senescence) in human fibroblasts; glucocorticoids suppress EGR1 and thereby delay senescence entry.","method":"B-RAF-V600E expression in fibroblasts, transcriptome analysis, siRNA knockdown of EGR1, glucocorticoid treatment, MEK inhibitors","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA epistasis places EGR1 between RAF and p15/p21 in senescence pathway, single lab","pmids":["31371485"],"is_preprint":false},{"year":2021,"finding":"TET2 is recruited to the MIF promoter and interacts with EGR1 and histone deacetylases; disruption of these interactions due to TET2 downregulation favors EGR1-driven transcription of MIF and its secretion from monocytes; EGR1 drives MIF overproduction in the absence of TET2.","method":"ChIP for TET2 at MIF promoter, co-IP of TET2/EGR1/HDAC complex, TET2 knockdown and knockout models, MIF secretion ELISA","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and ChIP demonstrate complex, loss-of-function validates EGR1-driven MIF transcription, single lab","pmids":["35115654"],"is_preprint":false},{"year":2022,"finding":"EGR1 directly binds the SOX9 gene promoter in renal tubular cells to activate SOX9 expression; EGR1 induction in early AKI promotes SOX9+ progenitor cell proliferation via the Wnt/β-catenin pathway; Egr1 knockout mice show aggravated AKI severity.","method":"ChIP assay, dual-luciferase reporter assay, RNA-seq, Egr1 knockout mice in IRI and nephrotoxic AKI models, immunofluorescence","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — ChIP and reporter assay confirm direct SOX9 promoter binding, validated in two Egr1 knockout AKI models, 58 citations","pmids":["35910788"],"is_preprint":false},{"year":2023,"finding":"Nuclear PD-L1 facilitates p-STAT3 binding to the EGR1 promoter, activating EGR1-mediated angiogenesis; HDAC2 inhibition restores PD-L1 acetylation and blocks its nuclear translocation, thereby attenuating EGR1-driven tumor angiogenesis.","method":"ChIP for p-STAT3 at EGR1 promoter, nPD-L1-deficient cell lines, in vitro and in vivo angiogenesis assays, HDAC2 inhibitor treatment","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms mechanism of EGR1 activation, functional in vivo angiogenesis rescue experiments, single lab","pmids":["36977660"],"is_preprint":false},{"year":2023,"finding":"EGR1 directly binds the SNAI2 promoter and recruits p300/CBP as a coactivator to drive SNAI2 transcription, thereby promoting EMT and invasion in pancreatic cancer; co-IP confirms EGR1-p300/CBP interaction.","method":"ChIP-qPCR for EGR1 at SNAI2 promoter, co-IP of EGR1 and p300/CBP, dual-luciferase reporter assay, transwell migration/invasion assays, in vivo liver metastasis model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and co-IP define direct binding and co-activator interaction, functional in vivo metastasis validation, single lab","pmids":["36932397"],"is_preprint":false},{"year":2024,"finding":"EGR1 directly binds the PFKL promoter and represses PFKL expression, thereby suppressing aerobic glycolysis (Warburg effect) in hepatocellular carcinoma; EGR1 overexpression inhibits HCC xenograft growth and sensitizes cells to sorafenib.","method":"ChIP for EGR1 at PFKL promoter, dual-luciferase reporter assay, EGR1 overexpression/KO in HCC cell lines and xenografts, human hepatoma organoids, glycolysis assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay confirm direct PFKL repression, validated in multiple in vivo models, single lab","pmids":["38287371"],"is_preprint":false},{"year":2024,"finding":"Egr1 regulates regenerative senescence in the heart; in neonatal hearts, Egr1 promotes angiogenesis and cardiomyocyte proliferation during regeneration; in adult hearts, agrin-induced senescence and repair require Egr1, which is activated by the integrin-FAK-ERK-Akt1 signaling axis in cardiac fibroblasts.","method":"Proteomics, single-cell RNA sequencing, Egr1 knockout/overexpression in neonatal and adult cardiac injury models, agrin treatment, integrin-FAK-ERK-Akt1 pathway inhibition","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — multi-omic profiling combined with in vivo loss-of-function in two distinct heart regeneration models with defined pathway (integrin-FAK-ERK-Akt1), 27 citations","pmids":["39196027"],"is_preprint":false},{"year":2007,"finding":"Egr1 haploinsufficiency cooperates with ENU-induced mutations to cause myeloproliferative disease and T-cell lymphomas in mice at increased rates; biallelic Egr1 mutations were not observed in MPDs from Egr1+/- mice, supporting a haploinsufficiency tumor suppressor role for EGR1 in myeloid malignancies associated with del(5q).","method":"Egr1 heterozygous and null mice treated with ENU, disease characterization by blood counts, flow cytometry, histopathology","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with defined phenotype and haploinsufficiency mechanism, 173 citations","pmids":["17420284"],"is_preprint":false},{"year":2008,"finding":"APE1/Ref-1 acetylation is required for EGR1-dependent PTEN gene activation; acetylated APE1 enhances binding to transcriptional complexes at the PTEN promoter; APE1-dependent PTEN expression requires EGR1, as shown by ectopic EGR1 expression in APE1-downregulated cells.","method":"APE1 siRNA knockdown, ectopic EGR1 expression, APE1 acetylation assays, PTEN expression analysis, HDAC inhibitor experiments","journal":"Free radical research","confidence":"Medium","confidence_rationale":"Tier 2 — functional epistasis between APE1 acetylation and EGR1 in PTEN transcription, single lab","pmids":["18324520"],"is_preprint":false},{"year":2019,"finding":"EGR1 directly transactivates the EGR1 splicing isoform; a newly identified EGR1 splicing isoform lacks part of the N-terminal activation domain, can enter the nucleus, but is unable to fully activate transcription compared to canonical EGR1.","method":"Identification of splice isoform by RT-PCR/sequencing, nuclear localization by immunofluorescence, transcriptional activation reporter assays","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single paper, partial functional characterization of isoform","pmids":["30925677"],"is_preprint":false},{"year":2018,"finding":"EGR1/EZH2/HDAC9 form a repressor complex that maintains high H3K27-Me3 at the EBF3 promoter to silence EBF3 in nasopharyngeal carcinoma; EGR1 is a component of this epigenetic silencing complex.","method":"Co-IP, ChIP for H3K27-Me3 and complex components at EBF3 promoter, rescue experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and ChIP identify EGR1 as part of repressor complex, single lab","pmids":["34906623"],"is_preprint":false},{"year":2021,"finding":"EGR1 directly binds the GADD45A promoter to activate its transcription in thyroid carcinoma cells treated with non-thermal plasma-activated medium; EGR1/GADD45α signaling mediates ROS-induced apoptotic cell death.","method":"ChIP for EGR1 at GADD45A promoter, EGR1 overexpression/siRNA, ROS scavengers, xenograft tumor models","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms direct GADD45A promoter binding, validated in xenograft models, single lab","pmids":["33477921"],"is_preprint":false},{"year":2021,"finding":"EGR1 upregulates expression of MYC and E2F pathway genes through the CBP/p300/H3K27ac/BRD4 axis in DLBCL, while repressing type I IFN pathway genes through interaction with the corepressor NAB2; EGR1 inhibition synergizes with BRD4 inhibitor JQ1 or lenalidomide in ABC DLBCL.","method":"EGR1 knockdown (genetic and pharmacologic), ChIP for H3K27ac and BRD4, co-IP with NAB2, xenograft models, combination drug assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and co-IP define mechanistic axes, functional validation in xenografts, single lab","pmids":["33980611"],"is_preprint":false}],"current_model":"EGR1 is a zinc-finger transcription factor that binds the consensus sequence CGCCCCCGC in a zinc-dependent manner; it is rapidly induced downstream of diverse growth factor and stress signals via the MAPK/ERK and PKC pathways, acts as both a transcriptional activator (of LHβ, PTEN, TAp73, heparanase, Per1, SOX9, DUSP4, and others) and repressor (of calsequestrin-2, 4E-BP1, PFKL), recruits co-activators such as p300/CBP and co-repressors NAB1/NAB2, is post-translationally regulated by phosphorylation (Akt at S350/T309, DNA-PKcs at S301 for stability) and sumoylation (ARF/Ubc9), epigenetically programs the brain methylome by recruiting TET1 for DNA demethylation, and orchestrates context-dependent cellular programs including reproductive axis control, synaptic plasticity, angiogenesis, fibrosis, autophagy, senescence, and cancer progression/suppression."},"narrative":{"teleology":[{"year":1988,"claim":"Identification of EGR1 as an immediate-early zinc-finger transcription factor that binds CGCCCCCGC established the gene's fundamental molecular identity and DNA-binding mechanism.","evidence":"cDNA cloning, zinc-dependent in vitro DNA binding, nuclear localization by immunocytochemistry in stimulated cells","pmids":["3127059","2109185"],"confidence":"High","gaps":["Three-dimensional structure of EGR1 zinc-finger/DNA complex not yet resolved at that time","Post-translational modifications beyond phosphorylation uncharacterized"]},{"year":1995,"claim":"Discovery of the NAB1/NAB2 corepressor system revealed that EGR1 transcriptional output is actively tuned by dedicated repressors binding the R1 domain, explaining how the same factor can activate or dampen gene expression.","evidence":"Yeast two-hybrid identification of NAB1, transcriptional reporter assays for NAB1 and NAB2, domain mapping of NCD2 repression domain","pmids":["7624335","8668170","9418898"],"confidence":"High","gaps":["Structural basis of NAB–R1 interaction unknown","Genome-wide extent of NAB-dependent repression not mapped"]},{"year":1996,"claim":"Egr1-knockout mouse phenotypes—female infertility from LHβ deficiency and reduced GH/body size—demonstrated that EGR1 is essential in vivo for pituitary-gonadal axis function and placed EGR1 as a direct transcriptional activator of LHβ through cooperation with SF-1 and Ptx1.","evidence":"Two independent Egr1-null mouse lines, LHβ promoter mutagenesis, co-IP/GST pulldown of EGR1–SF-1–Ptx1 interactions","pmids":["8703054","9440815","10082522"],"confidence":"High","gaps":["Mechanism of species-specific regulation of LHβ by SMAD3/EGR1 not fully resolved","EGR1 targets beyond LHβ in gonadotropes not catalogued"]},{"year":2001,"claim":"Evidence that EGR1 is required for prostate cancer progression from PIN to invasive carcinoma—but dispensable for tumor initiation—established EGR1 as a context-dependent oncogene that regulates the invasive transition, partly through direct control of cyclin D2, p19INK4d, and Fas.","evidence":"Egr1-null mice crossed to two transgenic prostate cancer models; ChIP and microarray identifying direct targets in prostate cancer cells","pmids":["11135623","12556466"],"confidence":"High","gaps":["Whether EGR1 pro-tumorigenic role generalizes beyond prostate cancer models unclear at this stage","Mechanism of EGR1-dependent invasive switch not fully delineated"]},{"year":2003,"claim":"Multiple lines of evidence placed EGR1 at the convergence of MAPK/ERK, PKC, PI3K, and AMPK signaling, establishing it as a signal-integration node that translates kinase cascades into transcriptional programs for angiogenesis (FGF-2), autophagy (LC3B, Atg4B), and metabolic control (DUSP4-mediated gluconeogenesis inhibition).","evidence":"DNAzyme knockdown and Egr1-KO Matrigel angiogenesis assays; ChIP on LC3B promoter with in vivo Egr1-KO emphysema protection; ChIP on DUSP4 promoter with siRNA epistasis in hepatocytes; EP4-PI3K-ERK pathway dissection","pmids":["12872165","18836406","16849326","12566441"],"confidence":"High","gaps":["How EGR1 selects among different target gene programs in different cell types remains unclear","Relative contribution of each upstream pathway in physiological contexts not quantified"]},{"year":2005,"claim":"In vivo studies in brain established that EGR1 mediates glucocorticoid-MAPK-driven contextual fear conditioning and is required for synaptic potentiation in the anterior cingulate cortex during persistent (but not acute) inflammatory pain, defining EGR1 as a neuronal plasticity effector.","evidence":"Egr1-KO behavioral and electrophysiological phenotypes; brain-specific GR-KO with hippocampal MAPK inhibitor infusions","pmids":["15629414","15834420"],"confidence":"High","gaps":["Precise downstream transcriptional targets mediating ACC plasticity not identified at that point","Whether EGR1's role in pain is cell-type specific within ACC unknown"]},{"year":2006,"claim":"Identification of EGR1 as a MAPK-dependent HGF/Snail pathway activator linked EGR1 to epithelial-mesenchymal transition; a Snail-EGR1 negative feedback loop was defined, and EGR1's role in EMT was later reinforced by its activation of SNAI2 via p300/CBP recruitment.","evidence":"shRNA knockdown, ChIP/EMSA for Snail and EGR1 reciprocal promoter binding; ChIP-qPCR and co-IP of EGR1–p300/CBP at SNAI2 promoter with in vivo metastasis validation","pmids":["16858414","36932397"],"confidence":"High","gaps":["Whether EGR1 drives EMT through Snail/SNAI2 in non-cancer physiological contexts unknown","Relative contribution of NAB-mediated repression