{"gene":"USF1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1998,"finding":"USF-1 binds cooperatively with Stat1 to an adjacent GAS/E-box motif on the CIITA promoter IV (PIV) to activate CIITA transcription in response to IFNγ; both Stat1 and USF-1 are essential, and Stat1 only binds the GAS site in the presence of USF-1 at the E box.","method":"Electrophoretic mobility shift assay (EMSA), cooperative binding assays, functional promoter deletion/mutagenesis, transfection reporter assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — EMSA cooperative binding plus functional mutagenesis of cis elements plus transient transfection, multiple orthogonal methods in one study","pmids":["9491997"],"is_preprint":false},{"year":1997,"finding":"TFII-I (a 120 kDa transcription factor) interacts physically and functionally with USF1; TFII-I stimulates USF1 binding to both Inr and E-box elements and the two proteins act synergistically to activate transcription through both elements of the adenovirus major late promoter in vivo. Domains of USF1 required for independent and synergistic activation functions were identified.","method":"cDNA cloning, ectopic expression, in vivo transcription assays, domain deletion analysis, cooperative DNA-binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal functional assays with domain mapping and in vivo transactivation, multiple orthogonal methods in single study","pmids":["9384587"],"is_preprint":false},{"year":2001,"finding":"USF-1 is phosphorylated and activated by the stress-responsive p38 kinase; this modification is required for UV-induced activation of the Tyrosinase promoter in pigment cells, while Mitf regulates basal Tyrosinase expression.","method":"In vitro kinase assay, reporter gene assays, USF-1 −/− mouse melanocytes, UV irradiation model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro phosphorylation assay plus loss-of-function (KO cells) with specific promoter readout, two orthogonal approaches","pmids":["11532965"],"is_preprint":false},{"year":2004,"finding":"UV-induced activation of the POMC and MC1R promoters is mediated by p38 stress-activated kinase signaling to USF-1; melanocytes from USF-1 −/− mice fail to up-regulate POMC and MC1R in response to UV irradiation.","method":"Loss-of-function mouse model (USF-1 −/−), reporter gene assays, UV irradiation, RT-PCR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with specific gene-expression readout plus reporter assays, replicated finding from same lab extending prior p38 paper","pmids":["15358786"],"is_preprint":false},{"year":2009,"finding":"USF-1 is phosphorylated on Thr-153 by p38 in response to UV/DNA damage/oxidative stress, and this phosphorylation is a prerequisite for subsequent acetylation of USF-1; phospho-acetylated USF-1 is nuclear, binds DNA, but displays altered (reduced) transcriptional activation toward pigmentation and cell-cycle genes.","method":"In vitro kinase assay, phospho-specific antibodies, acetylation assays, mutagenesis (T153A), reporter gene assays, nuclear localization studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted phosphorylation-dependent acetylation with mutagenesis, functional readout on target promoters, multiple orthogonal methods","pmids":["19389701"],"is_preprint":false},{"year":2007,"finding":"USF1 recruits histone modification complexes to the β-globin locus insulator: USF1 interacts directly with histone H4R3-specific methyltransferase PRMT1, and together with PCAF and SRC-1 forms a complex with both HMT and HAT activities. siRNA knockdown of USF1 causes localized loss of H4R3 methylation and other euchromatin marks at the insulator; a dominant-negative USF1 peptide abolishes insulator barrier function.