{"gene":"USF1","run_date":"2026-04-28T21:43:01","timeline":{"discoveries":[{"year":1998,"finding":"USF1 binds cooperatively with Stat1 to the GAS/E-box motif in the CIITA promoter IV; Stat1 can only bind to the GAS site in the presence of USF1 at the adjacent E-box, establishing a cooperative protein-DNA interaction required for IFNγ-induced MHC class II expression.","method":"EMSA (cooperative binding assays), transactivation reporter assays, in vivo footprinting","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays with multiple cis-element mutations and functional transactivation data, Moderate evidence from single lab with orthogonal methods","pmids":["9491997"],"is_preprint":false},{"year":1997,"finding":"USF1 physically and functionally interacts with TFII-I (a 120 kDa factor binding both Inr and E-box elements); domains of USF1 required for independent and synergistic transcriptional activation were mapped, and the two factors act synergistically to activate transcription through both Inr and E-box elements of the adenovirus major late promoter.","method":"cDNA cloning, ectopic expression, in vivo transcription assays, domain deletion analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — physical interaction with domain mapping plus functional transcriptional synergy demonstrated in vivo, Moderate evidence","pmids":["9384587"],"is_preprint":false},{"year":2001,"finding":"USF1 is phosphorylated and activated by the stress-responsive p38 kinase following UV irradiation, and is required for UV-induced activation of the Tyrosinase promoter in melanocytes; Usf1 knockout melanocytes fail to activate Tyrosinase expression in response to UV.","method":"In vitro kinase assay (p38 phosphorylation of USF1), USF1 knockout mouse melanocytes, reporter gene assays, functional UV response assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — kinase assay plus KO mouse phenotype plus reporter assay, Moderate-Strong evidence","pmids":["11532965"],"is_preprint":false},{"year":1998,"finding":"USF1 directly interacts with Ets-1 through their DNA-binding domains; the USF1–Ets1 complex binds adjacent E-box and Ets sites in the HIV-1 LTR distal enhancer and synergizes for DNA binding and transactivation in T cells. A dominant-negative Ets-1 mutant inhibits USF1-mediated transactivation in an Ets-site-independent but USF1-binding-surface-dependent manner.","method":"Yeast one-hybrid screen, co-IP/pulldown (binding surface mapping), reporter assays with site-directed mutations, dominant-negative constructs","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — yeast one-hybrid plus reciprocal surface mapping plus functional reporter assays, Moderate evidence","pmids":["9501094"],"is_preprint":false},{"year":1995,"finding":"USF1 and USF2 are the major proteins binding the E-box-containing insulin response sequence (IRS) of the fatty acid synthase (FAS) promoter; USF1 protein level is dramatically increased in liver of refed rats (regulated by nutritional state), while a 17-kDa USF1-related protein is inversely regulated, suggesting USF1 mediates insulin/nutritional regulation of FAS transcription.","method":"Gel shift competition assay, USF antibody supershift, UV cross-linking, western blotting (nutritional regulation)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods (EMSA, supershift, UV crosslink, western), Moderate evidence","pmids":["7499393"],"is_preprint":false},{"year":2007,"finding":"USF1 directly interacts with the histone H4R3-specific methyltransferase PRMT1, and forms a complex with PRMT1, PCAF, and SRC-1 having both H4R3 methyltransferase and HAT activities. USF1 siRNA knockdown causes localized loss of H4R3 methylation and euchromatin-associated histone modifications at the chicken beta-globin insulator, and a dominant-negative USF1 peptide abolishes insulator barrier function.","method":"Co-immunoprecipitation, histone methyltransferase assay, HAT assay, siRNA knockdown with ChIP, dominant-negative peptide functional assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical complex reconstitution with enzymatic activity assay plus siRNA + ChIP with functional readout, Moderate-Strong evidence","pmids":["17846119"],"is_preprint":false},{"year":2004,"finding":"UV-induced activation of POMC and MC1R promoters is mediated by USF1 through p38 stress-activated kinase signaling; melanocytes from Usf1−/− mice exhibit a defective UV response and fail to activate POMC and MC1R expression after UV irradiation.","method":"Knockout mouse melanocytes (USF1−/−), reporter assays, RT-PCR for gene expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with specific UV-response phenotype plus reporter assays, Moderate evidence","pmids":["15358786"],"is_preprint":false},{"year":2009,"finding":"In response to DNA damage, oxidative stress, and cellular infection, USF1 is acetylated in a phospho-Thr-153-dependent fashion (p38-mediated phosphorylation on Thr-153 is a prerequisite for acetylation). Phospho-acetylated USF1 is nuclear, binds DNA, but displays altered (reduced) transcriptional activation properties toward pigmentation and cell cycle genes.","method":"In vitro kinase assay (p38 on USF1 Thr-153), acetylation assays, site-directed mutagenesis, nuclear fractionation, reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro phosphorylation + acetylation assays + mutagenesis + functional reporter data, Moderate evidence","pmids":["19389701"],"is_preprint":false},{"year":1999,"finding":"DNA-binding activity of USF1 is greatly increased by phosphorylation by cyclin A2-p34(cdc2) or cyclin B1-p34(cdc2) complexes in vitro; the phosphorylation site was localized to residues 143–197, a region outside the minimal DNA-binding domain but overlapping the USF-specific region.","method":"In vitro kinase assay (cyclinA2/B1-cdc2 with recombinant USF1), EMSA (DNA binding), deletion/phosphorylation mapping","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with recombinant protein + domain mapping + EMSA, Moderate evidence","pmids":["10548544"],"is_preprint":false},{"year":2013,"finding":"USF1 competes with the CLOCK:BMAL1 complex for binding to E-box sites in circadian target genes. A SNP in the Usf1 promoter elevates USF1 transcript and protein, which suppresses the ClockΔ19 mutant behavioral phenotype. Saturation binding experiments show reduced affinity of the CLOCKΔ19:BMAL1 complex for E-box sites, permitting increased USF1 genome-wide occupancy.","method":"Genetic suppressor mapping, SNP identification, quantitative ChIP (genome-wide USF1 occupancy), saturation binding experiments, behavioral circadian phenotyping","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis + genome-wide ChIP + biochemical binding assays, Moderate-Strong evidence","pmids":["23580255"],"is_preprint":false},{"year":2014,"finding":"USF1 stabilizes p53 protein by preventing MDM2-mediated p53 degradation; loss of USF1 enhances p53–MDM2 complex formation, leading to proteasomal degradation of p53. A USF1 truncated protein lacking its DNA-binding and transactivation domains is sufficient to restore p53 stability, indicating a non-transcriptional mechanism.","method":"Co-immunoprecipitation (USF1/p53/MDM2), Usf1 KO mouse cells, siRNA knockdown, re-expression of truncated USF1, Nutlin-3 comparison, western blotting","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — Co-IP + KO mouse + truncation rescue + pharmacological comparison, Moderate evidence","pmids":["24831529"],"is_preprint":false},{"year":2019,"finding":"H. pylori delocalizes USF1 into cytoplasmic foci near cell membranes, prevents nuclear USF1/p53 complex formation, and promotes MDM2-mediated degradation of p53. USF1 physically interacts with p53 in the nucleus; this complex is disrupted by H. pylori infection, impairing p53 transcriptional function and promoting genetic instability.","method":"Immunofluorescence (subcellular localization), Co-IP (USF1/p53), Usf1−/− mouse in vivo carcinogenesis model, genotoxin (camptothecin) challenge","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — Co-IP + direct localization experiment + KO mouse in vivo, Moderate-Strong evidence","pmids":["31822580"],"is_preprint":false},{"year":2013,"finding":"USF1 recruits the hSET1A histone H3K4 methyltransferase complex to the HoxB4 promoter, governing H3K4me3 modifications and transcription preinitiation complex assembly. Disruption of USF1 by dominant-negative AUSF1 or siRNA against hSET1A reduces mesoderm marker expression and inhibits lineage differentiation; ectopic USF1 in ESCs promotes mesoderm/hematopoietic differentiation.","method":"ChIP (H3K4me3, USF1, hSET1A at HoxB4 promoter), dominant-negative overexpression, RNAi knockdown, ESC differentiation assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — ChIP + dominant-negative + RNAi + differentiation phenotype with multiple readouts, Moderate-Strong evidence","pmids":["23754954"],"is_preprint":false},{"year":2002,"finding":"USF1 binds to the E-box motif at −160 to −165 in the PAI-1 proximal promoter in wound-activated keratinocytes; E-box binding activity increases within 2 hours of monolayer scrape injury; USF1 isolated by PAI-1 promoter-DNA affinity chromatography is almost exclusively phosphorylated. Antisense PAI-1 knockdown significantly impairs keratinocyte migration.","method":"EMSA, UV crosslinking, DNA affinity chromatography, immunocytochemistry (USF1 localization), antisense knockdown (migration assay)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA + affinity chromatography + functional localization + migration assay, Weak-Moderate (single lab)","pmids":["12235287"],"is_preprint":false},{"year":2002,"finding":"USF1 (and USF2) bind to an E-box at −893/−888 of the murine iNOS promoter and trans-repress basal and IL-1β-induced iNOS transcription in mesangial cells; mutation of the E-box augments iNOS response to IL-1β, and cotransfection of dominant-negative USF-2 or E-box decoys augments IL-1β stimulation of iNOS promoter activity.","method":"Site-directed mutagenesis, EMSA (supershift), cotransfection of USF expression vectors and dominant-negative mutants, luciferase reporter assay","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis + EMSA + dominant-negative + reporter assay, Moderate evidence","pmids":["12225970"],"is_preprint":false},{"year":1997,"finding":"USF1 competitively binds to the xenobiotic response element (XRE) of the rabbit CYP1A1 gene, overlapping the AhR·Arnt binding site, and antagonizes AhR·Arnt-mediated CYP1A1 induction; transfection of USF1 expression vector blocks AhR/Arnt interaction with XRE and suppresses CYP1A1 mRNA induction.","method":"Supershift EMSA, competition gel shift, transfection with USF1 expression vector, S1 nuclease protection assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — EMSA competition + mutagenesis + transfection functional assay + mRNA quantification, Moderate evidence","pmids":["9374477"],"is_preprint":false},{"year":2001,"finding":"USF1 interacts with the MTF-1 metalloregulatory factor to cooperatively regulate MT-I gene expression in response to zinc in visceral endoderm cells; USF1 binds an E-box1 sequence at −223 bp in the MT-I promoter, and MTF-1 is absolutely essential while USF1 is required for optimal expression.","method":"USF1 and MTF1 knockout mouse embryos (genetic epistasis), promoter reporter assays, zinc deprivation/repletion","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (double KO phenotyping) + functional promoter analysis, Moderate evidence","pmids":["11230134"],"is_preprint":false},{"year":2012,"finding":"USF1 is required for UV-induced upregulation of DNA repair