versus p300/CBP activation at EMT gene promoters not resolved"]},{"year":2008,"claim":"An Akt–EGR1–ARF–PTEN feedback axis was defined: Akt phosphorylates EGR1 at S350/T309, promoting ARF/Ubc9-mediated sumoylation at K272, which is required for PTEN transactivation; separately, DNA-PKcs phosphorylation at S301 was shown to stabilize EGR1 protein by blocking proteasomal degradation.","evidence":"Site-directed mutagenesis of phospho- and SUMO-sites, ARF-KO mice, CRISPR-Cas9 S301A knockin in T cells, phosphoproteomics","pmids":["19057511","34562454"],"confidence":"High","gaps":["Whether additional kinases phosphorylate EGR1 at other sites is not comprehensively mapped","Interplay between sumoylation and S301 phosphorylation not tested"]},{"year":2007,"claim":"Egr1 haploinsufficiency cooperated with secondary mutations to cause myeloproliferative disease in mice without requiring biallelic loss, establishing a haploinsufficient tumor-suppressor role consistent with EGR1's location in the commonly deleted 5q region in myeloid malignancies.","evidence":"ENU mutagenesis in Egr1+/− mice with disease characterization by flow cytometry and histopathology","pmids":["17420284"],"confidence":"High","gaps":["Specific EGR1 target genes mediating myeloid tumor suppression not identified","Whether haploinsufficiency mechanism applies to human del(5q) MDS not directly tested"]},{"year":2015,"claim":"EGR1 was integrated into the circadian clock: CLOCK/BMAL1 activate EGR1 via an E-box, and EGR1 in turn directly binds the Per1 promoter and modulates amplitude of multiple core clock genes, placing EGR1 as a clock output effector.","evidence":"ChIP on Per1 promoter, E-box reporter assays, Egr1-KO mice with circadian light/feeding experiments","pmids":["26471974"],"confidence":"High","gaps":["Whether EGR1 functions as a core clock component or peripheral modulator not settled","Clock-dependent EGR1 targets beyond Per1 not genome-wide mapped"]},{"year":2019,"claim":"Genome-wide studies revealed that EGR1 recruits TET1 to catalyze DNA demethylation at thousands of loci during postnatal brain maturation; Egr1-KO and Tet1-KO frontal cortices share highly overlapping methylation and expression changes, establishing EGR1 as an epigenetic programmer of the neuronal methylome.","evidence":"EGR1 ChIP-seq, whole-genome bisulfite sequencing, RNA-seq in Egr1 and Tet1 KO frontal cortices, co-IP of EGR1–TET1","pmids":["31467272"],"confidence":"High","gaps":["Whether EGR1-TET1 interaction is direct or requires bridging factors not resolved at structural level","Whether EGR1 recruits TET1 outside the brain not established"]},{"year":2024,"claim":"Integration of proteomics and scRNA-seq in cardiac injury models showed EGR1 orchestrates regenerative senescence: promoting neonatal cardiac angiogenesis and cardiomyocyte proliferation, and mediating agrin-induced senescence in adult hearts via an integrin–FAK–ERK–Akt1 axis in cardiac fibroblasts.","evidence":"Proteomics and scRNA-seq in neonatal/adult heart injury; Egr1-KO/overexpression with agrin treatment; integrin-FAK-ERK-Akt1 pathway inhibition","pmids":["39196027"],"confidence":"High","gaps":["Whether EGR1-driven regenerative senescence is conserved in human hearts unknown","Direct transcriptional targets mediating the senescence-to-regeneration switch not catalogued"]},{"year":null,"claim":"A systematic understanding of how EGR1 selects between its activator and repressor functions at different loci—integrating cofactor recruitment (NAB1/2 vs. p300/CBP), post-translational modification state, and chromatin context—remains incomplete.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No genome-wide map of EGR1 cofactor occupancy distinguishing activator vs. repressor modes","Structural basis of EGR1–NAB vs. EGR1–p300 selectivity unresolved","Comprehensive catalog of cell-type-specific EGR1 target gene programs lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,15,22,28,35]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,11,13,15,19,20,22,24,29,43,45,46,53]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,50]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,11,15,19,20,24,29,43,45,46,53]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,18,21,34,41,47]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[35,51]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[19,52]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11,36,48]}],"complexes":["EGR1/NAB1 repressor complex","EGR1/NAB2 repressor complex","EGR1/EZH2/HDAC9 silencing complex"],"partners":["NAB1","NAB2","SF-1","SMAD3","TET1","EP300","MEF2A","EZH2"],"other_free_text":[]},"mechanistic_narrative":"EGR1 is a zinc-finger immediate-early transcription factor that integrates diverse extracellular signals—growth factors, stress, mechanical load, and metabolic cues—into context-dependent transcriptional programs governing reproduction, angiogenesis, synaptic plasticity, senescence, autophagy, and fibrosis. It binds the GC-rich consensus CGCCCCCGC through three zinc fingers in a zinc-dependent manner and acts as both a transcriptional activator (recruiting p300/CBP to targets such as LHβ, PTEN, SOX9, SNAI2, LC3B, Per1, and DUSP4) and a repressor (silencing calsequestrin-2, 4E-BP1, and PFKL, in part through NAB1/NAB2 corepressors or EZH2/HDAC complexes) [PMID:3127059, PMID:7624335, PMID:8703054, PMID:18836406, PMID:36932397, PMID:38287371, PMID:34906623]. EGR1 is induced primarily via the MEK/ERK–ELK1/SRF axis and is post-translationally regulated by Akt-dependent phosphorylation/ARF-mediated sumoylation that controls PTEN transactivation, and by DNA-PKcs phosphorylation at S301 that prevents proteasomal degradation [PMID:19057511, PMID:34562454]. During postnatal brain development EGR1 recruits TET1 to catalyze DNA demethylation at thousands of loci, epigenetically programming neuronal gene expression, while in hematopoietic cells EGR1 haploinsufficiency cooperates with secondary mutations to promote myeloproliferative disease, consistent with a tumor-suppressor role at chromosome 5q [PMID:31467272, PMID:17420284]."},"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":"8703054","id":"PMC_8703054","title":"Luteinizing hormone deficiency and female infertility in mice lacking the transcription factor NGFI-A (Egr-1).","date":"1996","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8703054","citation_count":425,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15556287","id":"PMC_15556287","title":"A gene for neuronal plasticity in the mammalian brain: Zif268/Egr-1/NGFI-A/Krox-24/TIS8/ZENK?","date":"2004","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/15556287","citation_count":312,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28321184","id":"PMC_28321184","title":"The Role of Early Growth Response 1 (EGR1) in Brain Plasticity and Neuropsychiatric Disorders.","date":"2017","source":"Frontiers in behavioral neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28321184","citation_count":280,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9440815","id":"PMC_9440815","title":"Multiple pituitary and ovarian defects in Krox-24 (NGFI-A, Egr-1)-targeted mice.","date":"1998","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/9440815","citation_count":232,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33842351","id":"PMC_33842351","title":"The Role of the Transcription Factor EGR1 in Cancer.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33842351","citation_count":210,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15834420","id":"PMC_15834420","title":"The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids.","date":"2005","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15834420","citation_count":195,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11135623","id":"PMC_11135623","title":"Impaired prostate tumorigenesis in Egr1-deficient mice.","date":"2001","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11135623","citation_count":150,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24484699","id":"PMC_24484699","title":"The transcription factor Zif268/Egr1, brain plasticity, and memory.","date":"2014","source":"Progress in molecular biology and translational science","url":"https://pubmed.ncbi.nlm.nih.gov/24484699","citation_count":149,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12556466","id":"PMC_12556466","title":"Egr1 promotes growth and survival of prostate cancer cells. 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synergistic transcriptional activation by EGR1 and steroidogenic factor-1 (SF-1), as demonstrated by LH-β deficiency in NGFI-A knockout mice and promoter analysis.\",\n      \"method\": \"Knockout mouse model, promoter binding site mutagenesis, mRNA analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic KO with defined molecular phenotype plus promoter mutagenesis, replicated by independent lab (PMID:9440815)\",\n      \"pmids\": [\"8703054\", \"9440815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"NAB1, a corepressor, physically interacts with the EGR1 R1 domain and actively represses EGR1-mediated transcription via its NCD2 domain; NAB1 does not block EGR1 DNA binding or nuclear localization but functions as a direct transcriptional repressor tethered through EGR1.\",\n      \"method\": \"Domain mapping by deletion mutagenesis, tethered repression assays, reporter gene assays, nuclear localization experiments\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution-level mutagenesis and functional reporter assays with multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"9418898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EGR1 directly regulates transcription of cyclin D2, p19INK4d, and Fas (CD95) in prostate cancer cells, promoting proliferation and survival; EGR1 binding to these gene promoters was confirmed by chromatin immunoprecipitation.\",\n      \"method\": \"Affymetrix microarray, real-time PCR, immunoblot, chromatin immunoprecipitation (ChIP), EGR1 antisense oligonucleotides\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, KD, expression) in single study\",\n      \"pmids\": [\"12556466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EGR1 directly binds the heparanase (HPSE) gene promoter in vivo and activates heparanase transcription in epithelial tumor cells via two functional EGR1 binding sites within a 280 bp critical promoter region; EGR1 can also repress heparanase in melanoma cells depending on tumor context.\",\n      \"method\": \"Chromatin immunoprecipitation, electrophoretic mobility shift assay (EMSA), site-directed mutagenesis, luciferase reporter assay, EGR1 expression vector transactivation\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assays, EMSA, site-directed mutagenesis, and ChIP in vivo, multiple cell lines\",\n      \"pmids\": [\"16093249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Glucocorticoid receptor activation in the hippocampus signals through the MAPK pathway to increase EGR1 mRNA and protein expression; MAPK pathway inhibition within hippocampus abolishes glucocorticoid-enhanced contextual fear conditioning, placing EGR1 downstream of glucocorticoid receptor-MAPK signaling in stress-related memory.\",\n      \"method\": \"Brain-specific glucocorticoid receptor knockout mice, in vivo MAPK inhibition, in vitro cell lines, behavioral assays\",\n      \"journal\": \"Nature Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO + pharmacological inhibition + behavioral phenotype, in vivo and in vitro\",\n      \"pmids\": [\"15834420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EGR1 is induced by AMPK activation and directly binds the DUSP4 promoter to activate its transcription, thereby inhibiting hepatic gluconeogenesis; siRNA depletion of EGR1 partially abrogates AICAR-mediated inhibition of PEPCK expression and glucose production.\",\n      \"method\": \"Reporter gene assay, real-time PCR, ChIP, siRNA knockdown, constitutively active AMPK expression\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirming direct promoter binding plus siRNA epistasis with functional metabolic readout\",\n      \"pmids\": [\"16849326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EGR1 has five functional binding sites in the TP73 P1 promoter and directly upregulates TAp73 transcription in response to genotoxic stress; EGR1, TAp73, and p53 form mutually reinforcing transcriptional feedback loops via non-consensus binding sites in each other's promoters to sustain apoptosis.\",\n      \"method\": \"Promoter reporter assays, EGR1 binding site mutagenesis, in vivo induction assays in Egr1-deficient mice\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — promoter mutagenesis, reporter assays, and in vivo genetic validation\",\n      \"pmids\": [\"16990849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EGR1 is sumoylated by the ARF/Ubc9/SUMO system at K272 in its repressor domain; this sumoylation depends on phosphorylation of EGR1 at S350 and T309 by Akt, which promotes interaction of EGR1 with ARF, and EGR1 sumoylation is required for PTEN transactivation in vivo.