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, dominant-negative peptide interference, histone modification assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct protein interaction (Co-IP), siRNA loss-of-function with defined histone-mark readout, dominant-negative functional assay; multiple orthogonal methods","pmids":["17846119"],"is_preprint":false},{"year":1998,"finding":"USF-1 directly interacts with Ets-1 through their respective DNA-binding domains; the USF-1/Ets-1 complex binds adjacent E-box and Ets sites on the HIV-1 LTR enhancer and the two factors synergize for transactivation. A dominant-negative Ets-1 that lacks DNA binding but retains the USF-1 interaction surface inhibits USF-1-mediated transactivation, demonstrating the importance of direct protein–protein contact.","method":"Yeast one-hybrid screen, Co-immunoprecipitation, EMSA, reporter gene assays, dominant-negative mutant analysis, domain mapping","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — yeast screen + Co-IP + EMSA + functional reporter assays + domain mapping + dominant-negative, multiple orthogonal methods","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; the amount of the 43 kDa USF1 protein is dramatically increased in liver of refed rats, while a 17 kDa USF1-related protein is high in fasted rats and decreases upon refeeding, indicating nutritional regulation of USF1 expression.","method":"Competition gel-shift assay, antibody supershift, UV cross-linking, immunoblotting of fasted/refed rat liver","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — UV cross-linking and antibody supershift identify USF1 at the FAS IRS; protein-level changes confirmed by Western blot across nutritional states; multiple orthogonal methods","pmids":["7499393"],"is_preprint":false},{"year":1999,"finding":"The DNA-binding affinity of recombinant USF-1 is greatly increased by phosphorylation with cyclin A2-p34(cdc2) or cyclin B1-p34(cdc2) complexes; the phosphorylation site(s) map to amino acids 143–197, outside the minimal DNA-binding domain but within the USF-specific region, and deletion studies show this region regulates DNA binding in a phosphorylation-dependent manner.","method":"In vitro kinase assay with cyclin–CDK complexes, recombinant USF-1, EMSA, deletion mutagenesis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined kinase complexes plus deletion mutagenesis; single lab but multiple orthogonal methods","pmids":["10548544"],"is_preprint":false},{"year":2013,"finding":"USF1 competes with the CLOCK:BMAL1 complex for E-box sites in circadian target genes; a SNP in the Usf1 promoter elevates Usf1 transcript and protein, increasing USF1 occupancy genome-wide and suppressing the ClockΔ19 behavioral phenotype. Saturation binding experiments show reduced affinity of the CLOCKΔ19:BMAL1 complex for E-box sites, permitting this increased USF1 occupancy.","method":"Genetic mapping, quantitative saturation binding, genome-wide ChIP, promoter-SNP analysis, behavioral circadian assays in mice","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic epistasis (suppressor mapping), in vitro binding affinity measurements, genome-wide ChIP; multiple orthogonal methods","pmids":["23580255"],"is_preprint":false},{"year":2014,"finding":"USF1 stabilizes the p53 protein by preventing p53-MDM2 complex formation and MDM2-mediated degradation of p53; in USF1-deficient cells, MDM2–p53 interaction is enhanced and p53 levels drop. A USF1 truncated protein lacking DNA-binding and transactivation domains can still restore p53 induction, indicating a non-transcriptional mechanism of USF1 in p53 stabilization.","method":"Co-immunoprecipitation (p53/MDM2), Usf1 −/− mouse and USF1-deficient melanoma cells, dominant-negative and truncation constructs, Nutlin-3 rescue, Western blotting","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP showing altered USF1-p53-MDM2 complex plus genetic KO readout plus truncation mutagenesis; multiple orthogonal methods","pmids":["24831529"],"is_preprint":false},{"year":2019,"finding":"H. pylori delocalizes USF1 into cytoplasmic foci near cell membranes, prevents USF1/p53 nuclear complex formation, and relocates USF1/p53 complexes to the cytoplasm, thereby impairing their transcriptional function and promoting proteasomal degradation of p53; Usf1 −/− mice show accelerated gastric carcinogenesis.","method":"Immunofluorescence localization, co-immunoprecipitation (USF1/p53), Usf1 −/− mouse model, H. pylori infection of gastric cell lines, camptothecin DNA-damage model","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct Co-IP of USF1/p53 