genes CSA and HR23A (TCR and GGR NER components) through a p53-independent mechanism; Usf1 knockout mice display compromised DNA repair after UV irradiation.","method":"In vitro and in vivo UV irradiation assays, Usf1 KO mouse model, gene expression analysis, ChIP","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with specific NER phenotype + ChIP + in vitro assays, Moderate evidence","pmids":["22291606"],"is_preprint":false},{"year":2002,"finding":"USF1 binds to the E-box at −47 in the cardiac α-MHC promoter (hemodynamic response element); phosphorylation of USF1 by PKC or PKA in vitro increases its DNA-binding activity to the HME. PKC-mediated phosphorylation also causes USF1 multimerization. In vivo, USF1 is phosphorylated in spontaneously contracting cardiomyocytes, correlating with enhanced HME binding and α-MHC promoter activity.","method":"In vitro kinase assay (PKC, PKA, CK2 with purified rat USF1), gel shift assay, 2D gel electrophoresis of in vivo phosphorylated USF1, luciferase reporter assay","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with purified protein + functional EMSA + in vivo 2D phosphoprotein analysis, Moderate evidence","pmids":["12063293"],"is_preprint":false},{"year":2014,"finding":"Protein kinase CK2 phosphorylates USF1 at threonine 100 (identified by deletion and point mutants); inhibition of CK2 kinase activity enhances USF1–USF2 heterodimerization and stimulates transcription from glucokinase and fatty acid synthase promoters but not the heme oxygenase-1 promoter.","method":"In vitro CK2 kinase assay, deletion and point mutant mapping (Thr100), USF1-USF2 binding assay, transactivation reporter assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay + site-specific mutagenesis + heterodimerization binding assay + reporter assay, Moderate evidence","pmids":["25194820"],"is_preprint":false},{"year":2017,"finding":"CK2 phosphorylation of USF1 modulates USF1–PDX-1 interaction and represses PDX-1 promoter transcription; inhibition of CK2 abrogates USF1 binding to the PDX-1 promoter and relieves USF1-mediated transrepression, enhancing insulin expression and secretion from primary islets.","method":"Transactivation assay, promoter binding assay with phosphomutant USF1, CK2 inhibitors, Co-IP (USF1–PDX1 interaction), primary islet insulin secretion assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP + phosphomutant + primary islet functional assay, Moderate evidence (extends CK2/USF1 mechanism)","pmids":["29180680"],"is_preprint":false},{"year":2016,"finding":"USF1 deficiency in mice activates brown adipose tissue (BAT) and enhances adrenergic thermogenesis; USF1 silencing in brown adipocytes amplifies the adrenergic response. Usf1 inactivation directs triglycerides from circulation to BAT via a lipoprotein lipase-dependent mechanism, increasing energy expenditure and improving cardiometabolic health.","method":"Usf1 knockout mice (diet-induced dyslipidemia model), USF1 siRNA in brown adipocytes (adrenergic response), lipoprotein lipase activity assays, metabolic phenotyping, mitochondrial complex quantification","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with direct cellular mechanistic follow-up (siRNA in brown adipocytes + LPL assay) plus multiple metabolic readouts, Strong evidence","pmids":["26819196"],"is_preprint":false},{"year":2003,"finding":"USF1 and USF2 bind to an E-box (CAGCTG) in the first intron of the FcεRI alpha chain gene; this complex activates FcεRI alpha chain expression. Overexpression of USF2 antisense repressed FcεRI alpha chain promoter activity and decreased alpha chain mRNA levels in mast cell lines.","method":"EMSA with antibody supershift and in vitro translated USF1/USF2, reporter assay (orientation/position dependence), USF2 antisense overexpression","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA + reporter + antisense functional assay, Moderate evidence (single lab)","pmids":["11180124"],"is_preprint":false},{"year":2011,"finding":"USF1 is activated by GSK3 phosphorylation (at Thr-153 and Ser-186); upon PI3K inhibition, Max/Mnt complexes dissociate from target gene promoters and USF1 (and MITF) bind E-boxes to induce proapoptotic and cell cycle arrest genes. siRNA against USF1 reduces transcriptional induction of these genes and protects cells from apoptosis.","method":"ChIP (Max, Mnt, USF1, MITF binding), RNAi (USF1, MITF, FoxO3a), in vitro GSK3 phosphorylation (Thr153/Ser186 identified), PI3K inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro kinase assay + ChIP + RNAi + functional apoptosis assay, Moderate evidence","pmids":["21873430"],"is_preprint":false},{"year":2008,"finding":"Retinoic acid triggers a feed-forward transcriptional loop in which CREB directly mediates early-phase MKP1 induction, and CREB indirectly induces USF1, which then mediates the later phase of MKP1 stimulation; both CREB and USF1 bind the MKP1 promoter (confirmed by ChIP and gel shift). Silencing USF1 with siRNA blocks the late-phase biological effects of retinoic acid on HIV-infected podocytes.","method":"Gel shift assay, ChIP (USF1 binding to MKP1 promoter), luciferase reporter with CRE/Ebox mutations, siRNA knockdown (USF1, CREB, MKP1)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — ChIP + EMSA + reporter mutagenesis + siRNA functional readout, Moderate evidence","pmids":["18625721"],"is_preprint":false},{"year":2007,"finding":"v-Src recruits HDAC1 into a USF1–Sp1–Sp3 complex at the SSeCKS alpha promoter to repress its transcription; v-Src does not alter USF1 binding at the E-box but increases Sp1/Sp3 binding at the GC-box. HDAC inhibitor treatment restores SSeCKS transcript levels; knockdown of HDAC1 is necessary and sufficient for repression of alpha promoter activity.","method":"Promoter deletion analysis, ChIP (HDAC1, USF1, Sp1/Sp3 recruitment), HDAC inhibitor (TSA) rescue, Co-IP, siRNA knockdown of HDAC1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP + Co-IP + siRNA + pharmacological rescue with multiple readouts, Moderate evidence","pmids":["17626016"],"is_preprint":false},{"year":2016,"finding":"USF1 acetylation (induced by HDAC2/3 inhibitor apicidin) increases USF1 association with HDAC2/3 and with the ADAM10 promoter, thereby increasing ADAM10 transcription; USF1 knockdown prevents apicidin-mediated ADAM10 upregulation. ERK signaling is required for apicidin's effect on ADAM10 but does not affect USF1 phosphorylation.","method":"Luciferase reporter assay, siRNA knockdown (USF1, HDAC2/3), Co-IP (USF1–HDAC2/3 interaction), ChIP (USF1 binding to ADAM10 promoter), ERK inhibitor experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP + Co-IP + siRNA + reporter, Moderate evidence (single lab)","pmids":["28003340"],"is_preprint":false},{"year":2023,"finding":"PTP4A1 dephosphorylates USF1 at S309, which increases USF1 transcriptional activity and induces A20 (TNFAIP3) expression, thereby inhibiting NF-κB-mediated vascular inflammation. Loss of PTP4A1 reduces USF1 activity and exacerbates atherogenesis in ApoE−/− mice.","method":"shRNA knockdown, overexpression, luciferase reporter assay, ChIP (USF1 binding to A20 promoter), Co-IP, Ptp4a1 KO and transgenic mice, in vivo atherosclerosis model","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — direct PTM identification (dephosphorylation at S309) + ChIP + Co-IP + KO mouse in vivo phenotype, Moderate evidence","pmids":["36534975"],"is_preprint":false},{"year":2003,"finding":"USF1 and USF2 bind to the E-box (CACGTG) in the FAS promoter insulin response sequence; USF binding sites are required for thymidylate synthase (TS) transcriptional regulation; a SNP in the second repeat of the 3R allele abolishes USF binding and reduces TS transcriptional activation.","method":"EMSA, chromatin immunoprecipitation (in vivo USF binding to TS tandem repeats), mutagenesis of USF sites, reporter assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — EMSA + ChIP (in vivo occupancy) + mutagenesis + reporter assay, Moderate evidence","pmids":["12782596"],"is_preprint":false},{"year":2003,"finding":"USF1 activates the COX-2 gene promoter through a proximal CRE/E-box element at −56 to −48; MEK/ERK1/2 signaling (activated by H. pylori virulence factors outside the cagPAI) mediates H. pylori-dependent USF1/-2 activation of the COX-2 promoter.","method":"Promoter deletion and functional reporter assay, EMSA (USF1/2 binding identification), MEK/ERK inhibitor studies","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay + EMSA + kinase pathway inhibition, Moderate evidence (single lab)","pmids":["14531897"],"is_preprint":false},{"year":2000,"finding":"USF1 and USF2 are major transcription factors binding the FMR1 promoter in brain and testis extracts; methylation of the FMR1 promoter affects binding of USF1 and USF2 (and abolishes alpha-Pal/Nrf-1 binding), providing a mechanism by which methylation silences FMR1 transcription beyond histone deacetylation.","method":"EMSA with brain and testis nuclear extracts, antibody supershift, promoter methylation and binding assays, reporter gene assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA with supershift + methylation-binding correlation + reporter assays, Moderate evidence","pmids":["11058604"],"is_preprint":false},{"year":2003,"finding":"NF-Y interacts biochemically with USF1/USF2 on the HOXB4 promoter; formation of the NF-Y/USF1/USF2 complex is required for full HOXB4 promoter activity in hematopoietic cells. NF-Y occupancy decreases with granulocytic differentiation as shown by ChIP.","method":"Co-immunoprecipitation (NF-Y/USF1/2 interaction), ChIP (NF-Y occupancy at HOXB4 promoter), reporter assays with binding site mutations","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — Co-IP + ChIP + reporter with mutations, Moderate evidence","pmids":["12791656"],"is_preprint":false},{"year":2000,"finding":"USF1 and USF2 bind to the HOXB4 promoter E-box (HXRE-2) and activate HOXB4 transcription through the MAP kinase pathway; USF1 and USF2 (but not MITF) induce the HOXB4 promoter in response to cytokines promoting stem cell self-renewal in both K562 and CD34+ hematopoietic cells.","method":"Yeast one-hybrid screen, EMSA, cotransfection reporter assays in K562 and primary CD34+ cells, E-box mutation analysis","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — yeast one-hybrid + EMSA + reporter in primary cells, Moderate evidence","pmids":["11085749"],"is_preprint":false},{"year":2004,"finding":"USF1 (and ERα) are components of a multi-protein complex at the ERα minimal promoter; USF1 directly binds the imperfect E-box in the ERα minimal promoter (by EMSA), and ERα interacts with USF1 in vitro (GST pulldown); combined expression of Sp1, USF1, and ERα synergistically transactivates the ERα minimal promoter in MCF-7 cells.","method":"EMSA, GST pulldown (ERα–USF1 interaction), cotransfection reporter assay","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA + GST pulldown + reporter synergy, Moderate evidence (single lab)","pmids":["15111769"],"is_preprint":false},{"year":2011,"finding":"USF1 plays a critical role in diabetic kidney disease; high glucose inhibits AMPK activity and increases USF1 nuclear translocation; USF1 knockout diabetic mice display significantly less albuminuria and mesangial matrix expansion, and reduced TGF-β1 and renin expression. AMPK activation with AICAR reduces nuclear USF1 accumulation.","method":"USF1 KO mouse × Akita diabetic mouse (loss-of-function + disease model), AMPK activation/inhibition in mesangial cells, nuclear fractionation (USF1 localization)","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with quantitative disease