\",\n      \"method\": \"In vivo sumoylation assay, phosphorylation site mutagenesis, co-immunoprecipitation, ARF knockout mice, PTEN expression analysis\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — site-directed mutagenesis of PTM sites, Co-IP, genetic KO validation in mice\",\n      \"pmids\": [\"19057511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EGR1 acts as a transcriptional repressor at the calsequestrin 2 (CSQ2) promoter; ChIP demonstrated direct EGR1 binding to the CSQ2 promoter, and overexpression of EGR1 reduced CSQ expression and impaired calcium release from ryanodine-sensitive stores, while an EGR1 (I293F) DNA-binding mutant had even stronger repressive effects.\",\n      \"method\": \"Chromatin immunoprecipitation, immunoblotting, EGR1 overexpression (wild-type and mutant), microspectrofluorimetry for calcium dynamics\",\n      \"journal\": \"Cardiovascular Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP, site mutant, and functional calcium assay in same study\",\n      \"pmids\": [\"19103607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ERK pathway inhibitor PMA and GM-CSF/p38 activation induce Egr-1 expression, which in turn suppresses 4E-BP1 promoter activity; dominant-negative Egr mutant (ZnEgr) blocks this repression, identifying 4E-BP1 as a direct transcriptional target of EGR1.\",\n      \"method\": \"Dominant-negative EGR mutant, reporter gene assay, ERK/p38 pathway pharmacological inhibition\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dominant-negative mutant and reporter assay, single lab\",\n      \"pmids\": [\"12618431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EGR1 regulates coordinated expression of numerous EGFR pathway target genes upon UV irradiation; ChIP-on-chip identified 288 EGR1-bound promoters including FasL, MAX, and RRAS2; siRNA knockdown confirmed EGR1-dependent apoptotic gene regulation and cell death.\",\n      \"method\": \"ChIP-on-chip, conventional ChIP, qRT-PCR, siRNA knockdown, apoptosis assays\",\n      \"journal\": \"Genome Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP plus siRNA functional validation with multiple orthogonal methods\",\n      \"pmids\": [\"19032775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Upon phorbol ester stimulation, phosphorylation of ELK1 and CREB via MEK1/2 and p38 kinases is required for EGR1 gene activation; subsequently NAB1 and NAB2 bind the EGR1 promoter to terminate transcription; SP1 and EGR1 do not directly compete for promoter binding.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), quantitative mapping of promoter occupancy, histone acetylation analysis\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct ChIP mapping of multiple factors at EGR1 promoter with temporal resolution\",\n      \"pmids\": [\"20582451\"],\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; this interaction modulates EGR1 recruitment to the LHB/Lhb promoter in a species-specific manner dependent on the presence of SMAD-binding elements (SBEs) in the promoter.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, ChIP, promoter reporter assays, promoter mutagenesis\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP with domain mapping plus ChIP and functional reporter assays\",\n      \"pmids\": [\"20149866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EGR1 binding sites in the brain (identified by ChIP-seq) are associated with activating chromatin marks; EGR1 target genes include synaptic plasticity genes Arc, Grin1, Syn2, Vamp2, Stx6 and AD-related genes Picalm, Psen2, App; conditions that upregulate Egr1 in brain (spatial memory test) also increase expression of these targets.\",\n      \"method\": \"ChIP-seq, gene expression profiling, in vivo genetic validation in APP23 mice\",\n      \"journal\": \"Neurobiology of Disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq with in vivo functional validation\",\n      \"pmids\": [\"24269917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EGR1 directly binds the Per1 promoter proximal region to activate its transcription; EGR1 itself is transactivated by the CLOCK/BMAL1 heterodimer through a conserved E-box element, and EGR1 regulates amplitude of hepatic clock gene expression (Bmal1, Per1, Per2, Rev-erbα, Rev-erbβ).\",\n      \"method\": \"ChIP, luciferase reporter assay, Egr1-deficient mice, circadian gene expression analysis\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirming direct Per1 promoter binding plus KO mice with functional circadian phenotype\",\n      \"pmids\": [\"26471974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EGR1 mRNA translation is regulated by the mTORC1/4E-BP1/2 axis; 4E-BP1/2 knockout cells translate EGR1 mRNA more efficiently, leading to higher EGR1 protein and suppressed adipose triglyceride lipase (ATGL) expression, promoting fat storage.\",\n      \"method\": \"35S-labeling translational assay, genetic ablation (TSC2-/-, 4E-BP1/2-/- MEFs), mTORC1 inhibitors, EGR1 knockdown\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — metabolic labeling directly measuring translation rate, combined with genetic models\",\n      \"pmids\": [\"25814662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EGR1 physically interacts with MEF2A and potently represses MEF2 transcriptional activity in cardiomyocytes; this interaction regulates expression of costamere genes.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assay, EGR1 knockdown in cardiomyocytes\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus functional reporter assay, single lab\",\n      \"pmids\": [\"26011708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EGR1 expression is sensitive to mechanical signals in tendon cells; EGR1 overexpression prevents downregulation of tendon gene expression when tension is released in 3D-engineered tendons and during tendon healing under reduced load conditions.\",\n      \"method\": \"3D-engineered tendon model with tension manipulation, EGR1 overexpression via ultrasound/microbubble delivery, in vivo tendon healing model\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro tension model plus in vivo overexpression with gene expression readout, single lab\",\n      \"pmids\": [\"27820865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EGR1 interacts with TBX2 protein; this interaction inhibits EGR1-dependent transcription of p21, PTEN, NDRG1, and CST6, and EGR1 activates BAX and dephosphorylated BAD to induce apoptosis via the intrinsic pathway in rhabdomyosarcoma.\",\n      \"method\": \"Co-immunoprecipitation, EGR1 overexpression, reporter gene assays, apoptosis assays (caspase activation), EGR1 shRNA knockdown\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus functional assays, single lab\",\n      \"pmids\": [\"29719592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EGR1 interacts with p300/CBP co-activator and directly binds the SNAI2 promoter to activate its transcription, promoting EMT in pancreatic cancer; this was confirmed by ChIP-qPCR, dual-luciferase reporter assay, and co-immunoprecipitation.\",\n      \"method\": \"ChIP-qPCR, dual-luciferase reporter assay, co-immunoprecipitation, transwell invasion assay, xenograft model\",\n      \"journal\": \"Journal of Translational Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirming direct promoter binding plus Co-IP for protein interaction plus in vivo validation\",\n      \"pmids\": [\"36932397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 recruits the DNA demethylase TET1 to thousands of EGR1 binding sites in the brain, resulting in hypomethylation specifically in mature neurons; EGR1 and TET1 co-regulate overlapping sets of genes with similar methylation profiles in frontal cortex.\",\n      \"method\": \"EGR1 ChIP-seq, DNA methylation profiling, Egr1 and Tet1 knockout mouse comparison, gene expression analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq plus methylation profiling plus two genetic KO models with convergent evidence\",\n      \"pmids\": [\"31467272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 binds the CMV viral genome upstream of the UL138 latency gene and is sufficient to promote UL138 expression; disruption of the EGR1 binding site upstream of UL138 prevents establishment of CMV latency in CD34+ hematopoietic progenitor cells.\",\n      \"method\": \"ChIP demonstrating EGR1 binding to viral genome, EGR1 binding site mutagenesis, latency assay in CD34+ HPCs\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus binding site mutagenesis with defined functional outcome (latency establishment)\",\n      \"pmids\": [\"31725811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MIR2052HG lncRNA interacts with EGR1 and facilitates its recruitment to the LMTK3 promoter, thereby driving LMTK3 transcription; demonstrated by RNA-binding protein immunoprecipitation and ChIP assays.\",\n      \"method\": \"RNA-binding protein immunoprecipitation, chromatin immunoprecipitation (ChIP), RNA-DNA dual FISH, luciferase assays\",\n      \"journal\": \"Breast Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP plus ChIP mapping EGR1 to LMTK3 promoter, single lab\",\n      \"pmids\": [\"30944027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-146a directly targets EGR1 mRNA (validated by luciferase assay); EGR1 upregulation in miR-146a-deficient B-cell tumors drives transcriptional targets that promote B-cell oncogenesis.\",\n      \"method\": \"Luciferase reporter assay for direct miRNA targeting, high-throughput sequencing, miR-146a overexpression\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — luciferase validation of direct targeting plus transcriptomic evidence, single lab\",\n      \"pmids\": [\"25906746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DNA-PKcs phosphorylates EGR1 at serine 301; this phosphorylation stabilizes EGR1 protein by preventing proteasomal degradation, and mutation of S301 to alanine reduces EGR1 protein levels and decreases EGR1-dependent IL-2 transcription in activated T cells.\",\n      \"method\": \"Quantitative phosphoproteomic screen, DNA-PKcs inhibitor (NU7441), shRNA knockdown, CRISPR-Cas9 S301A knock-in, proteasome inhibition assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — phosphoproteomic identification plus site-directed CRISPR knock-in mutagenesis plus functional transcriptional readout\",\n      \"pmids\": [\"34562454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGR1 upregulates MYC and E2F pathway genes through the CBP/p300/H3K27ac/BRD4 axis, while repressing type I IFN pathway genes through interaction with the corepressor NAB2 in diffuse large B-cell lymphoma.\",\n      \"method\": \"Genomic analysis, ChIP for histone marks, co-immunoprecipitation with NAB2, genetic and pharmacologic EGR1 inhibition, xenograft models\",\n      \"journal\": \"Molecular Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP/histone marks plus Co-IP plus KO/pharmacologic inhibition, single lab\",\n      \"pmids\": [\"33980611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EGR1 directly binds the SOX9 promoter to upregulate SOX9 expression in renal tubular epithelial cells after AKI, thereby promoting SOX9+ cell proliferation via the Wnt/β-catenin pathway; Egr1 genetic inhibition aggravates AKI severity.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, RNA-seq, Egr1 knockout mice, AKI (IRI and FA) models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus reporter assay confirming direct promoter binding plus genetic KO with functional phenotype\",\n      \"pmids\": [\"35910788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In VEEV-infected astrocytoma cells, EGR1 induction drives expression of inflammatory genes CXCL3, CXCL8, CXCL10, TNF, and PTGS2, and also partially regulates other transcription factors (ATF3, FOS, JUN, KLF4); EGR1-dependent PTGS2 expression contributes to VEEV-induced cell death.\",\n      \"method\": \"EGR1 siRNA knockdown, Celecoxib PTGS2 inhibition, gene expression analysis, viral infection models\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA epistasis with pharmacological rescue, defined gene expression readout\",\n      \"pmids\": [\"35746681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TET2 is recruited to the MIF promoter and interacts with EGR1 and histone deacetylases in healthy monocytes; disruption of TET2 expression favors EGR1-driven transcription of MIF gene and MIF secretion.\",\n      \"method\": \"ChIP demonstrating TET2 at MIF promoter, co-immunoprecipitation of TET2 with EGR1 and HDACs, TET2 knockdown in mice and human cells\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus Co-IP establishing interaction, genetic TET2 KD with functional MIF output\",\n      \"pmids\": [\"35115654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear PD-L1 (nPD-L1) facilitates p-STAT3 binding to the EGR1 promoter, resulting in activation of EGR1-mediated angiogenesis in uveal melanoma; HDAC2 inhibition restores PD-L1 acetylation and blocks its nuclear translocation, attenuating EGR1-driven tumor angiogenesis.\",\n      \"method\": \"ChIP for p-STAT3 at EGR1 promoter, nuclear fractionation, nPD-L1-deficient cell lines, in vivo xenograft models, HDAC2 inhibitor treatment\",\n      \"journal\": \"Cell Discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus functional nPD-L1 KD, in vivo validation, single lab\",\n      \"pmids\": [\"36977660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EGR1 directly binds the PFKL promoter region to repress its expression, thereby suppressing PFKL-mediated aerobic glycolysis and hepatocellular carcinoma growth.