complex, subcellular localization imaging, genetic KO in vivo model; multiple orthogonal approaches","pmids":["31822580"],"is_preprint":false},{"year":2013,"finding":"USF1 recruits the hSET1A histone H3K4 methyltransferase complex to the HoxB4 promoter, governing H3K4me3 deposition and transcriptional preinitiation complex assembly; dominant-negative AUSF1 or siRNA knockdown of hSET1A reduces mesoderm markers and inhibits lineage differentiation from ESCs.","method":"ChIP, Co-immunoprecipitation, siRNA knockdown, dominant-negative overexpression, ESC differentiation assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP (H3K4me3), Co-IP, loss-of-function with specific histone-mark and differentiation readouts; multiple orthogonal methods","pmids":["23754954"],"is_preprint":false},{"year":2001,"finding":"USF1 cooperates with MTF-1 to activate the metallothionein-I (MT-I) gene in visceral endoderm cells in response to zinc; USF1 binds an E-box1 element at -223 bp in the MT-I promoter and is required for optimal (but not basal) zinc-responsive MT-I expression, as shown by embryo genetics and promoter binding.","method":"MTF-1 and USF1 null mouse embryo genetics, EMSA, promoter mutagenesis, maternal zinc manipulation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (KO embryos) plus EMSA plus mutagenesis; replicated in multiple approaches","pmids":["11230134"],"is_preprint":false},{"year":2016,"finding":"USF1 deficiency in mice activates brown adipose tissue (BAT) thermogenesis, increases energy expenditure, and directs triglycerides from circulation to BAT via a lipoprotein lipase-dependent mechanism. In brown adipocytes, Usf1 silencing amplifies adrenergic response, indicating a direct negative regulatory role of USF1 in BAT activation.","method":"Usf1 −/− mice, BAT sympathectomy, diet-induced obesity model, siRNA silencing in brown adipocytes, adrenergic stimulation assays, lipoprotein lipase activity measurements","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with specific BAT/thermogenesis phenotype, siRNA in primary adipocytes, LPL mechanism; multiple orthogonal methods","pmids":["26819196"],"is_preprint":false},{"year":2014,"finding":"CK2 phosphorylates USF1 on Thr-100 (identified by deletion and point mutagenesis); CK2 phosphorylation of USF1 inhibits USF1-USF2 heterodimerization, and inhibition of CK2 stimulates transcription from glucokinase and FAS promoters but not HO-1 promoter, demonstrating promoter-specific regulation by CK2-mediated USF1 phosphorylation.","method":"In vitro kinase assay, deletion and point mutants, co-immunoprecipitation (USF1-USF2 interaction), reporter gene assays, CK2 inhibitors","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted phosphorylation with mutagenesis plus Co-IP for dimerization plus functional reporter assays; multiple orthogonal methods","pmids":["25194820"],"is_preprint":false},{"year":2017,"finding":"CK2 phosphorylates USF1 and strengthens USF1-PDX-1 interaction; USF1 transrepresses the PDX-1 promoter in a CK2-dependent manner, and this repression is abrogated by elevated glucose or CK2 inhibition. A phospho-mutant of USF1 reduces PDX-1 promoter binding, indicating that CK2-mediated USF1 phosphorylation modulates both PDX-1 transcription and USF1-PDX-1 protein interaction.","method":"Promoter luciferase assays, Co-immunoprecipitation (USF1-PDX-1), CK2 inhibitor treatment, USF1 phospho-mutant, primary islet insulin secretion assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of USF1-PDX-1 plus functional reporter plus phospho-mutant; single lab, consistent methods","pmids":["29180680"],"is_preprint":false},{"year":2002,"finding":"USF1 and USF2 trans-repress the iNOS gene in mesangial cells by binding an E-box at -893/-888; mutation of this E-box augments IL-1β-induced iNOS promoter activity. Cotransfection of USF-1 and USF-2 suppresses IL-1β-stimulated iNOS promoter activity, and dominant-negative USF-2 or cis-element decoys augment it.","method":"Site-directed mutagenesis of iNOS promoter E-box, EMSA, antibody supershift, cotransfection reporter assays, dominant-negative USF-2 constructs","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-directed