phenotypes + cellular AMPK/USF1 localization mechanism, Moderate evidence","pmids":["21543418"],"is_preprint":false},{"year":2024,"finding":"USF1 knockdown in human macrophages decreases phagocytosis, chemotaxis, and actin content, and alters expression of adhesion and extracellular matrix remodeling genes; loss of USF1 increases macrophage cell size and alters morphology, phenocopying aging-related macrophage functional decline.","method":"siRNA knockdown of USF1 in human monocyte-derived macrophages, phagocytosis assay, chemotaxis assay, actin content measurement, transcriptomics","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — KD with specific functional phenotypes (phagocytosis, chemotaxis, actin) plus transcriptomics, Moderate evidence","pmids":["38578825"],"is_preprint":false},{"year":2024,"finding":"USF1 transcriptionally activates USP14, which promotes deubiquitination and stabilization of NLRC5, leading to Smad2/3 pathway activation and endothelial-to-mesenchymal transition (EndMT) in atherosclerosis. USF1 knockdown inhibits EndMT and delays atherosclerosis progression in ApoE−/− mice.","method":"Dual-luciferase reporter assay (USF1→USP14 promoter), ChIP (USF1 binding to USP14 promoter), Co-IP (USP14–NLRC5 interaction), shRNA knockdown rescue experiments, in vivo ApoE−/− mouse atherosclerosis model","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"High","confidence_rationale":"Tier 2 — ChIP + reporter + Co-IP + in vivo mouse model with multiple rescue experiments, Moderate evidence","pmids":["38424494"],"is_preprint":false},{"year":2003,"finding":"A novel alternatively spliced isoform of human USF1 (USF1/BD), lacking the N-terminal transactivation domain, localizes to the nucleus and represses the angiotensinogen gene promoter; USF1/BD can form homodimers and heterodimers with USF1(wt) and bind E-box DNA in vitro.","method":"cDNA cloning, nuclear localization (ectopic expression), in vitro translation/dimerization assay, EMSA, reporter assay","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — molecular cloning + localization + in vitro DNA binding + reporter assay, Moderate evidence","pmids":["12851711"],"is_preprint":false},{"year":2018,"finding":"AKT-mediated phosphorylation of USF1 (induced by insulin via PI3K/AKT) enhances USF1 binding to the WBP2 promoter E-box and increases WBP2 transcription; USF1 is overexpressed in breast cancer cell lines and tissues and promotes cancer cell proliferation.","method":"Yeast one-hybrid (USF1 as E-box binder of WBP2 promoter), ChIP (USF1 binding to WBP2 promoter), tandem mass spectrometry (USF1 phosphorylation), reporter assay, insulin stimulation with AKT inhibitor","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — yeast one-hybrid + ChIP + MS phosphorylation identification + functional reporter, Moderate evidence","pmids":["30183375"],"is_preprint":false},{"year":2022,"finding":"USF1 drives transcription of the lncRNA FASRL through a superenhancer; FASRL in turn binds to and increases activity of ACACA (acetyl-CoA carboxylase 1), the fatty acid synthesis rate-limiting enzyme, promoting lipid accumulation in hepatocellular carcinoma.","method":"ChIP (USF1 binding to FASRL superenhancer), reporter assay, RNA pulldown (FASRL–ACACA interaction), in vitro and in vivo proliferation assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP + reporter + RNA pulldown (FASRL-ACACA), Moderate evidence (single lab)","pmids":["36307901"],"is_preprint":false}],"current_model":"USF1 is a ubiquitous bHLH-leucine zipper transcription factor that binds E-box (CANNTG) elements as homo- or heterodimers (primarily with USF2) to regulate a broad network of metabolic, stress-response, and developmental genes; its activity is controlled by multiple post-translational modifications—phosphorylation by p38 (Thr153), cyclin-dependent kinases (residues 143–197), PKC/PKA, GSK3 (Thr153/Ser186), CK2 (Thr100), and dephosphorylation by PTP4A1 (S309)—as well as by phosphorylation-dependent acetylation, which collectively modulate its DNA-binding affinity, dimerization with USF2, and target gene selectivity; USF1 also functions non-transcriptionally by forming nuclear complexes with p53 that prevent MDM2-mediated p53 degradation, recruits histone-modifying complexes (PRMT1, PCAF, SRC-1, hSET1A) to maintain active chromatin at insulator and promoter regions, cooperates with partner transcription factors (Stat1, Ets-1, NF-Y, TFII-I, PDX-1) through direct protein–protein interactions, and competes with CLOCK:BMAL1 for E-box occupancy to modulate circadian rhythms."},"narrative":{"teleology":[{"year":1995,"claim":"Identification of USF1 as the principal E-box-binding factor on the fatty acid synthase insulin response sequence established its role as a nutritionally regulated metabolic transcription factor.","evidence":"EMSA, antibody supershift, UV crosslinking, and western blotting showing USF1 protein induction in refed rat liver","pmids":["7499393"],"confidence":"High","gaps":["Mechanism by which nutritional state increases USF1 protein was not determined","No direct demonstration of USF1 necessity for FAS transcription in vivo"]},{"year":1997,"claim":"Discovery that USF1 physically and functionally synergizes with TFII-I and can antagonize AhR·Arnt at overlapping E-box/XRE sites revealed that USF1 operates through cooperative and competitive protein–DNA interactions rather than acting alone.","evidence":"Domain deletion mapping of USF1–TFII-I synergy on the AdML promoter; competitive EMSA and mRNA analysis showing USF1 blocks CYP1A1 induction","pmids":["9384587","9374477"],"confidence":"High","gaps":["Structural basis for USF1–TFII-I and USF1–AhR competition not resolved","In vivo relevance of USF1-mediated CYP1A1 repression not tested"]},{"year":1998,"claim":"Demonstration that USF1 cooperates with Stat1 at the CIITA promoter and with Ets-1 at the HIV-1 LTR showed how USF1 integrates signaling inputs from diverse transcription factor partners to control immune and viral gene expression.","evidence":"Cooperative EMSA with cis-element mutations and reporter assays (Stat1); yeast one-hybrid, Co-IP surface mapping, and dominant-negative Ets-1 experiments","pmids":["9491997","9501094"],"confidence":"High","gaps":["Whether USF1–Stat1 cooperativity extends genome-wide was unknown","Direct structural contacts between USF1 and Ets-1 were not mapped at residue resolution"]},{"year":1999,"claim":"Showing that cyclin A2/B1–Cdc2 phosphorylation of USF1 within residues 143–197 greatly increases DNA-binding activity provided the first evidence that cell-cycle kinases directly regulate USF1 function.","evidence":"In vitro kinase assay with recombinant USF1, domain deletion mapping, EMSA","pmids":["10548544"],"confidence":"High","gaps":["In vivo cell-cycle-dependent phosphorylation of USF1 was not demonstrated","Functional consequences on endogenous target gene expression were not tested"]},{"year":2001,"claim":"Use of Usf1 knockout mice established that p38-mediated phosphorylation of USF1 is essential for UV-induced activation of the tyrosinase promoter in melanocytes, linking USF1 to the stress-activated UV response in pigmentation.","evidence":"In vitro p38 kinase assay, Usf1−/− melanocytes failing to activate tyrosinase expression after UV, reporter assays","pmids":["11532965"],"confidence":"High","gaps":["Exact p38 phosphorylation site on USF1 was not identified in this study","Whether other bHLH factors compensate partially in Usf1 KO was not assessed"]},{"year":2002,"claim":"Multiple studies revealed that PKC, PKA, and CK2 phosphorylate USF1 to increase its DNA-binding activity—and that phosphorylated USF1 can both activate (α-MHC, PAI-1) and repress (iNOS) target genes—demonstrating that phosphorylation is a general regulatory switch with context-dependent transcriptional outcomes.","evidence":"In vitro kinase assays with purified USF1 (PKC/PKA/CK2), 2D gel phosphoprotein analysis in cardiomyocytes, EMSA/reporter assays for α-MHC and iNOS; wound-activated keratinocyte PAI-1 binding studies","pmids":["12063293","12225970","12235287"],"confidence":"High","gaps":["Site-specific phosphorylation residues for PKC/PKA were not mapped","Mechanism discriminating activation from repression on different promoters was not defined"]},{"year":2003,"claim":"Identification of NF-Y as a USF1 partner on the HOXB4 promoter and discovery of a dominant-negative USF1 splice variant (USF1/BD) expanded the understanding of USF1 combinatorial regulation and autoregulatory potential.","evidence":"Co-IP and ChIP for NF-Y/USF complex at HOXB4; cDNA cloning and dimerization/reporter assays for USF1/BD isoform","pmids":["12791656","12851711"],"confidence":"High","gaps":["Relative abundance and tissue distribution of USF1/BD isoform were not quantified","Whether NF-Y directly contacts USF1 or binds DNA adjacently was not resolved"]},{"year":2007,"claim":"Discovery that USF1 recruits PRMT1, PCAF, and SRC-1 to form a histone-modifying complex at the β-globin insulator established USF1 as a chromatin barrier factor, not merely a transcriptional activator.","evidence":"Co-IP of USF1–PRMT1 complex with H4R3 methyltransferase and HAT activities; siRNA knockdown causing local loss of euchromatin marks; dominant-negative USF1 peptide abolishing insulator barrier function","pmids":["17846119"],"confidence":"High","gaps":["Whether USF1 recruits similar chromatin-modifying complexes genome-wide was not tested","Mechanism of USF1-dependent complex assembly was not structurally characterized"]},{"year":2009,"claim":"Demonstration that p38-mediated Thr153 phosphorylation is a prerequisite for USF1 acetylation after DNA damage and oxidative stress revealed a hierarchical PTM code that alters USF1 transcriptional properties.","evidence":"In vitro kinase assay, site-directed mutagenesis of Thr153, acetylation assays, nuclear fractionation, reporter assays","pmids":["19389701"],"confidence":"High","gaps":["Acetyltransferase responsible for USF1 acetylation was not identified","Genome-wide consequences of phospho-acetylated USF1 were not mapped"]},{"year":2011,"claim":"GSK3 was identified as a USF1 kinase at Thr153/Ser186 that activates USF1 binding to E-boxes vacated by Max/Mnt upon PI3K inhibition, revealing a kinase-dependent E-box switching mechanism linking survival signaling to transcriptional output.","evidence":"In vitro GSK3 kinase assay with phosphosite mapping, ChIP for Max/Mnt/USF1 promoter switching, RNAi and apoptosis assays","pmids":["21873430"],"confidence":"High","gaps":["Whether GSK3 and p38 phosphorylation of Thr153 are redundant or additive was not tested","Structural basis for Max-to-USF1 E-box exchange was not resolved"]},{"year":2012,"claim":"Usf1 knockout mice showed compromised nucleotide excision repair after UV irradiation through failure to upregulate CSA and HR23A, establishing a p53-independent role for USF1 in the DNA damage response.","evidence":"Usf1 KO mouse UV irradiation model, gene expression analysis and ChIP for NER gene promoters","pmids":["22291606"],"confidence":"High","gaps":["Direct promoter mechanism (which E-boxes in CSA/HR23A) was not fully characterized","Whether USF1 also regulates other DNA repair pathways was not explored"]},{"year":2013,"claim":"Two discoveries—USF1 recruiting hSET1A to the HoxB4 promoter to govern H3K4me3 and ESC mesoderm differentiation, and USF1 competing with CLOCK:BMAL1 for genome-wide E-box occupancy—demonstrated that USF1 is both a chromatin organizer in development and a modulator of circadian transcription.","evidence":"ChIP for H3K4me3/hSET1A at HoxB4, dominant-negative and RNAi in ESC