\",\n      \"method\": \"ChIP demonstrating EGR1 binding to PFKL promoter, EGR1 overexpression/knockout, in vitro and in vivo HCC models, human organoids\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus gain/loss-of-function with metabolic phenotype, single lab\",\n      \"pmids\": [\"38287371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Egr1 regulates regenerative senescence in the heart; in cardiac fibroblasts it is activated by the integrin-FAK-ERK-Akt1 axis upon agrin stimulation, and in neonatal heart facilitates angiogenesis and cardiomyocyte proliferation; Egr1 orchestrates the senescence-associated secretory phenotype including cathepsins during heart regeneration.\",\n      \"method\": \"Proteomics, single-cell RNA sequencing, Egr1 knockout mouse models, neonatal regeneration and agrin-mediated adult cardiac repair models\",\n      \"journal\": \"Nature Cardiovascular Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-omic profiling plus genetic KO in two cardiac repair models identifying upstream pathway\",\n      \"pmids\": [\"39196027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EGR1 binds to two positive regulatory elements in the Dmrt1 proximal promoter in Sertoli cells and activates Dmrt1 transcription; DNase I footprinting and site-directed mutagenesis identified EGR1 binding sites as functionally required.\",\n      \"method\": \"DNase I footprinting, site-directed mutagenesis, luciferase reporter assay, nuclear extract binding assays\",\n      \"journal\": \"Biology of Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — footprinting plus site-directed mutagenesis plus reporter assay, single lab\",\n      \"pmids\": [\"11870074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 directly binds and transactivates the EGR1 target gene EGR1 in glucocorticoid-delayed senescence; EGR1 regulates p15 and p21 (CDKN2B and CDKN1A) expression, which are redundantly required for proliferative arrest induced by B-RAF-V600E; glucocorticoids suppress EGR1 to delay RAF-induced senescence.\",\n      \"method\": \"Transcriptome analysis, siRNA knockdown, RAF-MEK-ERK pathway analysis, senescence assays\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA epistasis with defined senescence phenotype, single lab\",\n      \"pmids\": [\"31371485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 splicing produces a shorter isoform lacking part of the N-terminal activation domain; this isoform can enter the nucleus but cannot fully activate transcription compared to canonical EGR1.\",\n      \"method\": \"Splice isoform identification and cloning, nuclear localization assay, transcriptional activity reporter assay\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional characterization of novel isoform with subcellular localization and transcriptional activity assays\",\n      \"pmids\": [\"30925677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Egr1 deficiency significantly delays the progression from prostatic intraepithelial neoplasia (PIN) to invasive carcinoma in two transgenic prostate cancer mouse models (CR2-T-Ag and TRAMP), without affecting tumor initiation or growth rate, establishing a specific role for EGR1 in tumor invasion.\",\n      \"method\": \"Egr1 knockout mice crossed with prostate cancer transgenic models, MRI, histopathology, survival analysis\",\n      \"journal\": \"Nature Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in two independent transgenic cancer models with specific mechanistic phenotype (invasion vs. initiation)\",\n      \"pmids\": [\"11135623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Egr1 knockdown in zebrafish specifically suppresses differentiation of parvalbumin- and GABA-positive amacrine cells and Islet1-positive horizontal cells in the retina, and causes prolonged ectopic expression of ptf1a, a transcription factor controlling AC and HC specification.\",\n      \"method\": \"Morpholino knockdown in zebrafish, immunohistochemistry, in situ hybridization\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown with specific cell-type differentiation phenotype and mechanistic link to ptf1a\",\n      \"pmids\": [\"23405257\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EGR1 is a zinc-finger transcription factor that is rapidly induced by diverse extracellular signals (growth factors, stress, MAPK/ERK activation) and directly binds GC-rich promoter elements to activate or repress target genes (including LH-β, PTEN, p73, heparanase, PFKL, Per1, SOX9, and many others); its activity is modulated post-translationally by Akt-dependent phosphorylation (S350/T309) promoting sumoylation, by DNA-PKcs phosphorylation (S301) stabilizing the protein against proteasomal degradation, and by interaction with co-repressors NAB1/NAB2 that terminate transcription, while it also recruits TET1 to demethylate target loci and physically cooperates with partners such as SF-1, SMAD3, p300/CBP, and MEF2A to regulate context-specific transcriptional programs in processes ranging from reproductive hormone synthesis and neuronal plasticity to tendon mechanosensing and cardiac regeneration.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"EGR1 (Egr-1) is an immediate-early response gene encoding a nuclear protein with three zinc fingers that binds the consensus sequence CGCCCCCGC in a zinc-dependent manner and functions as a transcriptional regulator.\",\n      \"method\": \"cDNA cloning, sequence analysis, cell fractionation, immunocytochemistry, in vitro DNA binding assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original characterization with multiple orthogonal methods (structural prediction, nuclear localization, zinc-dependent DNA binding in vitro), foundational paper with 1237 citations\",\n      \"pmids\": [\"3127059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The EGR1 protein is an ~80 kDa short-lived, phosphorylated nuclear protein that binds with high affinity to the sequence CGCCCCCGC in a zinc-dependent manner; identified by anti-EGR1 antiserum in serum-stimulated fibroblasts and NGF-treated PC12 cells.\",\n      \"method\": \"Antisera generation, cell fractionation, immunocytochemistry, in vitro DNA binding assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical characterization of the protein (size, phosphorylation, nuclear location, DNA binding) with multiple orthogonal methods\",\n      \"pmids\": [\"2109185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"NAB1 is a corepressor that interacts with the R1 inhibitory domain of NGFI-A/EGR1 and represses EGR1-mediated transcription; identified by yeast two-hybrid screening and shown not to affect EGR3 or NGFI-G, demonstrating specificity.\",\n      \"method\": \"Yeast two-hybrid, transcriptional reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid plus functional repression assays, replicated and extended in subsequent NAB1/NAB2 studies, 240 citations\",\n      \"pmids\": [\"7624335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NAB2, a second corepressor closely related to NAB1, interacts with the R1 domain of NGFI-A/EGR1 and Krox20 and represses their transcriptional activity; NAB2 expression is itself induced by the same stimuli (serum, NGF) that induce NGFI-A.\",\n      \"method\": \"Protein interaction assays, transcriptional reporter assays, expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional characterization with multiple assays, 328 citations\",\n      \"pmids\": [\"8668170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"EGR1 (NGFI-A) is required for luteinizing hormone beta (LH-β) transcription in pituitary gonadotropes; NGFI-A-deficient female mice are infertile due to LH-β deficiency, and a canonical NGFI-A binding site in the LH-β promoter is required for synergistic activation by NGFI-A and SF-1.\",\n      \"method\": \"Knockout mice (ES cell-derived), ovariectomy experiments, promoter-reporter assays, in situ hybridization\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mouse model combined with promoter mutagenesis, 425 citations\",\n      \"pmids\": [\"8703054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"NAB1 repression of EGR1-mediated transcription is active (not passive blockade of DNA binding or nuclear localization); the repression function maps to the NCD2 domain in the C-terminal half of NAB1 and works on heterologous activation domains when NAB1 is tethered directly to DNA.\",\n      \"method\": \"Deletion and replacement mutagenesis, tethered-repressor assays, nuclear localization assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-function mutagenesis with multiple domain-swap and tethering experiments, 97 citations\",\n      \"pmids\": [\"9418898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"EGR1 (Krox-24) deficiency in mice causes reduced body size and sterility in both sexes due to pituitary defects: somatotropes are reduced in number and GH content is decreased, while gonadotropes fail specifically to synthesize LH-β; additionally, ovarian LH receptor expression is prevented, implicating EGR1 at two levels of the pituitary-gonadal axis.\",\n      \"method\": \"Knockout mouse generation, histological analysis, RIA, immunohistochemistry, in situ hybridization\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independent Egr1 knockout allele with detailed in vivo phenotypic characterization, 232 citations\",\n      \"pmids\": [\"9440815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EGR1 is a downstream effector of GnRH signaling via PKC activation; EGR1 directly interacts with both Ptx1 and SF-1 transcription factors, and these interactions synergistically enhance LH-β promoter transcription.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, promoter-reporter assays, PKC inhibitor experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein-protein interaction demonstrated by pulldown plus functional synergy in reporter assays, 225 citations\",\n      \"pmids\": [\"10082522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EGR1 regulates transcription of multiple vascular biology genes and is induced by hemodynamic forces and growth factors in vascular smooth muscle and endothelial cells, placing EGR1 as a convergence point for vascular stress signaling.\",\n      \"method\": \"Promoter-reporter assays, EMSA, in vivo vascular injury models (review synthesizing primary experimental data)\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — synthesis of experimental data from multiple studies, pathway placement in vascular biology\",\n      \"pmids\": [\"10079243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"EGR1 protects cells against UV-induced damage; NIH3T3 cells constitutively expressing antisense Egr-1 (unable to produce Egr-1 response) grow significantly slower after UV irradiation; the Egr-1 response to UV is dependent on tyrosine kinase, protein kinase C activities, and c-Ha-Ras, and is mediated by oxidative stress rather than direct DNA damage.\",\n      \"method\": \"Antisense oligonucleotides, kinase inhibitors, cell growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined phenotypic readout and pathway dissection, single lab\",\n      \"pmids\": [\"7845671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"EGR1 is required for progression of prostate cancer from PIN to invasive carcinoma; Egr1-deficient mice in two transgenic prostate cancer models show significantly delayed progression to invasive carcinoma without affecting tumor initiation or growth rate.\",\n      \"method\": \"Egr1 knockout crossed with CR2-T-Ag and TRAMP transgenic prostate cancer models; MRI, histopathology, survival analysis\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent mouse models with in vivo loss-of-function, defined phenotypic transition point, 150 citations\",\n      \"pmids\": [\"11135623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EGR1 directly regulates transcription of cyclin D2, p19INK4d, and Fas/CD95 in prostate cancer cells; EGR1-mediated inhibition of Fas expression contributes to resistance to FasL-induced apoptosis.\",\n      \"method\": \"Affymetrix microarray, real-time PCR, immunoblot, chromatin immunoprecipitation (ChIP), antisense oligonucleotides\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP validates direct promoter binding, loss-of-function with antisense confirms target regulation, 133 citations\",\n      \"pmids\": [\"12556466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EGR1 supports FGF-dependent angiogenesis; EGR1 DNAzymes inhibit microvascular endothelial cell replication, migration, and tube formation, block Matrigel angiogenesis in mice, and suppress endothelial FGF-2 (but not VEGF) expression; Egr1-deficient mice also show impaired angiogenesis.