mutagenesis of binding site plus dominant-negative plus EMSA; multiple orthogonal methods in one study","pmids":["12225970"],"is_preprint":false},{"year":2002,"finding":"USF1 binds the PAI-1 proximal promoter E-box (CACGTG at -160 to -165) in a growth-state-dependent manner; phosphorylated USF1 (isolated by promoter-DNA affinity chromatography) is the predominant E-box-binding form in wound-stimulated cells. Wounding induces USF1 nuclear accumulation and E-box binding within 2 h, correlating with PAI-1 transcriptional induction.","method":"EMSA, UV cross-linking, deoxyoligonucleotide affinity chromatography, immunocytochemistry, Western blotting, in vitro wound model","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (affinity chromatography, EMSA, UV cross-linking) identifying phospho-USF1 as wound-responsive E-box binder; single lab","pmids":["12235287"],"is_preprint":false},{"year":2002,"finding":"Purified rat USF1 is phosphorylated in vitro by PKC and PKA (but not casein kinase II); phosphorylated USF1 by either kinase shows increased DNA-binding activity to the cardiac α-MHC HME E-box, and PKC phosphorylation additionally promotes USF1 multimer formation. In vivo, USF1 is found in at least two phosphorylated forms in ventricular myocytes.","method":"In vitro kinase assay (PKC, PKA, CK2), EMSA, 2D gel electrophoresis of in vivo phosphorylated nuclear proteins","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted phosphorylation assay by defined kinases plus in vivo 2D gel confirmation; multiple orthogonal approaches","pmids":["12063293"],"is_preprint":false},{"year":2003,"finding":"A USF1/USF2 heterodimer binds a CAGCTG (E-box) element in the first intron of the FcεRI α-chain gene and activates its expression; overexpression of antisense USF2 represses FcεRI α-chain promoter activity and decreases α-chain mRNA in mast cell lines.","method":"EMSA with antibodies and in vitro-translated proteins, cotransfection reporter assays, antisense USF2 knockdown","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA with defined proteins plus functional reporter plus antisense knockdown; single lab, consistent approaches","pmids":["11180124"],"is_preprint":false},{"year":2000,"finding":"USF1 and USF2 bind the HOXB4 promoter E-box (HXRE-2) in vitro and in K562 cells; cotransfection assays show USF-1 and USF-2 (but not MITF) induce the HOXB4 promoter in K562 and CD34+ cells via MAPK pathway activation.","method":"Yeast one-hybrid screen, EMSA, cotransfection reporter assays in K562 and CD34+ cells, HXRE-2 mutagenesis","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast one-hybrid identifies USF2, EMSA confirms USF1/2, functional reporter assays; single lab with multiple orthogonal approaches","pmids":["11085749"],"is_preprint":false},{"year":2003,"finding":"NF-Y and USF1/2 interact biochemically on the HOXB4 promoter (identified by Co-IP), and the NF-Y/USF1/2 complex is required for full HOXB4 promoter activity in hematopoietic cells; ChIP shows reduced NF-Y occupancy in more differentiated granulocytic cells consistent with lower HOXB4 expression.","method":"Co-immunoprecipitation (NF-Y/USF1-2 interaction), ChIP, cotransfection reporter assays, E-box mutagenesis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of protein complex plus ChIP for in vivo occupancy plus functional reporter; single lab","pmids":["12791656"],"is_preprint":false},{"year":2007,"finding":"v-Src down-regulates the SSeCKS/AKAP12 alpha promoter by recruiting HDAC1 into a USF1-Sp1-Sp3 complex; v-Src does not alter USF1 binding to the E-box but increases Sp1/Sp3 binding. HDAC1 recruitment is necessary and sufficient for promoter repression; TSA (HDAC inhibitor) restores SSeCKS levels.","method":"Promoter deletion analysis, chromatin immunoprecipitation, cotransfection reporter assays, TSA and 5-azacytidine treatment, protein expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating HDAC1 recruitment, functional reporter with mutagenesis, pharmacological rescue; single lab","pmids":["17626016"],"is_preprint":false},{"year":2011,"finding":"USF1 is required for TGF-β1 and renin gene expression in diabetic kidney disease; high