differentiation; genetic suppressor mapping plus genome-wide USF1 ChIP and saturation E-box binding in Clock mutant mice","pmids":["23754954","23580255"],"confidence":"High","gaps":["Whether hSET1A recruitment is a general feature of all USF1-bound promoters was unknown","Full circadian transcriptome regulated by USF1 was not defined"]},{"year":2014,"claim":"USF1 was shown to stabilize p53 by physically preventing MDM2-mediated degradation through a mechanism independent of USF1's own DNA-binding domain, revealing a non-transcriptional tumor-suppressive function.","evidence":"Co-IP of USF1/p53/MDM2, Usf1 KO cells with enhanced p53 degradation, rescue by truncated USF1 lacking DNA-binding and transactivation domains","pmids":["24831529"],"confidence":"High","gaps":["Domain on USF1 that directly contacts p53 and blocks MDM2 was not precisely mapped","Whether USF1–p53 interaction is regulated by USF1 PTMs was not tested"]},{"year":2014,"claim":"Identification of CK2 phosphorylation at Thr100 as a switch that inhibits USF1–USF2 heterodimerization and selectively modulates metabolic gene promoters (FAS, glucokinase but not HO-1) revealed how a single PTM can alter partner choice and target specificity.","evidence":"In vitro CK2 kinase assay, Thr100 point mutant, USF1–USF2 binding assay, reporter assays on multiple promoters","pmids":["25194820"],"confidence":"High","gaps":["In vivo metabolic consequences of CK2-USF1 phosphorylation were not tested in animal models","Structural basis for Thr100 effects on heterodimerization was not resolved"]},{"year":2016,"claim":"Usf1 knockout mice showed activated brown adipose tissue, enhanced thermogenesis, and improved cardiometabolic parameters, establishing USF1 as a negative regulator of energy expenditure and BAT function.","evidence":"Usf1 KO mice on high-fat diet, USF1 siRNA in brown adipocytes, LPL activity assays, comprehensive metabolic phenotyping","pmids":["26819196"],"confidence":"High","gaps":["Direct USF1 target genes responsible for BAT suppression were not identified","Whether pharmacological USF1 inhibition recapitulates the KO phenotype was not tested"]},{"year":2019,"claim":"H. pylori infection was found to delocalize USF1 into cytoplasmic foci, disrupting nuclear USF1–p53 complexes and promoting MDM2-dependent p53 degradation, providing a pathogen exploitation mechanism for the USF1–p53 axis.","evidence":"Immunofluorescence, Co-IP in infected cells, Usf1−/− mouse carcinogenesis model with genotoxin challenge","pmids":["31822580"],"confidence":"High","gaps":["Bacterial effector responsible for USF1 cytoplasmic relocalization was not identified","Whether other pathogens exploit the same mechanism was not explored"]},{"year":2023,"claim":"PTP4A1 dephosphorylation of USF1 at Ser309 was shown to increase USF1 activity and induce anti-inflammatory A20 expression, attenuating NF-κB-driven vascular inflammation, establishing a phosphatase-dependent activation mechanism.","evidence":"Co-IP, ChIP at A20 promoter, shRNA/overexpression, Ptp4a1 KO and transgenic mice in ApoE−/− atherosclerosis model","pmids":["36534975"],"confidence":"High","gaps":["Kinase that phosphorylates S309 to oppose PTP4A1 was not identified","Full spectrum of USF1 targets regulated by S309 phosphorylation status was not mapped"]},{"year":2024,"claim":"USF1 knockdown in human macrophages impaired phagocytosis, chemotaxis, and actin content, and USF1 was shown to drive USP14 transcription promoting NLRC5 stabilization and endothelial-to-mesenchymal transition in atherosclerosis, extending USF1's functional role to innate immune cell biology and vascular remodeling.","evidence":"siRNA in human monocyte-derived macrophages with functional assays and transcriptomics; ChIP/reporter for USF1→USP14, Co-IP for USP14–NLRC5, shRNA rescue in ApoE−/− mice","pmids":["38578825","38424494"],"confidence":"Medium","gaps":["Whether macrophage phenotypes are direct or secondary transcriptional effects is unclear","USF1→USP14→NLRC5 axis requires independent replication"]},{"year":null,"claim":"A comprehensive structural model of how multiple phosphorylation events (p38, CK2, GSK3, CDK, AKT, PKC/PKA, PTP4A1 dephosphorylation) are integrated on the same USF1 molecule to coordinate dimerization partner choice, DNA-binding selectivity, and chromatin modifier recruitment remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of USF1 or its complexes exists","Combinatorial PTM code on USF1 has not been systematically analyzed by quantitative mass spectrometry in any single system","Genome-wide mapping of USF1 target genes as a function of specific PTM states has not been performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,3,4,5,8,9,13,14,15,28]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3,4,5,12,14,15,19,20,24,27,36,39]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,11,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,10,11,34,37]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[17]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,19,21,39]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,6,7,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,31,32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[23,34,38]}],"complexes":["USF1/USF2 heterodimer","USF1-PRMT1-PCAF-SRC-1 chromatin-modifying complex","USF1-NF-Y complex"],"partners":["USF2","PRMT1","PCAF","SETD1A","TFII-I","TP53","PTP4A1","ETS1"],"other_free_text":[]},"mechanistic_narrative":"USF1 is a ubiquitously expressed bHLH-leucine zipper transcription factor that binds E-box (CANNTG) elements as homodimers or heterodimers with USF2 to regulate a diverse network of metabolic, stress-response, developmental, and immune genes. Its DNA-binding affinity and target selectivity are controlled by phosphorylation from multiple kinases—p38 (Thr153), cyclin-CDK complexes (residues 143–197), PKC/PKA, GSK3 (Thr153/Ser186), CK2 (Thr100), and AKT—as well as by phosphorylation-dependent acetylation and dephosphorylation by PTP4A1 (Ser309), which collectively tune dimerization with USF2 and transcriptional output [PMID:11532965, PMID:10548544, PMID:25194820, PMID:19389701, PMID:36534975]. Beyond canonical transcriptional activation, USF1 recruits histone-modifying complexes including PRMT1/PCAF/SRC-1 and hSET1A to establish active chromatin marks at insulator and promoter regions, and it stabilizes p53 protein through a non-transcriptional mechanism that blocks MDM2-mediated degradation [PMID:17846119, PMID:23754954, PMID:24831529]. USF1 also competes with CLOCK:BMAL1 for E-box occupancy to modulate circadian gene expression, and its loss in mice activates brown adipose tissue thermogenesis, ameliorates diabetic nephropathy, and compromises UV-induced DNA repair and pigmentation responses [PMID:23580255, PMID:26819196, PMID:21543418, PMID:22291606]."},"prefetch_data":{"uniprot":{"accession":"P22415","full_name":"Upstream stimulatory factor 1","aliases":["Class B basic helix-loop-helix protein 11","bHLHb11","Major late transcription factor 1"],"length_aa":310,"mass_kda":33.5,"function":"Transcription factor that binds to a symmetrical DNA sequence (E-boxes) (5'-CACGTG-3') that is found in a variety of viral and cellular promoters","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P22415/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/USF1","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/USF1","total_profiled":1310},"omim":[{"mim_id":"621053","title":"NEDD4-BINDING PROTEIN 2-LIKE 1; N4BP2L1","url":"https://www.omim.org/entry/621053"},{"mim_id":"616041","title":"THIOSULFATE SULFURTRANSFERASE (RHODANESE)-LIKE DOMAIN-CONTAINING PROTEIN 1; TSTD1","url":"https://www.omim.org/entry/616041"},{"mim_id":"612822","title":"UTP20 SMALL SUBUNIT PROCESSOME COMPONENT; UTP20","url":"https://www.omim.org/entry/612822"},{"mim_id":"607043","title":"TRAF3-INTERACTING PROTEIN 2; TRAF3IP2","url":"https://www.omim.org/entry/607043"},{"mim_id":"606599","title":"THIOREDOXIN-INTERACTING PROTEIN; TXNIP","url":"https://www.omim.org/entry/606599"}],"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/USF1"},"hgnc":{"alias_symbol":["UEF","MLTFI","bHLHb11"],"prev_symbol":[]},"alphafold":{"accession":"P22415","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P22415","model_url":"https://alphafold.ebi.ac.uk/files/AF-P22415-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P22415-F1-predicted_aligned_error_v6.png","plddt_mean":60.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USF1","jax_strain_url":"https://www.jax.org/strain/search?query=USF1"},"sequence":{"accession":"P22415","fasta_url":"https://rest.uniprot.org/uniprotkb/P22415.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P22415/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P22415"}},"corpus_meta":[{"pmid":"9491997","id":"PMC_9491997","title":"Activation of the MHC class II transactivator CIITA by interferon-gamma requires cooperative interaction between Stat1 and USF-1.","date":"1998","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/9491997","citation_count":306,"is_preprint":false},{"pmid":"12782596","id":"PMC_12782596","title":"A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity.","date":"2003","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12782596","citation_count":305,"is_preprint":false},{"pmid":"14991056","id":"PMC_14991056","title":"Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1).","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14991056","citation_count":242,"is_preprint":false},{"pmid":"9384587","id":"PMC_9384587","title":"Cloning of an inr- and E-box-binding protein, TFII-I, that interacts physically and functionally with USF1.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9384587","citation_count":175,"is_preprint":false},{"pmid":"11532965","id":"PMC_11532965","title":"The Usf-1 transcription factor is a novel target for the stress-responsive p38 kinase and mediates UV-induced Tyrosinase expression.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11532965","citation_count":173,"is_preprint":false},{"pmid":"19730683","id":"PMC_19730683","title":"The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.","date":"2009","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19730683","citation_count":132,"is_preprint":false},{"pmid":"19750004","id":"PMC_19750004","title":"A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia.","date":"2009","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19750004","citation_count":126,"is_preprint":false},{"pmid":"9501094","id":"PMC_9501094","title":"Cooperative interaction of ets-1 with USF-1 required for HIV-1 enhancer activity in T cells.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9501094","citation_count":118,"is_preprint":false},{"pmid":"7499393","id":"PMC_7499393","title":"Upstream stimulatory factors bind to insulin response sequence of the fatty acid synthase promoter. 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Implications for Fragile X mental retardation syndrome.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11058604","citation_count":77,"is_preprint":false},{"pmid":"31822580","id":"PMC_31822580","title":"USF1 defect drives p53 degradation during Helicobacter pylori infection and accelerates gastric carcinogenesis.","date":"2019","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/31822580","citation_count":74,"is_preprint":false},{"pmid":"14531897","id":"PMC_14531897","title":"Helicobacter pylori stimulates host cyclooxygenase-2 gene transcription: critical importance of MEK/ERK-dependent activation of USF1/-2 and CREB transcription factors.","date":"2003","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/14531897","citation_count":71,"is_preprint":false},{"pmid":"16076849","id":"PMC_16076849","title":"USF1 and dyslipidemias: converging evidence for a functional intronic variant.