\",\n      \"method\": \"DNAzyme knockdown, Matrigel plug assays, Egr1 knockout mice, endothelial cell functional assays (proliferation, migration, tube formation)\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent methods (DNAzyme and knockout), multiple in vitro and in vivo readouts, 322 citations\",\n      \"pmids\": [\"12872165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EGR1 mediates inhibition of 4E-BP1 expression downstream of ERK and p38 MAPK activation; a dominant-negative EGR mutant (ZnEgr) blocks PMA-induced and GM-CSF-induced repression of the 4e-bp1 promoter, showing EGR1 directly represses 4E-BP1 transcription.\",\n      \"method\": \"Dominant-negative EGR mutant, promoter-reporter assays, MAPK inhibitors, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dominant-negative approach plus promoter assays, single lab, 52 citations\",\n      \"pmids\": [\"12618431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HGF induces cell scattering through a MAPK/EGR1/Snail pathway; EGR1 is required for HGF-induced upregulation of Snail, which in turn represses E-cadherin and claudin-3; Snail also binds the EGR1 promoter establishing a negative feedback loop.\",\n      \"method\": \"shRNA knockdown, promoter-reporter assays, ChIP, EMSA, invasion assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pathway epistasis established by shRNA knockdown with defined EMT phenotype, promoter binding confirmed by ChIP/EMSA, 293 citations\",\n      \"pmids\": [\"16858414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EGR1 directly binds the heparanase gene promoter in vivo and activates heparanase transcription in multiple tumor cell lines (prostate, breast, colon adenocarcinomas) through two functional EGR1 sites; EGR1 can also repress heparanase promoter activity in melanoma cells, demonstrating cell-type-dependent dual regulation.\",\n      \"method\": \"ChIP, EMSA, site-directed mutagenesis, transactivation reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vivo ChIP combined with EMSA and mutagenesis of binding sites in multiple cell lines, 76 citations\",\n      \"pmids\": [\"16093249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EGR1 is required for behavioral responses to persistent inflammatory pain but not acute pain; Egr1 knockout mice show significantly reduced nociceptive responses to peripheral inflammation, and inflammation triggers EGR1 upregulation in the anterior cingulate cortex; synaptic potentiation by theta-burst stimulation in ACC is reduced in Egr1 knockout mice.\",\n      \"method\": \"Egr1 knockout mice, behavioral pain assays, LTP electrophysiology in ACC slices\",\n      \"journal\": \"The journal of pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout mouse with specific behavioral and electrophysiological phenotypes, 51 citations\",\n      \"pmids\": [\"15629414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The MAPK pathway and EGR1 mediate stress-related behavioral effects of glucocorticoids; glucocorticoid receptor activation increases MAPK pathway protein activity and EGR1 mRNA/protein in hippocampus; MAPK inhibition within hippocampus abolishes glucocorticoid-induced enhancement of contextual fear conditioning.\",\n      \"method\": \"Brain-specific GR knockout mice, cell lines with inducible GR, MAPK activity assays, hippocampal drug infusions, behavioral fear conditioning\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological dissection of pathway in vivo with behavioral readout, 195 citations\",\n      \"pmids\": [\"15834420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EGR1 is induced via PI3K/ERK signaling downstream of the EP4 (but not EP2) prostaglandin receptor; PGE2 stimulation of EP4 leads to phosphorylation of ERKs through PI3K and subsequent functional EGR1 protein expression.\",\n      \"method\": \"Selective EP receptor agonists, PI3K inhibitors, ERK phosphorylation assays, Western blotting for EGR1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological dissection of receptor-specific pathway, single lab, 261 citations\",\n      \"pmids\": [\"12566441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EGR1 transactivates the TP73 P1 promoter (but not P2) through five distinct EGR1-binding sites, upregulating TAp73; induction of TAp73 by genotoxic stress requires EGR1 in vivo; EGR1, p53, and p73 form an inter-regulating network with non-consensus p53-binding sites in each other's promoters creating feedback loops for sustained apoptotic signaling.\",\n      \"method\": \"Promoter-reporter assays, EMSA, ChIP, in vivo stress models (EGR1-deficient mice)\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple promoter binding sites characterized by EMSA and ChIP, validated in vivo with EGR1-deficient mice, 87 citations\",\n      \"pmids\": [\"16990849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AMPK activation induces EGR1 expression, which directly binds the DUSP4 promoter to activate DUSP4 transcription; EGR1 and DUSP4 together mediate AMPK-dependent inhibition of hepatic gluconeogenesis (repressing PEPCK and G6Pase promoter activity and expression).\",\n      \"method\": \"Transcriptional profiling, reporter assays, ChIP, siRNA knockdown, glucose production assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct binding to DUSP4 promoter; siRNA epistasis places EGR1 upstream of DUSP4 in gluconeogenesis inhibition, 68 citations\",\n      \"pmids\": [\"16849326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EGR1 is phosphorylated by Akt at S350 and T309; this phosphorylation promotes interaction of EGR1 with ARF, leading to ARF/Ubc9/SUMO-mediated sumoylation of EGR1 at K272 in its repressor domain; sumoylated EGR1 is required for PTEN transactivation in vivo—defining an Akt-EGR1-ARF-PTEN axis.\",\n      \"method\": \"Site-directed mutagenesis, co-IP, sumoylation assays, ARF knockout mice, in vivo PTEN expression analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — specific phosphorylation sites and sumoylation site identified by mutagenesis, validated in knockout mice, 115 citations\",\n      \"pmids\": [\"19057511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EGR1 directly binds the calsequestrin 2 (CSQ2) promoter and acts as a transcriptional repressor; overexpression of Egr-1 reduces CSQ expression and abolishes calcium release from CSQ-dependent ryanodine-sensitive stores, while leaving calreticulin-dependent IP3-sensitive stores unaffected; EGR1 forms a complex with NFAT3 at the CSQ2 promoter.\",\n      \"method\": \"Adenoviral overexpression, immunoblot, in vivo and in vitro ChIP, calcium imaging (fura-2), co-IP, site-directed mutagenesis (I293F)\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — ChIP confirms direct promoter binding, mutagenesis defines functional domain, calcium imaging links repression to functional consequence, 27 citations\",\n      \"pmids\": [\"19103607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Upon induction, EGR1 occupies its own gene promoter without competing with Sp1; phosphorylation of ELK1 and CREB via MEK1/2 and p38 kinases is required for EGR1 gene induction; NAB1 and NAB2 bind the EGR1 promoter to terminate transcription; histone acetylation changes accompany activation.\",\n      \"method\": \"ChIP, pharmacological kinase inhibition, quantitative promoter occupancy mapping\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative ChIP mapping of factor binding kinetics at EGR1 promoter, single lab, 32 citations\",\n      \"pmids\": [\"20582451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Egr-1 directly binds the LC3B autophagy gene promoter (with E2F-4) and activates LC3B expression in response to cigarette smoke extract (CSE); Egr-1 also activates Atg4B; Egr1-deficient mice resist cigarette smoke-induced autophagy, apoptosis, and emphysema.\",\n      \"method\": \"ChIP, siRNA knockdown, Egr1 knockout mice, HDAC activity assays, electron microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct LC3B promoter binding, validated in vivo with Egr1 knockout mice showing protection from emphysema, 389 citations\",\n      \"pmids\": [\"18836406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The transcription factors Egr1 and Egr2 have opposing roles in adipocyte differentiation: Egr1 inhibits adipogenesis (overexpression blocks, knockdown potentiates differentiation), while Egr2 promotes it; pro-adipogenic effects of IBMX involve suppression of Egr1's inhibitory influence.\",\n      \"method\": \"Ectopic expression, siRNA knockdown, 3T3-L1 adipocyte differentiation assays, promoter-reporter assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with quantitative differentiation readout, single lab, 82 citations\",\n      \"pmids\": [\"19229250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-183 directly targets and downregulates EGR1 mRNA in multiple tumor types (synovial sarcoma, rhabdomyosarcoma, colon cancer); miR-183 knockdown derepresses EGR1, activating a miR-183-EGR1-PTEN tumor suppressor network; EGR1 mediates the effect of miR-183 on cell migration.\",\n      \"method\": \"miRNA overexpression/knockdown, luciferase reporter assays (3′UTR), integrative genomic analysis, migration assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3′UTR targeting validated by luciferase assay, functional rescue experiments, 249 citations\",\n      \"pmids\": [\"21118966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SMAD3 physically interacts with EGR1 via the SMAD3 MH2 domain and the EGR1 DNA-binding domain; SMAD3 modulates EGR1 occupancy at the LHB promoter in a species-specific manner: SMAD3 inhibits EGR1-driven human LHB transcription and reduces EGR1 promoter recruitment, while potentiating EGR1-driven murine Lhb transcription when SMAD-binding elements (SBEs) are present.\",\n      \"method\": \"Co-IP, GST pulldown, ChIP, domain-mapping mutagenesis, promoter-reporter assays with SBE swap mutants\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct interaction mapped to specific domains by pulldown and mutagenesis, functional consequence demonstrated with ChIP and promoter-swap experiments, 19 citations\",\n      \"pmids\": [\"20149866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Genome-wide EGR1 ChIP-seq in APP23 Alzheimer's disease model mouse brains identifies EGR1 binding near genes for synaptic plasticity (Arc, Grin1, Syn2, Vamp2, Stx6) and AD-related genes (Picalm, Psen2, App); EGR1 binding correlates with activating chromatin marks; conditions that upregulate Egr1 (spatial memory task) also increase expression of these targets.\",\n      \"method\": \"ChIP-seq, quantitative ChIP-PCR, behavioral testing, protein expression analysis in APP23 vs. wild-type mice\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide binding mapped and validated, in vivo correlation with EGR1 induction, 67 citations\",\n      \"pmids\": [\"24269917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EGR1 directly binds the proximal Per1 promoter to activate its transcription; EGR1 is itself transcriptionally activated by the CLOCK/BMAL1 heterodimer through a conserved E-box element; EGR1 regulates the amplitude of multiple core clock genes (Bmal1, Per1, Per2, Rev-erbα, Rev-erbβ) in hepatocytes.\",\n      \"method\": \"ChIP, E-box reporter assays, Egr1 knockout mice with light/feeding phase experiments, qRT-PCR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct Per1 promoter binding, validated in Egr1 knockout mice with circadian phenotype, 35 citations\",\n      \"pmids\": [\"26471974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EGR1 functions as a potent repressor of MEF2 transcriptional activity; EGR1 physically interacts with MEF2A, and costamere gene expression in cardiomyocytes is dependent on EGR1 transcriptional activity.\",\n      \"method\": \"Co-IP, transcription reporter assays, siRNA knockdown of EGR1 in cardiomyocytes, bioinformatic promoter analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction and functional repression demonstrated, single lab, 15 citations\",\n      \"pmids\": [\"26011708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EGR1 translation is regulated by the mTORC1/4E-BP axis; 4E-BP1/2-null cells translate EGR1 mRNA more efficiently despite lower mRNA levels; mTORC1 inhibitors (rapamycin, PP242) suppress EGR1 protein without increasing mRNA; EGR1-dependent repression of adipose triglyceride lipase (ATGL) promotes fat storage.\",\n      \"method\": \"35S-methionine labeling (translation assay), 4E-BP1/2 and TSC2 genetic knockout MEFs, mTORC1 inhibitors, siRNA, adipocyte lipid accumulation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct translation assay with isotope labeling confirms post-transcriptional regulation; multiple genetic models, 25 citations\",\n      \"pmids\": [\"25814662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EGR1 expression is mechanosensitive in tendon cells; EGR1 directly responds to mechanical signals and overexpression of EGR1 prevents downregulation of tendon-specific genes (e.g., Scx, Col1) when tension is released from 3D-engineered tendons or during tendon healing under reduced mechanical load.\",\n      \"method\": \"3D tendon organoid culture with tension release, in vivo tendon healing with reduced load, ultrasound/microbubble-mediated EGR1 overexpression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo gain-of-function with mechanically controlled conditions, single lab, 52 citations\",\n      \"pmids\": [\"27820865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Egr-1 deficiency protects mice from renal inflammation and fibrosis; Egr1-/- mice on an adenine-rich diet show attenuated NF-κB activity, reduced cytokine/chemokine expression, and reduced TGFβ signaling and fibrotic area; in vitro, Egr-1 deficiency blunts primary tubular epithelial cell responses to TNFα and TGFβ.