glucose inhibits AMPK activity and increases USF1 nuclear translocation in mesangial cells. Activation of AMPK with AICAR stimulates AMPK and reduces nuclear USF1 accumulation, indicating AMPK regulates USF1 nuclear localization.","method":"USF1 −/− mice crossed with Akita diabetic mice, mesangial cell culture, AMPK activation with AICAR, nuclear fractionation, Western blotting","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with disease phenotype plus pharmacological AMPK manipulation with subcellular localization readout; single lab","pmids":["21543418"],"is_preprint":false},{"year":2011,"finding":"USF1 is activated downstream of PI3K/Akt/GSK3 signaling; GSK3 phosphorylates USF1 on the previously described activating site Thr-153 as well as on a newly identified site Ser-186. USF1 (together with MITF) drives transcription of proapoptotic and cell-cycle arrest genes when PI3K is inhibited, coordinately with FoxO.","method":"ChIP, siRNA knockdown, pharmacological PI3K inhibition, identification of GSK3 phosphorylation sites on USF1, gene expression profiling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus siRNA plus phosphorylation site identification; single lab, multiple methods","pmids":["21873430"],"is_preprint":false},{"year":2008,"finding":"Retinoic acid triggers a feed-forward loop in which CREB (activated directly by PKA) induces USF1 expression, and the induced USF1 then binds the MKP1 promoter E-box to drive the late phase of MKP1 transcription; both CREB and USF1 binding to the MKP1 promoter were confirmed by ChIP.","method":"ChIP (CREB and USF1 binding to MKP1 promoter), gel-shift assay, siRNA knockdown of CREB and USF1, MKP1 promoter reporter with CRE/E-box mutations","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus EMSA plus siRNA knockdown plus mutant reporter; single lab","pmids":["18625721"],"is_preprint":false},{"year":2003,"finding":"H. pylori activates COX-2 gene transcription via a proximal CRE/E-box element at -56 to -48 in the cox-2 promoter; USF1/2 and CREB transcription factors binding to this element transmit H. pylori-dependent COX-2 transcription, and this is mediated by MEK/ERK1/2 signaling activated by bacterial virulence factors outside the cagPAI.","method":"Promoter deletion analysis, EMSA (USF1/2 and CREB binding), MEK/ERK inhibitor experiments, reporter assays, mRNA/protein quantification","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus functional promoter analysis plus signaling pathway inhibitor; single lab, consistent methods","pmids":["14531897"],"is_preprint":false},{"year":2004,"finding":"USF-1 and ERα form a multi-protein complex with Sp1 at the ERα minimal promoter; Sp1 and USF-1 bind directly to the promoter (shown by EMSA), while ERα interacts with USF-1 in vitro (GST pull-down) without directly binding DNA, and combined overexpression causes synergistic transactivation.","method":"EMSA, GST pull-down, cotransfection reporter assays","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — GST pull-down plus EMSA plus functional reporter; single lab","pmids":["15111769"],"is_preprint":false},{"year":2004,"finding":"USF1 and USF2 constitutively bind an E-box in the proximal promoter of the human HO-1 gene in vivo (confirmed by ChIP and DMS footprinting); overexpression of USF1 or USF2 enhances basal HO-1 expression, and a dominant-negative USF reduces it, showing USFs are required for high-level HO-1 expression.","method":"ChIP, DMS in vivo footprinting, EMSA, dominant-negative USF overexpression, reporter assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vivo DMS footprinting plus ChIP plus dominant-negative loss-of-function plus reporter assays; multiple orthogonal methods","pmids":["15242350"],"is_preprint":false},{"year":2012,"finding":"USF-1 up-regulates CSA and HR23A gene expression in response to UV irradiation, which are key players in TCR and GGR sub-pathways of nucleotide excision repair, through a p53-independent mechanism; Usf1 −/− mice show compromised UV-induced DNA repair.","method":"In vitro and in vivo UV irradiation assays, Usf1 −/− mouse model, mRNA quantification, NER activity assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with