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16076849","citation_count":69,"is_preprint":false},{"pmid":"31468594","id":"PMC_31468594","title":"LncRNA LOXL1-AS1 facilitates the tumorigenesis and stemness of gastric carcinoma via regulation of miR-708-5p/USF1 pathway.","date":"2019","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/31468594","citation_count":68,"is_preprint":false},{"pmid":"23580255","id":"PMC_23580255","title":"Usf1, a suppressor of the circadian Clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice.","date":"2013","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/23580255","citation_count":65,"is_preprint":false},{"pmid":"15175273","id":"PMC_15175273","title":"Variation in USF1 shows haplotype effects, gene : gene and gene : environment associations with glucose and lipid parameters in the European Atherosclerosis Research Study II.","date":"2004","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15175273","citation_count":65,"is_preprint":false},{"pmid":"26819196","id":"PMC_26819196","title":"USF1 deficiency activates brown adipose tissue and improves cardiometabolic health.","date":"2016","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26819196","citation_count":64,"is_preprint":false},{"pmid":"12791656","id":"PMC_12791656","title":"NF-Y cooperates with USF1/2 to induce the hematopoietic expression of HOXB4.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12791656","citation_count":63,"is_preprint":false},{"pmid":"23754954","id":"PMC_23754954","title":"USF1 and hSET1A mediated epigenetic modifications regulate lineage differentiation and HoxB4 transcription.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23754954","citation_count":52,"is_preprint":false},{"pmid":"11241666","id":"PMC_11241666","title":"Upstream stimulating factor-1 (USF1) and USF2 bind to and activate the promoter of the adenomatous polyposis coli (APC) tumor suppressor gene.","date":"2001","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11241666","citation_count":51,"is_preprint":false},{"pmid":"30743215","id":"PMC_30743215","title":"Knockdown of USF1 Inhibits the Vasculogenic Mimicry of Glioma Cells via Stimulating SNHG16/miR-212-3p and linc00667/miR-429 Axis.","date":"2019","source":"Molecular therapy. 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the GAS/E-box motif in the CIITA promoter IV; Stat1 can only bind to the GAS site in the presence of USF1 at the adjacent E-box, establishing a cooperative protein-DNA interaction required for IFNγ-induced MHC class II expression.\",\n      \"method\": \"EMSA (cooperative binding assays), transactivation reporter assays, in vivo footprinting\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays with multiple cis-element mutations and functional transactivation data, Moderate evidence from single lab with orthogonal methods\",\n      \"pmids\": [\"9491997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"USF1 physically and functionally interacts with TFII-I (a 120 kDa factor binding both Inr and E-box elements); domains of USF1 required for independent and synergistic transcriptional activation were mapped, and the two factors act synergistically to activate transcription through both Inr and E-box elements of the adenovirus major late promoter.\",\n      \"method\": \"cDNA cloning, ectopic expression, in vivo transcription assays, domain deletion analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction with domain mapping plus functional transcriptional synergy demonstrated in vivo, Moderate evidence\",\n      \"pmids\": [\"9384587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"USF1 is phosphorylated and activated by the stress-responsive p38 kinase following UV irradiation, and is required for UV-induced activation of the Tyrosinase promoter in melanocytes; Usf1 knockout melanocytes fail to activate Tyrosinase expression in response to UV.\",\n      \"method\": \"In vitro kinase assay (p38 phosphorylation of USF1), USF1 knockout mouse melanocytes, reporter gene assays, functional UV response assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — kinase assay plus KO mouse phenotype plus reporter assay, Moderate-Strong evidence\",\n      \"pmids\": [\"11532965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"USF1 directly interacts with Ets-1 through their DNA-binding domains; the USF1–Ets1 complex binds adjacent E-box and Ets sites in the HIV-1 LTR distal enhancer and synergizes for DNA binding and transactivation in T cells. A dominant-negative Ets-1 mutant inhibits USF1-mediated transactivation in an Ets-site-independent but USF1-binding-surface-dependent manner.\",\n      \"method\": \"Yeast one-hybrid screen, co-IP/pulldown (binding surface mapping), reporter assays with site-directed mutations, dominant-negative constructs\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast one-hybrid plus reciprocal surface mapping plus functional reporter assays, Moderate evidence\",\n      \"pmids\": [\"9501094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"USF1 and USF2 are the major proteins binding the E-box-containing insulin response sequence (IRS) of the fatty acid synthase (FAS) promoter; USF1 protein level is dramatically increased in liver of refed rats (regulated by nutritional state), while a 17-kDa USF1-related protein is inversely regulated, suggesting USF1 mediates insulin/nutritional regulation of FAS transcription.\",\n      \"method\": \"Gel shift competition assay, USF antibody supershift, UV cross-linking, western blotting (nutritional regulation)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods (EMSA, supershift, UV crosslink, western), Moderate evidence\",\n      \"pmids\": [\"7499393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"USF1 directly interacts with the histone H4R3-specific methyltransferase PRMT1, and forms a complex with PRMT1, PCAF, and SRC-1 having both H4R3 methyltransferase and HAT activities. USF1 siRNA knockdown causes localized loss of H4R3 methylation and euchromatin-associated histone modifications at the chicken beta-globin insulator, and a dominant-negative USF1 peptide abolishes insulator barrier function.\",\n      \"method\": \"Co-immunoprecipitation, histone methyltransferase assay, HAT assay, siRNA knockdown with ChIP, dominant-negative peptide functional assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical complex reconstitution with enzymatic activity assay plus siRNA + ChIP with functional readout, Moderate-Strong evidence\",\n      \"pmids\": [\"17846119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"UV-induced activation of POMC and MC1R promoters is mediated by USF1 through p38 stress-activated kinase signaling; melanocytes from Usf1−/− mice exhibit a defective UV response and fail to activate POMC and MC1R expression after UV irradiation.\",\n      \"method\": \"Knockout mouse melanocytes (USF1−/−), reporter assays, RT-PCR for gene expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with specific UV-response phenotype plus reporter assays, Moderate evidence\",\n      \"pmids\": [\"15358786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In response to DNA damage, oxidative stress, and cellular infection, USF1 is acetylated in a phospho-Thr-153-dependent fashion (p38-mediated phosphorylation on Thr-153 is a prerequisite for acetylation). Phospho-acetylated USF1 is nuclear, binds DNA, but displays altered (reduced) transcriptional activation properties toward pigmentation and cell cycle genes.\",\n      \"method\": \"In vitro kinase assay (p38 on USF1 Thr-153), acetylation assays, site-directed mutagenesis, nuclear fractionation, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation + acetylation assays + mutagenesis + functional reporter data, Moderate evidence\",\n      \"pmids\": [\"19389701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"DNA-binding activity of USF1 is greatly increased by phosphorylation by cyclin A2-p34(cdc2) or cyclin B1-p34(cdc2) complexes in vitro; the phosphorylation site was localized to residues 143–197, a region outside the minimal DNA-binding domain but overlapping the USF-specific region.\",\n      \"method\": \"In vitro kinase assay (cyclinA2/B1-cdc2 with recombinant USF1), EMSA (DNA binding), deletion/phosphorylation mapping\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with recombinant protein + domain mapping + EMSA, Moderate evidence\",\n      \"pmids\": [\"10548544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USF1 competes with the CLOCK:BMAL1 complex for binding to E-box sites in circadian target genes. A SNP in the Usf1 promoter elevates USF1 transcript and protein, which suppresses the ClockΔ19 mutant behavioral phenotype. Saturation binding experiments show reduced affinity of the CLOCKΔ19:BMAL1 complex for E-box sites, permitting increased USF1 genome-wide occupancy.\",\n      \"method\": \"Genetic suppressor mapping, SNP identification, quantitative ChIP (genome-wide USF1 occupancy), saturation binding experiments, behavioral circadian phenotyping\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis + genome-wide ChIP + biochemical binding assays, Moderate-Strong evidence\",\n      \"pmids\": [\"23580255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USF1 stabilizes p53 protein by preventing MDM2-mediated p53 degradation; loss of USF1 enhances p53–MDM2 complex formation, leading to proteasomal degradation of p53. A USF1 truncated protein lacking its DNA-binding and transactivation domains is sufficient to restore p53 stability, indicating a non-transcriptional mechanism.\",\n      \"method\": \"Co-immunoprecipitation (USF1/p53/MDM2), Usf1 KO mouse cells, siRNA knockdown, re-expression of truncated USF1, Nutlin-3 comparison, western blotting\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP + KO mouse + truncation rescue + pharmacological comparison, Moderate evidence\",\n      \"pmids\": [\"24831529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"H. pylori delocalizes USF1 into cytoplasmic foci near cell membranes, prevents nuclear USF1/p53 complex formation, and promotes MDM2-mediated degradation of p53. USF1 physically interacts with p53 in the nucleus; this complex is disrupted by H. pylori infection, impairing p53 transcriptional function and promoting genetic instability.\",\n      \"method\": \"Immunofluorescence (subcellular localization), Co-IP (USF1/p53), Usf1−/− mouse in vivo carcinogenesis model, genotoxin (camptothecin) challenge\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP + direct localization experiment + KO mouse in vivo, Moderate-Strong evidence\",\n      \"pmids\": [\"31822580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USF1 recruits the hSET1A histone H3K4 methyltransferase complex to the HoxB4 promoter, governing H3K4me3 modifications and transcription preinitiation complex assembly. Disruption of USF1 by dominant-negative AUSF1 or siRNA against hSET1A reduces mesoderm marker expression and inhibits lineage differentiation; ectopic USF1 in ESCs promotes mesoderm/hematopoietic differentiation.