\",\n      \"method\": \"Egr1 knockout mice, adenine-induced TIN model, primary tubular epithelial cell cultures with cytokine treatment, NF-κB activity assays\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockout model with mechanistic in vitro validation, multiple signaling pathway readouts, 81 citations\",\n      \"pmids\": [\"26960759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ER stress activates EGR1 transcription via a SRC-RAS-RAF-MEK-ERK cascade leading to ELK1 phosphorylation; ELK1 and SRF are constitutively bound to the EGR1 promoter, but phospho-ELK1 abundance increases upon ER stress; ELK1 knockdown completely blocks ER stress-induced EGR1 mRNA increase.\",\n      \"method\": \"siRNA knockdown of ELK1 and SRF, ERK pathway inhibitors, ChIP for promoter occupancy of phospho-ELK1 and phospho-SRF, kinase cascade inhibitors\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms promoter occupancy changes, siRNA epistasis identifies ELK1 as required mediator, single lab\",\n      \"pmids\": [\"30290239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 recruits TET1 to specific genomic loci to mediate DNA demethylation during postnatal brain development; EGR1 ChIP-seq shows thousands of binding sites that become hypomethylated in mature neurons; frontal cortices from Egr1 or Tet1 knockout mice share highly similar gene expression and methylation profiles.\",\n      \"method\": \"EGR1 ChIP-seq, whole-genome bisulfite sequencing, Egr1 and Tet1 knockout mice, RNA-seq, co-IP\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — genome-wide binding and methylation data, validated in two independent knockout models with parallel methylome and transcriptome analysis, 116 citations\",\n      \"pmids\": [\"31467272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 regulates angiogenic and osteoclastogenic factors (PDGFA, TGFB1, SPP1, IL6, IL8, TGFA) in prostate cancer metastases; FN14 (TNFRSF12A) ligation drives NF-κB-independent, MEK-dependent EGR1 expression; EGR1 depletion reduces metastasis number/size, blood vessel density in metastases, and osteolytic bone lesion area.\",\n      \"method\": \"EGR1 knockdown in metastasis model (DU145/RasB1), intracardiac injection metastasis assays, histology for vascularization and osteoclasts, MEK inhibitor experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in defined metastasis model with multiple in vivo readouts and pathway placement (MEK-dependent), 125 citations\",\n      \"pmids\": [\"31312026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 binds the CMV viral genome upstream of the UL138 latency gene and is sufficient to promote UL138 expression; disruption of EGR1 binding upstream of UL138 prevents establishment of CMV latency in CD34+ hematopoietic progenitor cells; EGR1 is induced via MEK/ERK downstream of EGFR signaling and is important for hematopoietic stemness.\",\n      \"method\": \"EGR1 ChIP on viral genome, site-directed mutagenesis of EGR1 binding sites, CD34+ HPC infection/latency assays, MEK/ERK/PI3K inhibition\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct ChIP on viral genome plus functional mutagenesis of binding site with defined latency phenotype, 60 citations\",\n      \"pmids\": [\"31725811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MIR2052HG lncRNA interacts with EGR1 protein and facilitates EGR1 recruitment to the LMTK3 promoter; EGR1 is required for LMTK3 transcription, which sustains ERα levels in breast cancer cells.\",\n      \"method\": \"RNA-binding protein immunoprecipitation (RIP), ChIP, RNA-DNA dual FISH, luciferase reporter assays\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP and ChIP confirm EGR1-RNA interaction and promoter occupancy, single lab\",\n      \"pmids\": [\"30944027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fasting and glucose restriction activate EGR1 via regulation of PKA and AMPK pathways; EGR1 functions as the mammalian ortholog of yeast Msn2/4 stress-resistance transcription factors; EGR1 activates cardioprotective peptides ANP and BNP, contributing to protection against doxorubicin toxicity.\",\n      \"method\": \"Fasting/glucose restriction experiments in mice, PKA and AMPK pharmacological manipulation, cardiac gene expression analysis, doxorubicin toxicity assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement via pharmacological manipulation and dietary intervention, functional phenotype (cardioprotection), single lab\",\n      \"pmids\": [\"28358805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DNA-PKcs phosphorylates EGR1 at serine 301; this phosphorylation stabilizes EGR1 by preventing proteasomal degradation; S301A mutation (via CRISPR-Cas9) reduces EGR1 protein levels and decreases EGR1-dependent IL-2 transcription in activated T cells.\",\n      \"method\": \"Quantitative phosphoproteomic screen in T cells, DNA-PKcs inhibitor (NU7441) and shRNA knockdown, CRISPR-Cas9 S301A knockin, proteasome inhibitor rescue, IL-2 reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — phosphosite identified by mass spectrometry, validated by CRISPR knockin mutagenesis, functional consequence on protein stability and target gene transcription, 18 citations\",\n      \"pmids\": [\"34562454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RAF-induced oncogenic signaling activates EGR1 transcription via the MEK-ERK MAPK pathway; EGR1 in turn regulates p15 (CDKN2B) and p21 (CDKN1A) expression, which are redundantly required for B-RAF-V600E-induced proliferative arrest (senescence) in human fibroblasts; glucocorticoids suppress EGR1 and thereby delay senescence entry.\",\n      \"method\": \"B-RAF-V600E expression in fibroblasts, transcriptome analysis, siRNA knockdown of EGR1, glucocorticoid treatment, MEK inhibitors\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA epistasis places EGR1 between RAF and p15/p21 in senescence pathway, single lab\",\n      \"pmids\": [\"31371485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TET2 is recruited to the MIF promoter and interacts with EGR1 and histone deacetylases; disruption of these interactions due to TET2 downregulation favors EGR1-driven transcription of MIF and its secretion from monocytes; EGR1 drives MIF overproduction in the absence of TET2.\",\n      \"method\": \"ChIP for TET2 at MIF promoter, co-IP of TET2/EGR1/HDAC complex, TET2 knockdown and knockout models, MIF secretion ELISA\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and ChIP demonstrate complex, loss-of-function validates EGR1-driven MIF transcription, single lab\",\n      \"pmids\": [\"35115654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EGR1 directly binds the SOX9 gene promoter in renal tubular cells to activate SOX9 expression; EGR1 induction in early AKI promotes SOX9+ progenitor cell proliferation via the Wnt/β-catenin pathway; Egr1 knockout mice show aggravated AKI severity.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, RNA-seq, Egr1 knockout mice in IRI and nephrotoxic AKI models, immunofluorescence\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay confirm direct SOX9 promoter binding, validated in two Egr1 knockout AKI models, 58 citations\",\n      \"pmids\": [\"35910788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear PD-L1 facilitates p-STAT3 binding to the EGR1 promoter, activating EGR1-mediated angiogenesis; HDAC2 inhibition restores PD-L1 acetylation and blocks its nuclear translocation, thereby attenuating EGR1-driven tumor angiogenesis.\",\n      \"method\": \"ChIP for p-STAT3 at EGR1 promoter, nPD-L1-deficient cell lines, in vitro and in vivo angiogenesis assays, HDAC2 inhibitor treatment\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms mechanism of EGR1 activation, functional in vivo angiogenesis rescue experiments, single lab\",\n      \"pmids\": [\"36977660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EGR1 directly binds the SNAI2 promoter and recruits p300/CBP as a coactivator to drive SNAI2 transcription, thereby promoting EMT and invasion in pancreatic cancer; co-IP confirms EGR1-p300/CBP interaction.\",\n      \"method\": \"ChIP-qPCR for EGR1 at SNAI2 promoter, co-IP of EGR1 and p300/CBP, dual-luciferase reporter assay, transwell migration/invasion assays, in vivo liver metastasis model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and co-IP define direct binding and co-activator interaction, functional in vivo metastasis validation, single lab\",\n      \"pmids\": [\"36932397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EGR1 directly binds the PFKL promoter and represses PFKL expression, thereby suppressing aerobic glycolysis (Warburg effect) in hepatocellular carcinoma; EGR1 overexpression inhibits HCC xenograft growth and sensitizes cells to sorafenib.\",\n      \"method\": \"ChIP for EGR1 at PFKL promoter, dual-luciferase reporter assay, EGR1 overexpression/KO in HCC cell lines and xenografts, human hepatoma organoids, glycolysis assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay confirm direct PFKL repression, validated in multiple in vivo models, single lab\",\n      \"pmids\": [\"38287371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Egr1 regulates regenerative senescence in the heart; in neonatal hearts, Egr1 promotes angiogenesis and cardiomyocyte proliferation during regeneration; in adult hearts, agrin-induced senescence and repair require Egr1, which is activated by the integrin-FAK-ERK-Akt1 signaling axis in cardiac fibroblasts.\",\n      \"method\": \"Proteomics, single-cell RNA sequencing, Egr1 knockout/overexpression in neonatal and adult cardiac injury models, agrin treatment, integrin-FAK-ERK-Akt1 pathway inhibition\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-omic profiling combined with in vivo loss-of-function in two distinct heart regeneration models with defined pathway (integrin-FAK-ERK-Akt1), 27 citations\",\n      \"pmids\": [\"39196027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Egr1 haploinsufficiency cooperates with ENU-induced mutations to cause myeloproliferative disease and T-cell lymphomas in mice at increased rates; biallelic Egr1 mutations were not observed in MPDs from Egr1+/- mice, supporting a haploinsufficiency tumor suppressor role for EGR1 in myeloid malignancies associated with del(5q).\",\n      \"method\": \"Egr1 heterozygous and null mice treated with ENU, disease characterization by blood counts, flow cytometry, histopathology\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with defined phenotype and haploinsufficiency mechanism, 173 citations\",\n      \"pmids\": [\"17420284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"APE1/Ref-1 acetylation is required for EGR1-dependent PTEN gene activation; acetylated APE1 enhances binding to transcriptional complexes at the PTEN promoter; APE1-dependent PTEN expression requires EGR1, as shown by ectopic EGR1 expression in APE1-downregulated cells.\",\n      \"method\": \"APE1 siRNA knockdown, ectopic EGR1 expression, APE1 acetylation assays, PTEN expression analysis, HDAC inhibitor experiments\",\n      \"journal\": \"Free radical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional epistasis between APE1 acetylation and EGR1 in PTEN transcription, single lab\",\n      \"pmids\": [\"18324520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGR1 directly transactivates the EGR1 splicing isoform; a newly identified EGR1 splicing isoform lacks part of the N-terminal activation domain, can enter the nucleus, but is unable to fully activate transcription compared to canonical EGR1.\",\n      \"method\": \"Identification of splice isoform by RT-PCR/sequencing, nuclear localization by immunofluorescence, transcriptional activation reporter assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single paper, partial functional characterization of isoform\",\n      \"pmids\": [\"30925677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EGR1/EZH2/HDAC9 form a repressor complex that maintains high H3K27-Me3 at the EBF3 promoter to silence EBF3 in nasopharyngeal carcinoma; EGR1 is a component of this epigenetic silencing complex.\",\n      \"method\": \"Co-IP, ChIP for H3K27-Me3 and complex components at EBF3 promoter, rescue experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and ChIP identify EGR1 as part of repressor complex, single lab\",\n      \"pmids\": [\"34906623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGR1 directly binds the GADD45A promoter to activate its transcription in thyroid carcinoma cells treated with non-thermal plasma-activated medium; EGR1/GADD45α signaling mediates ROS-induced apoptotic cell death.\",\n      \"method\": \"ChIP for EGR1 at GADD45A promoter, EGR1 overexpression/siRNA, ROS scavengers, xenograft tumor models\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct GADD45A promoter binding, validated in xenograft models, single lab\",\n      \"pmids\": [\"33477921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGR1 upregulates expression of MYC and E2F pathway genes through the CBP/p300/H3K27ac/BRD4 axis in DLBCL, while repressing type I IFN pathway genes through interaction with the corepressor NAB2; EGR1 inhibition synergizes with BRD4 inhibitor JQ1 or lenalidomide in ABC DLBCL.\",\n      \"method\": \"EGR1 knockdown (genetic and pharmacologic), ChIP for H3K27ac and BRD4, co-IP with NAB2, xenograft models, combination drug assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and co-IP define mechanistic axes, functional validation in xenografts, single lab\",\n      \"pmids\": [\"33980611\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EGR1 is a zinc-finger transcription factor that binds the consensus sequence CGCCCCCGC in a zinc-dependent manner; it is rapidly induced downstream of diverse growth factor and stress signals via the MAPK/ERK and PKC pathways, acts as both a transcriptional activator (of LHβ, PTEN, TAp73, heparanase, Per1, SOX9, DUSP4, and others) and repressor (of calsequestrin-2, 4E-BP1, PFKL), recruits co-activators such as p300/CBP and co-repressors NAB1/NAB2, is post-translationally regulated by phosphorylation (Akt at S350/T309, DNA-PKcs at S301 for stability) and sumoylation (ARF/Ubc9), epigenetically programs the brain methylome by recruiting TET1 for DNA demethylation, and orchestrates context-dependent cellular programs including reproductive axis control, synaptic plasticity, angiogenesis, fibrosis, autophagy, senescence, and cancer progression/suppression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EGR1 is an immediate-early zinc-finger transcription factor that functions as a signal-responsive master regulator linking extracellular stimuli—including growth factors, stress, glucocorticoids, and mechanical load—to diverse transcriptional programs controlling cell proliferation, apoptosis, differentiation, metabolism, and synaptic plasticity. EGR1 is rapidly induced through MAPK/ERK, p38, and AMPK pathways and directly binds GC-rich elements in target gene promoters (including LH-β, PTEN, p73, Per1, SOX9, PFKL, heparanase, and numerous synaptic plasticity genes) to activate or repress transcription in a context-dependent manner [PMID:8703054, PMID:16093249, PMID:19032775, PMID:24269917, PMID:26471974, PMID:38287371]. Its transcriptional output is shaped by post-translational modifications—Akt-dependent phosphorylation at S350/T309 promotes ARF-mediated sumoylation required for PTEN transactivation, while DNA-PKcs phosphorylation at S301 stabilizes the protein against proteasomal degradation [PMID:19057511, PMID:34562454]—and by physical interactions with co-activators (p300/CBP, SF-1, SMAD3) and co-repressors (NAB1, NAB2, TBX2) that tune target gene selection [PMID:9418898, PMID:20149866, PMID:36932397, PMID:33980611]. EGR1 additionally recruits the DNA demethylase TET1 to its binding sites in neurons, coupling activity-dependent transcription to epigenetic remodeling [PMID:31467272].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing EGR1 as an essential physiological transcription factor: Egr1-knockout mice revealed that EGR1 is required for LH-β gene transcription and female fertility, and synergizes with SF-1 at the LH-β promoter, moving EGR1 from a generic immediate-early gene to a factor with defined in vivo transcriptional targets.\",\n      \"evidence\": \"Egr1 knockout mouse phenotype plus LH-β promoter mutagenesis and mRNA analysis\",\n      \"pmids\": [\"8703054\", \"9440815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of EGR1/SF-1 synergy at the molecular level was not resolved\", \"Whether EGR1 acts on other reproductive gene promoters was unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defining how EGR1 transcriptional activity is terminated: NAB1 was shown to bind the EGR1 R1 domain and actively repress EGR1-mediated transcription without blocking DNA binding or nuclear entry, establishing a co-repressor-based negative feedback mechanism.\",\n      \"evidence\": \"Domain deletion mutagenesis, tethered repression assays, and reporter gene assays\",\n      \"pmids\": [\"9418898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NAB1 and NAB2 have redundant or distinct roles in vivo was unresolved\", \"The chromatin-level mechanism of NAB-mediated repression was undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Expanding EGR1's direct target repertoire to cell cycle and survival genes: ChIP confirmed EGR1 binding to cyclin D2, p19INK4d, and Fas promoters in prostate cancer cells, establishing EGR1 as a direct transcriptional regulator of proliferation and apoptosis genes.\",\n      \"evidence\": \"ChIP, Affymetrix microarray, EGR1 antisense knockdown in prostate cancer cells\",\n      \"pmids\": [\"12556466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EGR1 activates or represses these targets depended on context that was not fully delineated\", \"Contribution of co-factors to target selectivity was unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linking EGR1 to upstream signaling cascades in the brain: glucocorticoid receptor activation was shown to induce EGR1 via the MAPK pathway in hippocampus, and MAPK inhibition abolished glucocorticoid-enhanced memory, positioning EGR1 as a downstream effector of stress-hormone signaling in neuronal plasticity.\",\n      \"evidence\": \"Brain-specific GR knockout mice, in vivo MAPK inhibition, behavioral fear-conditioning assays\",\n      \"pmids\": [\"15834420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct EGR1 target genes mediating memory consolidation were not identified\", \"Whether EGR1 is sufficient or merely necessary for memory enhancement was not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating EGR1 as a metabolic regulator and genotoxic stress responder: EGR1 was found to directly activate DUSP4 transcription downstream of AMPK to suppress hepatic gluconeogenesis, and separately to transactivate TAp73 through five binding sites in its promoter, forming feedback loops with p53 family members to sustain apoptosis.\",\n      \"evidence\": \"ChIP, siRNA epistasis with metabolic readouts; promoter mutagenesis and Egr1-deficient mice for p73 regulation\",\n      \"pmids\": [\"16849326\", \"16990849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the AMPK-EGR1-DUSP4 axis operates in vivo was not demonstrated\", \"Relative contributions of EGR1 versus p53 in the apoptotic feedback loop were unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealing post-translational regulation of EGR1 function: Akt-dependent phosphorylation at S350/T309 was shown to promote ARF/Ubc9-mediated sumoylation at K272, which is required for EGR1 to transactivate PTEN in vivo; separately, genome-wide ChIP-on-chip identified 288 EGR1-bound promoters after UV stress, confirming EGR1 as a coordinator of large-scale apoptotic transcriptional responses.\",\n      \"evidence\": \"Sumoylation assays with site-directed mutagenesis, ARF knockout mice, PTEN expression; ChIP-on-chip with siRNA validation\",\n      \"pmids\": [\"19057511\", \"19032775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether sumoylation affects EGR1 activity at all targets or only PTEN was unknown\", \"The phosphatase or desumoylase reversing these modifications was not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapping the temporal regulatory logic at the EGR1 promoter and revealing partner interactions: ELK1/CREB phosphorylation via MEK1/2 and p38 was shown to be required for EGR1 induction, followed by NAB1/NAB2-mediated transcriptional termination; additionally, SMAD3 was found to physically interact with EGR1's DNA-binding domain via its MH2 domain, modulating EGR1 recruitment to the LHB promoter.\",\n      \"evidence\": \"ChIP temporal mapping of promoter occupancy; reciprocal Co-IP with domain mapping and promoter mutagenesis\",\n      \"pmids\": [\"20582451\", \"20149866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NAB proteins are recruited with temporal specificity was unclear\", \"Whether SMAD3-EGR1 cooperation extends beyond reproductive genes was not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining genome-wide EGR1 occupancy in the brain and linking it to synaptic plasticity and neurodegeneration: ChIP-seq revealed EGR1 binding at promoters of synaptic genes (Arc, Grin1, Syn2) and AD-associated genes (App, Psen2, Picalm), with occupancy correlating with activating chromatin marks and spatial memory-dependent expression.\",\n      \"evidence\": \"ChIP-seq in mouse brain, gene expression profiling, APP23 transgenic mice\",\n      \"pmids\": [\"24269917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal role of EGR1 at individual synaptic targets was not tested by genetic perturbation\", \"Whether EGR1 binding is altered in human AD brain was unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Integrating EGR1 into the circadian clock and translational control networks: EGR1 was found to be a direct CLOCK/BMAL1 target that in turn activates Per1 transcription, regulating circadian amplitude in liver; independently, EGR1 mRNA translation was shown to be controlled by the mTORC1/4E-BP axis, with derepressed translation increasing EGR1 protein and suppressing ATGL to promote fat storage.\",\n      \"evidence\": \"ChIP and Egr1-KO mice with circadian phenotype; metabolic labeling in 4E-BP1/2-knockout MEFs\",\n      \"pmids\": [\"26471974\", \"25814662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EGR1's circadian role extends beyond the liver was not explored\", \"The relative importance of transcriptional versus translational control of EGR1 levels in different tissues was unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing EGR1 as an epigenetic regulator through TET1 recruitment: EGR1 was shown to recruit the DNA demethylase TET1 to thousands of binding sites in the brain, causing site-specific hypomethylation in mature neurons, with convergent evidence from both Egr1- and Tet1-knockout mice.\",\n      \"evidence\": \"ChIP-seq, DNA methylation profiling, dual genetic KO comparison in mouse frontal cortex\",\n      \"pmids\": [\"31467272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TET1 recruitment depends on direct physical interaction or intermediary factors was not established\", \"The functional consequences of EGR1-TET1-mediated demethylation at individual loci were not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extending EGR1's function beyond host genes to viral latency: EGR1 was found to bind the CMV genome upstream of UL138 and drive latency gene expression; disruption of the EGR1 binding site prevented CMV latency establishment in CD34+ hematopoietic progenitors.\",\n      \"evidence\": \"ChIP of EGR1 on viral genome, EGR1-site mutagenesis, latency assay in CD34+ HPCs\",\n      \"pmids\": [\"31725811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other immediate-early transcription factors cooperate with EGR1 at the CMV genome was unknown\", \"Relevance to other herpesvirus latency programs was not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying a second stabilizing phosphorylation axis: DNA-PKcs was shown to phosphorylate EGR1 at S301, preventing proteasomal degradation and sustaining EGR1-dependent IL-2 transcription in activated T cells, revealing a distinct post-translational mechanism from the Akt-sumoylation axis.\",\n      \"evidence\": \"Phosphoproteomics, DNA-PKcs inhibitor, CRISPR S301A knock-in, proteasome inhibition\",\n      \"pmids\": [\"34562454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ubiquitin ligase targeting EGR1 for degradation was not identified\", \"Whether S301 phosphorylation and S350/T309-Akt phosphorylation are coordinated or independent was not examined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connecting EGR1 to tissue repair and metabolic reprogramming: EGR1 was shown to directly bind the SOX9 promoter to promote renal tubular regeneration after AKI via Wnt/β-catenin signaling, and to repress PFKL transcription to suppress aerobic glycolysis in hepatocellular carcinoma, further illustrating context-dependent activator/repressor duality.\",\n      \"evidence\": \"ChIP plus reporter assays, Egr1-KO mice with AKI; ChIP plus gain/loss-of-function in HCC models and organoids\",\n      \"pmids\": [\"35910788\", \"38287371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines whether EGR1 acts as activator or repressor at a given promoter was not mechanistically explained\", \"Whether EGR1's metabolic targets extend beyond PFKL in glycolysis was not explored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing EGR1 in cardiac regeneration: EGR1 was activated by integrin-FAK-ERK-Akt1 signaling upon agrin stimulation in cardiac fibroblasts and shown to orchestrate regenerative senescence and the senescence-associated secretory phenotype including cathepsins, promoting angiogenesis and cardiomyocyte proliferation in neonatal hearts.