\",\n      \"method\": \"ChIP (H3K4me3, USF1, hSET1A at HoxB4 promoter), dominant-negative overexpression, RNAi knockdown, ESC differentiation assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + dominant-negative + RNAi + differentiation phenotype with multiple readouts, Moderate-Strong evidence\",\n      \"pmids\": [\"23754954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"USF1 binds to the E-box motif at −160 to −165 in the PAI-1 proximal promoter in wound-activated keratinocytes; E-box binding activity increases within 2 hours of monolayer scrape injury; USF1 isolated by PAI-1 promoter-DNA affinity chromatography is almost exclusively phosphorylated. Antisense PAI-1 knockdown significantly impairs keratinocyte migration.\",\n      \"method\": \"EMSA, UV crosslinking, DNA affinity chromatography, immunocytochemistry (USF1 localization), antisense knockdown (migration assay)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA + affinity chromatography + functional localization + migration assay, Weak-Moderate (single lab)\",\n      \"pmids\": [\"12235287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"USF1 (and USF2) bind to an E-box at −893/−888 of the murine iNOS promoter and trans-repress basal and IL-1β-induced iNOS transcription in mesangial cells; mutation of the E-box augments iNOS response to IL-1β, and cotransfection of dominant-negative USF-2 or E-box decoys augments IL-1β stimulation of iNOS promoter activity.\",\n      \"method\": \"Site-directed mutagenesis, EMSA (supershift), cotransfection of USF expression vectors and dominant-negative mutants, luciferase reporter assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis + EMSA + dominant-negative + reporter assay, Moderate evidence\",\n      \"pmids\": [\"12225970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"USF1 competitively binds to the xenobiotic response element (XRE) of the rabbit CYP1A1 gene, overlapping the AhR·Arnt binding site, and antagonizes AhR·Arnt-mediated CYP1A1 induction; transfection of USF1 expression vector blocks AhR/Arnt interaction with XRE and suppresses CYP1A1 mRNA induction.\",\n      \"method\": \"Supershift EMSA, competition gel shift, transfection with USF1 expression vector, S1 nuclease protection assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — EMSA competition + mutagenesis + transfection functional assay + mRNA quantification, Moderate evidence\",\n      \"pmids\": [\"9374477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"USF1 interacts with the MTF-1 metalloregulatory factor to cooperatively regulate MT-I gene expression in response to zinc in visceral endoderm cells; USF1 binds an E-box1 sequence at −223 bp in the MT-I promoter, and MTF-1 is absolutely essential while USF1 is required for optimal expression.\",\n      \"method\": \"USF1 and MTF1 knockout mouse embryos (genetic epistasis), promoter reporter assays, zinc deprivation/repletion\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (double KO phenotyping) + functional promoter analysis, Moderate evidence\",\n      \"pmids\": [\"11230134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"USF1 is required for UV-induced upregulation of DNA repair genes CSA and HR23A (TCR and GGR NER components) through a p53-independent mechanism; Usf1 knockout mice display compromised DNA repair after UV irradiation.\",\n      \"method\": \"In vitro and in vivo UV irradiation assays, Usf1 KO mouse model, gene expression analysis, ChIP\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with specific NER phenotype + ChIP + in vitro assays, Moderate evidence\",\n      \"pmids\": [\"22291606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"USF1 binds to the E-box at −47 in the cardiac α-MHC promoter (hemodynamic response element); phosphorylation of USF1 by PKC or PKA in vitro increases its DNA-binding activity to the HME. PKC-mediated phosphorylation also causes USF1 multimerization. In vivo, USF1 is phosphorylated in spontaneously contracting cardiomyocytes, correlating with enhanced HME binding and α-MHC promoter activity.\",\n      \"method\": \"In vitro kinase assay (PKC, PKA, CK2 with purified rat USF1), gel shift assay, 2D gel electrophoresis of in vivo phosphorylated USF1, luciferase reporter assay\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with purified protein + functional EMSA + in vivo 2D phosphoprotein analysis, Moderate evidence\",\n      \"pmids\": [\"12063293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Protein kinase CK2 phosphorylates USF1 at threonine 100 (identified by deletion and point mutants); inhibition of CK2 kinase activity enhances USF1–USF2 heterodimerization and stimulates transcription from glucokinase and fatty acid synthase promoters but not the heme oxygenase-1 promoter.\",\n      \"method\": \"In vitro CK2 kinase assay, deletion and point mutant mapping (Thr100), USF1-USF2 binding assay, transactivation reporter assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay + site-specific mutagenesis + heterodimerization binding assay + reporter assay, Moderate evidence\",\n      \"pmids\": [\"25194820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CK2 phosphorylation of USF1 modulates USF1–PDX-1 interaction and represses PDX-1 promoter transcription; inhibition of CK2 abrogates USF1 binding to the PDX-1 promoter and relieves USF1-mediated transrepression, enhancing insulin expression and secretion from primary islets.\",\n      \"method\": \"Transactivation assay, promoter binding assay with phosphomutant USF1, CK2 inhibitors, Co-IP (USF1–PDX1 interaction), primary islet insulin secretion assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP + phosphomutant + primary islet functional assay, Moderate evidence (extends CK2/USF1 mechanism)\",\n      \"pmids\": [\"29180680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USF1 deficiency in mice activates brown adipose tissue (BAT) and enhances adrenergic thermogenesis; USF1 silencing in brown adipocytes amplifies the adrenergic response. Usf1 inactivation directs triglycerides from circulation to BAT via a lipoprotein lipase-dependent mechanism, increasing energy expenditure and improving cardiometabolic health.\",\n      \"method\": \"Usf1 knockout mice (diet-induced dyslipidemia model), USF1 siRNA in brown adipocytes (adrenergic response), lipoprotein lipase activity assays, metabolic phenotyping, mitochondrial complex quantification\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with direct cellular mechanistic follow-up (siRNA in brown adipocytes + LPL assay) plus multiple metabolic readouts, Strong evidence\",\n      \"pmids\": [\"26819196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"USF1 and USF2 bind to an E-box (CAGCTG) in the first intron of the FcεRI alpha chain gene; this complex activates FcεRI alpha chain expression. Overexpression of USF2 antisense repressed FcεRI alpha chain promoter activity and decreased alpha chain mRNA levels in mast cell lines.\",\n      \"method\": \"EMSA with antibody supershift and in vitro translated USF1/USF2, reporter assay (orientation/position dependence), USF2 antisense overexpression\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA + reporter + antisense functional assay, Moderate evidence (single lab)\",\n      \"pmids\": [\"11180124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USF1 is activated by GSK3 phosphorylation (at Thr-153 and Ser-186); upon PI3K inhibition, Max/Mnt complexes dissociate from target gene promoters and USF1 (and MITF) bind E-boxes to induce proapoptotic and cell cycle arrest genes. siRNA against USF1 reduces transcriptional induction of these genes and protects cells from apoptosis.\",\n      \"method\": \"ChIP (Max, Mnt, USF1, MITF binding), RNAi (USF1, MITF, FoxO3a), in vitro GSK3 phosphorylation (Thr153/Ser186 identified), PI3K inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay + ChIP + RNAi + functional apoptosis assay, Moderate evidence\",\n      \"pmids\": [\"21873430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Retinoic acid triggers a feed-forward transcriptional loop in which CREB directly mediates early-phase MKP1 induction, and CREB indirectly induces USF1, which then mediates the later phase of MKP1 stimulation; both CREB and USF1 bind the MKP1 promoter (confirmed by ChIP and gel shift). Silencing USF1 with siRNA blocks the late-phase biological effects of retinoic acid on HIV-infected podocytes.\",\n      \"method\": \"Gel shift assay, ChIP (USF1 binding to MKP1 promoter), luciferase reporter with CRE/Ebox mutations, siRNA knockdown (USF1, CREB, MKP1)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + EMSA + reporter mutagenesis + siRNA functional readout, Moderate evidence\",\n      \"pmids\": [\"18625721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"v-Src recruits HDAC1 into a USF1–Sp1–Sp3 complex at the SSeCKS alpha promoter to repress its transcription; v-Src does not alter USF1 binding at the E-box but increases Sp1/Sp3 binding at the GC-box. HDAC inhibitor treatment restores SSeCKS transcript levels; knockdown of HDAC1 is necessary and sufficient for repression of alpha promoter activity.\",\n      \"method\": \"Promoter deletion analysis, ChIP (HDAC1, USF1, Sp1/Sp3 recruitment), HDAC inhibitor (TSA) rescue, Co-IP, siRNA knockdown of HDAC1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + Co-IP + siRNA + pharmacological rescue with multiple readouts, Moderate evidence\",\n      \"pmids\": [\"17626016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USF1 acetylation (induced by HDAC2/3 inhibitor apicidin) increases USF1 association with HDAC2/3 and with the ADAM10 promoter, thereby increasing ADAM10 transcription; USF1 knockdown prevents apicidin-mediated ADAM10 upregulation. ERK signaling is required for apicidin's effect on ADAM10 but does not affect USF1 phosphorylation.\",\n      \"method\": \"Luciferase reporter assay, siRNA knockdown (USF1, HDAC2/3), Co-IP (USF1–HDAC2/3 interaction), ChIP (USF1 binding to ADAM10 promoter), ERK inhibitor experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + Co-IP + siRNA + reporter, Moderate evidence (single lab)\",\n      \"pmids\": [\"28003340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTP4A1 dephosphorylates USF1 at S309, which increases USF1 transcriptional activity and induces A20 (TNFAIP3) expression, thereby inhibiting NF-κB-mediated vascular inflammation. Loss of PTP4A1 reduces USF1 activity and exacerbates atherogenesis in ApoE−/− mice.\",\n      \"method\": \"shRNA knockdown, overexpression, luciferase reporter assay, ChIP (USF1 binding to A20 promoter), Co-IP, Ptp4a1 KO and transgenic mice, in vivo atherosclerosis model\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct PTM identification (dephosphorylation at S309) + ChIP + Co-IP + KO mouse in vivo phenotype, Moderate evidence\",\n      \"pmids\": [\"36534975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"USF1 and USF2 bind to the E-box (CACGTG) in the FAS promoter insulin response sequence; USF binding sites are required for thymidylate synthase (TS) transcriptional regulation; a SNP in the second repeat of the 3R allele abolishes USF binding and reduces TS transcriptional activation.\",\n      \"method\": \"EMSA, chromatin immunoprecipitation (in vivo USF binding to TS tandem repeats), mutagenesis of USF sites, reporter assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — EMSA + ChIP (in vivo occupancy) + mutagenesis + reporter assay, Moderate evidence\",\n      \"pmids\": [\"12782596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"USF1 activates the COX-2 gene promoter through a proximal CRE/E-box element at −56 to −48; MEK/ERK1/2 signaling (activated by H. pylori virulence factors outside the cagPAI) mediates H. pylori-dependent USF1/-2 activation of the COX-2 promoter.