\",\n      \"evidence\": \"Proteomics, single-cell RNA-seq, Egr1-KO mice in neonatal and agrin-mediated adult cardiac repair models\",\n      \"pmids\": [\"39196027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific EGR1 target genes driving the SASP in cardiac fibroblasts were not fully delineated\", \"Whether EGR1 is sufficient to promote adult cardiac regeneration without agrin co-stimulation was not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for EGR1's context-dependent switch between transcriptional activation and repression; the identity of the E3 ubiquitin ligase(s) controlling EGR1 proteasomal turnover; and how co-factor competition (NAB1/NAB2 vs. p300/CBP vs. TBX2) is coordinated genome-wide to determine target gene selection across different cell types and stimuli.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length EGR1 with co-factors exists\", \"The E3 ligase mediating EGR1 degradation is unidentified\", \"Genome-wide rules governing co-factor selectivity at EGR1-bound sites remain undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 3, 6, 8, 10, 13, 14, 19, 20, 21, 26, 30, 32]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 6, 7, 8, 9, 10, 14, 19, 25, 26, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 7, 34]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 6, 7, 10, 14, 19, 25, 26, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 11, 24, 31]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 33]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 10, 18]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [24, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 36]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NAB1\",\n      \"NAB2\",\n      \"SF-1\",\n      \"SMAD3\",\n      \"TET1\",\n      \"TBX2\",\n      \"MEF2A\",\n      \"EP300\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"EGR1 is a zinc-finger immediate-early transcription factor that integrates diverse extracellular signals—growth factors, stress, mechanical load, and metabolic cues—into context-dependent transcriptional programs governing reproduction, angiogenesis, synaptic plasticity, senescence, autophagy, and fibrosis. It binds the GC-rich consensus CGCCCCCGC through three zinc fingers in a zinc-dependent manner and acts as both a transcriptional activator (recruiting p300/CBP to targets such as LHβ, PTEN, SOX9, SNAI2, LC3B, Per1, and DUSP4) and a repressor (silencing calsequestrin-2, 4E-BP1, and PFKL, in part through NAB1/NAB2 corepressors or EZH2/HDAC complexes) [PMID:3127059, PMID:7624335, PMID:8703054, PMID:18836406, PMID:36932397, PMID:38287371, PMID:34906623]. EGR1 is induced primarily via the MEK/ERK–ELK1/SRF axis and is post-translationally regulated by Akt-dependent phosphorylation/ARF-mediated sumoylation that controls PTEN transactivation, and by DNA-PKcs phosphorylation at S301 that prevents proteasomal degradation [PMID:19057511, PMID:34562454]. During postnatal brain development EGR1 recruits TET1 to catalyze DNA demethylation at thousands of loci, epigenetically programming neuronal gene expression, while in hematopoietic cells EGR1 haploinsufficiency cooperates with secondary mutations to promote myeloproliferative disease, consistent with a tumor-suppressor role at chromosome 5q [PMID:31467272, PMID:17420284].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Identification of EGR1 as an immediate-early zinc-finger transcription factor that binds CGCCCCCGC established the gene's fundamental molecular identity and DNA-binding mechanism.\",\n      \"evidence\": \"cDNA cloning, zinc-dependent in vitro DNA binding, nuclear localization by immunocytochemistry in stimulated cells\",\n      \"pmids\": [\"3127059\", \"2109185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Three-dimensional structure of EGR1 zinc-finger/DNA complex not yet resolved at that time\", \"Post-translational modifications beyond phosphorylation uncharacterized\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Discovery of the NAB1/NAB2 corepressor system revealed that EGR1 transcriptional output is actively tuned by dedicated repressors binding the R1 domain, explaining how the same factor can activate or dampen gene expression.\",\n      \"evidence\": \"Yeast two-hybrid identification of NAB1, transcriptional reporter assays for NAB1 and NAB2, domain mapping of NCD2 repression domain\",\n      \"pmids\": [\"7624335\", \"8668170\", \"9418898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NAB–R1 interaction unknown\", \"Genome-wide extent of NAB-dependent repression not mapped\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Egr1-knockout mouse phenotypes—female infertility from LHβ deficiency and reduced GH/body size—demonstrated that EGR1 is essential in vivo for pituitary-gonadal axis function and placed EGR1 as a direct transcriptional activator of LHβ through cooperation with SF-1 and Ptx1.\",\n      \"evidence\": \"Two independent Egr1-null mouse lines, LHβ promoter mutagenesis, co-IP/GST pulldown of EGR1–SF-1–Ptx1 interactions\",\n      \"pmids\": [\"8703054\", \"9440815\", \"10082522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of species-specific regulation of LHβ by SMAD3/EGR1 not fully resolved\", \"EGR1 targets beyond LHβ in gonadotropes not catalogued\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Evidence that EGR1 is required for prostate cancer progression from PIN to invasive carcinoma—but dispensable for tumor initiation—established EGR1 as a context-dependent oncogene that regulates the invasive transition, partly through direct control of cyclin D2, p19INK4d, and Fas.\",\n      \"evidence\": \"Egr1-null mice crossed to two transgenic prostate cancer models; ChIP and microarray identifying direct targets in prostate cancer cells\",\n      \"pmids\": [\"11135623\", \"12556466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EGR1 pro-tumorigenic role generalizes beyond prostate cancer models unclear at this stage\", \"Mechanism of EGR1-dependent invasive switch not fully delineated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Multiple lines of evidence placed EGR1 at the convergence of MAPK/ERK, PKC, PI3K, and AMPK signaling, establishing it as a signal-integration node that translates kinase cascades into transcriptional programs for angiogenesis (FGF-2), autophagy (LC3B, Atg4B), and metabolic control (DUSP4-mediated gluconeogenesis inhibition).\",\n      \"evidence\": \"DNAzyme knockdown and Egr1-KO Matrigel angiogenesis assays; ChIP on LC3B promoter with in vivo Egr1-KO emphysema protection; ChIP on DUSP4 promoter with siRNA epistasis in hepatocytes; EP4-PI3K-ERK pathway dissection\",\n      \"pmids\": [\"12872165\", \"18836406\", \"16849326\", \"12566441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EGR1 selects among different target gene programs in different cell types remains unclear\", \"Relative contribution of each upstream pathway in physiological contexts not quantified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"In vivo studies in brain established that EGR1 mediates glucocorticoid-MAPK-driven contextual fear conditioning and is required for synaptic potentiation in the anterior cingulate cortex during persistent (but not acute) inflammatory pain, defining EGR1 as a neuronal plasticity effector.\",\n      \"evidence\": \"Egr1-KO behavioral and electrophysiological phenotypes; brain-specific GR-KO with hippocampal MAPK inhibitor infusions\",\n      \"pmids\": [\"15629414\", \"15834420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise downstream transcriptional targets mediating ACC plasticity not identified at that point\", \"Whether EGR1's role in pain is cell-type specific within ACC unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of EGR1 as a MAPK-dependent HGF/Snail pathway activator linked EGR1 to epithelial-mesenchymal transition; a Snail-EGR1 negative feedback loop was defined, and EGR1's role in EMT was later reinforced by its activation of SNAI2 via p300/CBP recruitment.\",\n      \"evidence\": \"shRNA knockdown, ChIP/EMSA for Snail and EGR1 reciprocal promoter binding; ChIP-qPCR and co-IP of EGR1–p300/CBP at SNAI2 promoter with in vivo metastasis validation\",\n      \"pmids\": [\"16858414\", \"36932397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EGR1 drives EMT through Snail/SNAI2 in non-cancer physiological contexts unknown\", \"Relative contribution of NAB-mediated repression versus p300/CBP activation at EMT gene promoters not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"An Akt–EGR1–ARF–PTEN feedback axis was defined: Akt phosphorylates EGR1 at S350/T309, promoting ARF/Ubc9-mediated sumoylation at K272, which is required for PTEN transactivation; separately, DNA-PKcs phosphorylation at S301 was shown to stabilize EGR1 protein by blocking proteasomal degradation.\",\n      \"evidence\": \"Site-directed mutagenesis of phospho- and SUMO-sites, ARF-KO mice, CRISPR-Cas9 S301A knockin in T cells, phosphoproteomics\",\n      \"pmids\": [\"19057511\", \"34562454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional kinases phosphorylate EGR1 at other sites is not comprehensively mapped\", \"Interplay between sumoylation and S301 phosphorylation not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Egr1 haploinsufficiency cooperated with secondary mutations to cause myeloproliferative disease in mice without requiring biallelic loss, establishing a haploinsufficient tumor-suppressor role consistent with EGR1's location in the commonly deleted 5q region in myeloid malignancies.\",\n      \"evidence\": \"ENU mutagenesis in Egr1+/− mice with disease characterization by flow cytometry and histopathology\",\n      \"pmids\": [\"17420284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific EGR1 target genes mediating myeloid tumor suppression not identified\", \"Whether haploinsufficiency mechanism applies to human del(5q) MDS not directly tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"EGR1 was integrated into the circadian clock: CLOCK/BMAL1 activate EGR1 via an E-box, and EGR1 in turn directly binds the Per1 promoter and modulates amplitude of multiple core clock genes, placing EGR1 as a clock output effector.\",\n      \"evidence\": \"ChIP on Per1 promoter, E-box reporter assays, Egr1-KO mice with circadian light/feeding experiments\",\n      \"pmids\": [\"26471974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EGR1 functions as a core clock component or peripheral modulator not settled\", \"Clock-dependent EGR1 targets beyond Per1 not genome-wide mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genome-wide studies revealed that EGR1 recruits TET1 to catalyze DNA demethylation at thousands of loci during postnatal brain maturation; Egr1-KO and Tet1-KO frontal cortices share highly overlapping methylation and expression changes, establishing EGR1 as an epigenetic programmer of the neuronal methylome.\",\n      \"evidence\": \"EGR1 ChIP-seq, whole-genome bisulfite sequencing, RNA-seq in Egr1 and Tet1 KO frontal cortices, co-IP of EGR1–TET1\",\n      \"pmids\": [\"31467272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EGR1-TET1 interaction is direct or requires bridging factors not resolved at structural level\", \"Whether EGR1 recruits TET1 outside the brain not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Integration of proteomics and scRNA-seq in cardiac injury models showed EGR1 orchestrates regenerative senescence: promoting neonatal cardiac angiogenesis and cardiomyocyte proliferation, and mediating agrin-induced senescence in adult hearts via an integrin–FAK–ERK–Akt1 axis in cardiac fibroblasts.\",\n      \"evidence\": \"Proteomics and scRNA-seq in neonatal/adult heart injury; Egr1-KO/overexpression with agrin treatment; integrin-FAK-ERK-Akt1 pathway inhibition\",\n      \"pmids\": [\"39196027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EGR1-driven regenerative senescence is conserved in human hearts unknown\", \"Direct transcriptional targets mediating the senescence-to-regeneration switch not catalogued\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A systematic understanding of how EGR1 selects between its activator and repressor functions at different loci—integrating cofactor recruitment (NAB1/2 vs. p300/CBP), post-translational modification state, and chromatin context—remains incomplete.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide map of EGR1 cofactor occupancy distinguishing activator vs. repressor modes\", \"Structural basis of EGR1–NAB vs. EGR1–p300 selectivity unresolved\", \"Comprehensive catalog of cell-type-specific EGR1 target gene programs lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 15, 22, 28, 35]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 11, 13, 15, 19, 20, 22, 24, 29, 43, 45, 46, 53]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 50]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 11, 15, 19, 20, 24, 29, 43, 45, 46, 53]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 18, 21, 34, 41, 47]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [35, 51]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [19, 52]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11, 36, 48]}\n    ],\n    \"complexes\": [\n      \"EGR1/NAB1 repressor complex\",\n      \"EGR1/NAB2 repressor complex\",\n      \"EGR1/EZH2/HDAC9 silencing complex\"\n    ],\n    \"partners\": [\n      \"NAB1\",\n      \"NAB2\",\n      \"SF-1\",\n      \"SMAD3\",\n      \"TET1\",\n      \"EP300\",\n      \"MEF2A\",\n      \"EZH2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}