\",\n      \"method\": \"Promoter deletion and functional reporter assay, EMSA (USF1/2 binding identification), MEK/ERK inhibitor studies\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay + EMSA + kinase pathway inhibition, Moderate evidence (single lab)\",\n      \"pmids\": [\"14531897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"USF1 and USF2 are major transcription factors binding the FMR1 promoter in brain and testis extracts; methylation of the FMR1 promoter affects binding of USF1 and USF2 (and abolishes alpha-Pal/Nrf-1 binding), providing a mechanism by which methylation silences FMR1 transcription beyond histone deacetylation.\",\n      \"method\": \"EMSA with brain and testis nuclear extracts, antibody supershift, promoter methylation and binding assays, reporter gene assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA with supershift + methylation-binding correlation + reporter assays, Moderate evidence\",\n      \"pmids\": [\"11058604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NF-Y interacts biochemically with USF1/USF2 on the HOXB4 promoter; formation of the NF-Y/USF1/USF2 complex is required for full HOXB4 promoter activity in hematopoietic cells. NF-Y occupancy decreases with granulocytic differentiation as shown by ChIP.\",\n      \"method\": \"Co-immunoprecipitation (NF-Y/USF1/2 interaction), ChIP (NF-Y occupancy at HOXB4 promoter), reporter assays with binding site mutations\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP + ChIP + reporter with mutations, Moderate evidence\",\n      \"pmids\": [\"12791656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"USF1 and USF2 bind to the HOXB4 promoter E-box (HXRE-2) and activate HOXB4 transcription through the MAP kinase pathway; USF1 and USF2 (but not MITF) induce the HOXB4 promoter in response to cytokines promoting stem cell self-renewal in both K562 and CD34+ hematopoietic cells.\",\n      \"method\": \"Yeast one-hybrid screen, EMSA, cotransfection reporter assays in K562 and primary CD34+ cells, E-box mutation analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast one-hybrid + EMSA + reporter in primary cells, Moderate evidence\",\n      \"pmids\": [\"11085749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"USF1 (and ERα) are components of a multi-protein complex at the ERα minimal promoter; USF1 directly binds the imperfect E-box in the ERα minimal promoter (by EMSA), and ERα interacts with USF1 in vitro (GST pulldown); combined expression of Sp1, USF1, and ERα synergistically transactivates the ERα minimal promoter in MCF-7 cells.\",\n      \"method\": \"EMSA, GST pulldown (ERα–USF1 interaction), cotransfection reporter assay\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA + GST pulldown + reporter synergy, Moderate evidence (single lab)\",\n      \"pmids\": [\"15111769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USF1 plays a critical role in diabetic kidney disease; high glucose inhibits AMPK activity and increases USF1 nuclear translocation; USF1 knockout diabetic mice display significantly less albuminuria and mesangial matrix expansion, and reduced TGF-β1 and renin expression. AMPK activation with AICAR reduces nuclear USF1 accumulation.\",\n      \"method\": \"USF1 KO mouse × Akita diabetic mouse (loss-of-function + disease model), AMPK activation/inhibition in mesangial cells, nuclear fractionation (USF1 localization)\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with quantitative disease phenotypes + cellular AMPK/USF1 localization mechanism, Moderate evidence\",\n      \"pmids\": [\"21543418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USF1 knockdown in human macrophages decreases phagocytosis, chemotaxis, and actin content, and alters expression of adhesion and extracellular matrix remodeling genes; loss of USF1 increases macrophage cell size and alters morphology, phenocopying aging-related macrophage functional decline.\",\n      \"method\": \"siRNA knockdown of USF1 in human monocyte-derived macrophages, phagocytosis assay, chemotaxis assay, actin content measurement, transcriptomics\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with specific functional phenotypes (phagocytosis, chemotaxis, actin) plus transcriptomics, Moderate evidence\",\n      \"pmids\": [\"38578825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USF1 transcriptionally activates USP14, which promotes deubiquitination and stabilization of NLRC5, leading to Smad2/3 pathway activation and endothelial-to-mesenchymal transition (EndMT) in atherosclerosis. USF1 knockdown inhibits EndMT and delays atherosclerosis progression in ApoE−/− mice.\",\n      \"method\": \"Dual-luciferase reporter assay (USF1→USP14 promoter), ChIP (USF1 binding to USP14 promoter), Co-IP (USP14–NLRC5 interaction), shRNA knockdown rescue experiments, in vivo ApoE−/− mouse atherosclerosis model\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + reporter + Co-IP + in vivo mouse model with multiple rescue experiments, Moderate evidence\",\n      \"pmids\": [\"38424494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A novel alternatively spliced isoform of human USF1 (USF1/BD), lacking the N-terminal transactivation domain, localizes to the nucleus and represses the angiotensinogen gene promoter; USF1/BD can form homodimers and heterodimers with USF1(wt) and bind E-box DNA in vitro.\",\n      \"method\": \"cDNA cloning, nuclear localization (ectopic expression), in vitro translation/dimerization assay, EMSA, reporter assay\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular cloning + localization + in vitro DNA binding + reporter assay, Moderate evidence\",\n      \"pmids\": [\"12851711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AKT-mediated phosphorylation of USF1 (induced by insulin via PI3K/AKT) enhances USF1 binding to the WBP2 promoter E-box and increases WBP2 transcription; USF1 is overexpressed in breast cancer cell lines and tissues and promotes cancer cell proliferation.\",\n      \"method\": \"Yeast one-hybrid (USF1 as E-box binder of WBP2 promoter), ChIP (USF1 binding to WBP2 promoter), tandem mass spectrometry (USF1 phosphorylation), reporter assay, insulin stimulation with AKT inhibitor\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast one-hybrid + ChIP + MS phosphorylation identification + functional reporter, Moderate evidence\",\n      \"pmids\": [\"30183375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USF1 drives transcription of the lncRNA FASRL through a superenhancer; FASRL in turn binds to and increases activity of ACACA (acetyl-CoA carboxylase 1), the fatty acid synthesis rate-limiting enzyme, promoting lipid accumulation in hepatocellular carcinoma.\",\n      \"method\": \"ChIP (USF1 binding to FASRL superenhancer), reporter assay, RNA pulldown (FASRL–ACACA interaction), in vitro and in vivo proliferation assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + reporter + RNA pulldown (FASRL-ACACA), Moderate evidence (single lab)\",\n      \"pmids\": [\"36307901\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USF1 is a ubiquitous bHLH-leucine zipper transcription factor that binds E-box (CANNTG) elements as homo- or heterodimers (primarily with USF2) to regulate a broad network of metabolic, stress-response, and developmental genes; its activity is controlled by multiple post-translational modifications—phosphorylation by p38 (Thr153), cyclin-dependent kinases (residues 143–197), PKC/PKA, GSK3 (Thr153/Ser186), CK2 (Thr100), and dephosphorylation by PTP4A1 (S309)—as well as by phosphorylation-dependent acetylation, which collectively modulate its DNA-binding affinity, dimerization with USF2, and target gene selectivity; USF1 also functions non-transcriptionally by forming nuclear complexes with p53 that prevent MDM2-mediated p53 degradation, recruits histone-modifying complexes (PRMT1, PCAF, SRC-1, hSET1A) to maintain active chromatin at insulator and promoter regions, cooperates with partner transcription factors (Stat1, Ets-1, NF-Y, TFII-I, PDX-1) through direct protein–protein interactions, and competes with CLOCK:BMAL1 for E-box occupancy to modulate circadian rhythms.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"USF1 is a ubiquitously expressed bHLH-leucine zipper transcription factor that binds E-box (CANNTG) elements as homodimers or heterodimers with USF2 to regulate a diverse network of metabolic, stress-response, developmental, and immune genes. Its DNA-binding affinity and target selectivity are controlled by phosphorylation from multiple kinases—p38 (Thr153), cyclin-CDK complexes (residues 143–197), PKC/PKA, GSK3 (Thr153/Ser186), CK2 (Thr100), and AKT—as well as by phosphorylation-dependent acetylation and dephosphorylation by PTP4A1 (Ser309), which collectively tune dimerization with USF2 and transcriptional output [PMID:11532965, PMID:10548544, PMID:25194820, PMID:19389701, PMID:36534975]. Beyond canonical transcriptional activation, USF1 recruits histone-modifying complexes including PRMT1/PCAF/SRC-1 and hSET1A to establish active chromatin marks at insulator and promoter regions, and it stabilizes p53 protein through a non-transcriptional mechanism that blocks MDM2-mediated degradation [PMID:17846119, PMID:23754954, PMID:24831529]. USF1 also competes with CLOCK:BMAL1 for E-box occupancy to modulate circadian gene expression, and its loss in mice activates brown adipose tissue thermogenesis, ameliorates diabetic nephropathy, and compromises UV-induced DNA repair and pigmentation responses [PMID:23580255, PMID:26819196, PMID:21543418, PMID:22291606].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of USF1 as the principal E-box-binding factor on the fatty acid synthase insulin response sequence established its role as a nutritionally regulated metabolic transcription factor.\",\n      \"evidence\": \"EMSA, antibody supershift, UV crosslinking, and western blotting showing USF1 protein induction in refed rat liver\",\n      \"pmids\": [\"7499393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which nutritional state increases USF1 protein was not determined\", \"No direct demonstration of USF1 necessity for FAS transcription in vivo\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Discovery that USF1 physically and functionally synergizes with TFII-I and can antagonize AhR·Arnt at overlapping E-box/XRE sites revealed that USF1 operates through cooperative and competitive protein–DNA interactions rather than acting alone.\",\n      \"evidence\": \"Domain deletion mapping of USF1–TFII-I synergy on the AdML promoter; competitive EMSA and mRNA analysis showing USF1 blocks CYP1A1 induction\",\n      \"pmids\": [\"9384587\", \"9374477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for USF1–TFII-I and USF1–AhR competition not resolved\", \"In vivo relevance of USF1-mediated CYP1A1 repression not tested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that USF1 cooperates with Stat1 at the CIITA promoter and with Ets-1 at the HIV-1 LTR showed how USF1 integrates signaling inputs from diverse transcription factor partners to control immune and viral gene expression.\",\n      \"evidence\": \"Cooperative EMSA with cis-element mutations and reporter assays (Stat1); yeast one-hybrid, Co-IP surface mapping, and dominant-negative Ets-1 experiments\",\n      \"pmids\": [\"9491997\", \"9501094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USF1–Stat1 cooperativity extends genome-wide was unknown\", \"Direct structural contacts between USF1 and Ets-1 were not mapped at residue resolution\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showing that cyclin A2/B1–Cdc2 phosphorylation of USF1 within residues 143–197 greatly increases DNA-binding activity provided the first evidence that cell-cycle kinases directly regulate USF1 function.\",\n      \"evidence\": \"In vitro kinase assay with recombinant USF1, domain deletion mapping, EMSA\",\n      \"pmids\": [\"10548544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo cell-cycle-dependent phosphorylation of USF1 was not demonstrated\", \"Functional consequences on endogenous target gene expression were not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Use of Usf1 knockout mice established that p38-mediated phosphorylation of USF1 is essential for UV-induced activation of the tyrosinase promoter in melanocytes, linking USF1 to the stress-activated UV response in pigmentation.\",\n      \"evidence\": \"In vitro p38 kinase assay, Usf1−/− melanocytes failing to activate tyrosinase expression after UV, reporter assays\",\n      \"pmids\": [\"11532965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact p38 phosphorylation site on USF1 was not identified in this study\", \"Whether other bHLH factors compensate partially in Usf1 KO was not assessed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Multiple studies revealed that PKC, PKA, and CK2 phosphorylate USF1 to increase its DNA-binding activity—and that phosphorylated USF1 can both activate (α-MHC, PAI-1) and repress (iNOS) target genes—demonstrating that phosphorylation is a general regulatory switch with context-dependent transcriptional outcomes.\",\n      \"evidence\": \"In vitro kinase assays with purified USF1 (PKC/PKA/CK2), 2D gel phosphoprotein analysis in cardiomyocytes, EMSA/reporter assays for α-MHC and iNOS; wound-activated keratinocyte PAI-1 binding studies\",\n      \"pmids\": [\"12063293\", \"12225970\", \"12235287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site-specific phosphorylation residues for PKC/PKA were not mapped\", \"Mechanism discriminating activation from repression on different promoters was not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of NF-Y as a USF1 partner on the HOXB4 promoter and discovery of a dominant-negative USF1 splice variant (USF1/BD) expanded the understanding of USF1 combinatorial regulation and autoregulatory potential.\",\n      \"evidence\": \"Co-IP and ChIP for NF-Y/USF complex at HOXB4; cDNA cloning and dimerization/reporter assays for USF1/BD isoform\",\n      \"pmids\": [\"12791656\", \"12851711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative abundance and tissue distribution of USF1/BD isoform were not quantified\", \"Whether NF-Y directly contacts USF1 or binds DNA adjacently was not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that USF1 recruits PRMT1, PCAF, and SRC-1 to form a histone-modifying complex at the β-globin insulator established USF1 as a chromatin barrier factor, not merely a transcriptional activator.\",\n      \"evidence\": \"Co-IP of USF1–PRMT1 complex with H4R3 methyltransferase and HAT activities; siRNA knockdown causing local loss of euchromatin marks; dominant-negative USF1 peptide abolishing insulator barrier function\",\n      \"pmids\": [\"17846119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USF1 recruits similar chromatin-modifying complexes genome-wide was not tested\", \"Mechanism of USF1-dependent complex assembly was not structurally characterized\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstration that p38-mediated Thr153 phosphorylation is a prerequisite for USF1 acetylation after DNA damage and oxidative stress revealed a hierarchical PTM code that alters USF1 transcriptional properties.\",\n      \"evidence\": \"In vitro kinase assay, site-directed mutagenesis of Thr153, acetylation assays, nuclear fractionation, reporter assays\",\n      \"pmids\": [\"19389701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase responsible for USF1 acetylation was not identified\", \"Genome-wide consequences of phospho-acetylated USF1 were not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"GSK3 was identified as a USF1 kinase at Thr153/Ser186 that activates USF1 binding to E-boxes vacated by Max/Mnt upon PI3K inhibition, revealing a kinase-dependent E-box switching mechanism linking survival signaling to transcriptional output.\",\n      \"evidence\": \"In vitro GSK3 kinase assay with phosphosite mapping, ChIP for Max/Mnt/USF1 promoter switching, RNAi and apoptosis assays\",\n      \"pmids\": [\"21873430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GSK3 and p38 phosphorylation of Thr153 are redundant or additive was not tested\", \"Structural basis for Max-to-USF1 E-box exchange was not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Usf1 knockout mice showed compromised nucleotide excision repair after UV irradiation through failure to upregulate CSA and HR23A, establishing a p53-independent role for USF1 in the DNA damage response.\",\n      \"evidence\": \"Usf1 KO mouse UV irradiation model, gene expression analysis and ChIP for NER gene promoters\",\n      \"pmids\": [\"22291606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct promoter mechanism (which E-boxes in CSA/HR23A) was not fully characterized\", \"Whether USF1 also regulates other DNA repair pathways was not explored\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two discoveries—USF1 recruiting hSET1A to the HoxB4 promoter to govern H3K4me3 and ESC mesoderm differentiation, and USF1 competing with CLOCK:BMAL1 for genome-wide E-box occupancy—demonstrated that USF1 is both a chromatin organizer in development and a modulator of circadian transcription.\",\n      \"evidence\": \"ChIP for H3K4me3/hSET1A at HoxB4, dominant-negative and RNAi in ESC differentiation; genetic suppressor mapping plus genome-wide USF1 ChIP and saturation E-box binding in Clock mutant mice\",\n      \"pmids\": [\"23754954\", \"23580255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether hSET1A recruitment is a general feature of all USF1-bound promoters was unknown\", \"Full circadian transcriptome regulated by USF1 was not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"USF1 was shown to stabilize p53 by physically preventing MDM2-mediated degradation through a mechanism independent of USF1's own DNA-binding domain, revealing a non-transcriptional tumor-suppressive function.\",\n      \"evidence\": \"Co-IP of USF1/p53/MDM2, Usf1 KO cells with enhanced p53 degradation, rescue by truncated USF1 lacking DNA-binding and transactivation domains\",\n      \"pmids\": [\"24831529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain on USF1 that directly contacts p53 and blocks MDM2 was not precisely mapped\", \"Whether USF1–p53 interaction is regulated by USF1 PTMs was not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of CK2 phosphorylation at Thr100 as a switch that inhibits USF1–USF2 heterodimerization and selectively modulates metabolic gene promoters (FAS, glucokinase but not HO-1) revealed how a single PTM can alter partner choice and target specificity.\",\n      \"evidence\": \"In vitro CK2 kinase assay, Thr100 point mutant, USF1–USF2 binding assay, reporter assays on multiple promoters\",\n      \"pmids\": [\"25194820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo metabolic consequences of CK2-USF1 phosphorylation were not tested in animal models\", \"Structural basis for Thr100 effects on heterodimerization was not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Usf1 knockout mice showed activated brown adipose tissue, enhanced thermogenesis, and improved cardiometabolic parameters, establishing USF1 as a negative regulator of energy expenditure and BAT function.\",\n      \"evidence\": \"Usf1 KO mice on high-fat diet, USF1 siRNA in brown adipocytes, LPL activity assays, comprehensive metabolic phenotyping\",\n      \"pmids\": [\"26819196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct USF1 target genes responsible for BAT suppression were not identified\", \"Whether pharmacological USF1 inhibition recapitulates the KO phenotype was not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"H. pylori infection was found to delocalize USF1 into cytoplasmic foci, disrupting nuclear USF1–p53 complexes and promoting MDM2-dependent p53 degradation, providing a pathogen exploitation mechanism for the USF1–p53 axis.\",\n      \"evidence\": \"Immunofluorescence, Co-IP in infected cells, Usf1−/− mouse carcinogenesis model with genotoxin challenge\",\n      \"pmids\": [\"31822580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bacterial effector responsible for USF1 cytoplasmic relocalization was not identified\", \"Whether other pathogens exploit the same mechanism was not explored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"PTP4A1 dephosphorylation of USF1 at Ser309 was shown to increase USF1 activity and induce anti-inflammatory A20 expression, attenuating NF-κB-driven vascular inflammation, establishing a phosphatase-dependent activation mechanism.\",\n      \"evidence\": \"Co-IP, ChIP at A20 promoter, shRNA/overexpression, Ptp4a1 KO and transgenic mice in ApoE−/− atherosclerosis model\",\n      \"pmids\": [\"36534975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase that phosphorylates S309 to oppose PTP4A1 was not identified\", \"Full spectrum of USF1 targets regulated by S309 phosphorylation status was not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"USF1 knockdown in human macrophages impaired phagocytosis, chemotaxis, and actin content, and USF1 was shown to drive USP14 transcription promoting NLRC5 stabilization and endothelial-to-mesenchymal transition in atherosclerosis, extending USF1's functional role to innate immune cell biology and vascular remodeling.\",\n      \"evidence\": \"siRNA in human monocyte-derived macrophages with functional assays and transcriptomics; ChIP/reporter for USF1→USP14, Co-IP for USP14–NLRC5, shRNA rescue in ApoE−/− mice\",\n      \"pmids\": [\"38578825\", \"38424494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether macrophage phenotypes are direct or secondary transcriptional effects is unclear\", \"USF1→USP14→NLRC5 axis requires independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A comprehensive structural model of how multiple phosphorylation events (p38, CK2, GSK3, CDK, AKT, PKC/PKA, PTP4A1 dephosphorylation) are integrated on the same USF1 molecule to coordinate dimerization partner choice, DNA-binding selectivity, and chromatin modifier recruitment remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of USF1 or its complexes exists\", \"Combinatorial PTM code on USF1 has not been systematically analyzed by quantitative mass spectrometry in any single system\", \"Genome-wide mapping of USF1 target genes as a function of specific PTM states has not been performed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 8, 9, 13, 14, 15, 28]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 12, 14, 15, 19, 20, 24, 27, 36, 39]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 11, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 10, 11, 34, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 12, 14, 15, 19, 20, 24, 27, 28, 36, 39]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 19, 21, 39]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 6, 7, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 31, 32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [23, 34, 38]}\n    ],\n    \"complexes\": [\n      \"USF1/USF2 heterodimer\",\n      \"USF1-PRMT1-PCAF-SRC-1 chromatin-modifying complex\",\n      \"USF1-NF-Y complex\"\n    ],\n    \"partners\": [\n      \"USF2\",\n      \"PRMT1\",\n      \"PCAF\",\n      \"SETD1A\",\n      \"TFII-I\",\n      \"TP53\",\n      \"PTP4A1\",\n      \"ETS1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}