NER readout plus gene expression analysis; single lab","pmids":["22291606"],"is_preprint":false},{"year":2003,"finding":"A novel alternative splicing isoform of USF1, termed USF1/BD, lacks the N-terminal transactivation domain; it localizes to the nucleus, retains DNA-binding activity as both homodimer and heterodimer with wild-type USF1, and represses the angiotensinogen gene promoter when transfected into cells.","method":"cDNA cloning, nuclear localization assay (ectopic expression), in vitro translation DNA-binding assay, reporter gene assay","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab with in vitro binding and reporter assay; limited mechanistic follow-up","pmids":["12851711"],"is_preprint":false},{"year":1997,"finding":"USF1 suppresses CYP1A1 induction by competing with the AhR·Arnt complex for binding to the XRE, which overlaps with a USF1 E-box binding site; transfection of USF1 into HepG2 cells prevents AhR·Arnt–XRE interaction and depresses MC-induced CYP1A1 mRNA induction.","method":"EMSA, antibody supershift, XRE-TK/Luc reporter cotransfection, S1 nuclease protection assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA competition plus reporter gene functional assay plus mRNA quantification; single lab, multiple consistent methods","pmids":["9374477"],"is_preprint":false},{"year":2004,"finding":"Pea3 cooperates with USF-1 for transactivation of the bax promoter without directly binding DNA; E-boxes in the minimal bax promoter are required for Pea3 transactivation potential, and USF-1 can form a ternary complex with Pea3 and DNA (shown by antibody-mediated EMSA supershift).","method":"Pea3 overexpression and siRNA, reporter gene assays, EMSA with antibody supershift demonstrating ternary complex","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — EMSA ternary-complex evidence plus functional reporter; single lab","pmids":["15466854"],"is_preprint":false},{"year":2019,"finding":"USF1 is required for maintenance of spermatogonial stem cells (SSCs) in mice; Usf1 −/− mice show SSC over-proliferation and age-dependent depletion of SSCs leading to progressive spermatogenic decline, testicular atrophy, and reduced sperm production, demonstrating a direct role in maintaining SSC quiescence.","method":"Usf1 −/− mouse model, histology, immunostaining for SSC and Sertoli markers, spermatogenesis assessment","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with specific SSC-proliferation phenotype; single lab","pmids":["30759202"],"is_preprint":false},{"year":2016,"finding":"USF1 (and USF2) binding to the FAS gene E-box promoter element drives FAS transcription in adipocytes; knockdown of USF1 represses adipogenesis along with decreased FAS expression, while USF1 overexpression enhances adipogenesis and FAS expression; valproic acid suppresses adipogenesis partly by down-regulating USF1.","method":"ChIP (USF1 binding to FAS promoter E-box), siRNA knockdown, overexpression, luciferase reporter assay, adipogenesis quantification","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus siRNA and overexpression with phenotypic readout; single lab","pmids":["24511897"],"is_preprint":false},{"year":2018,"finding":"AKT phosphorylates USF-1 in response to insulin/PI3K signaling, enhancing USF-1 binding to the WBP2 promoter E-box and increasing WBP2 transcription; this was identified by yeast one-hybrid, confirmed by ChIP and tandem mass spectrometry, and the phosphorylation-dependent E-box binding demonstrated by reporter assay.","method":"Yeast one-hybrid, ChIP, tandem mass spectrometry (phosphorylation site), luciferase reporter with E-box mutation, AKT inhibitor treatment","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast one-hybrid plus ChIP plus mass-spec phosphorylation plus reporter; single lab","pmids":["30183375"],"is_preprint":false},{"year":2023,"finding":"PTP4A1 increases the transcriptional activity of USF1 by dephosphorylating its S309 residue, which in turn drives transcription of TNFAIP3/A20 and thereby inhibits NF-κB activity and vascular inflammation; shown by ChIP, luciferase reporter, and Co-IP assays.","method":"ChIP, luciferase reporter, Co-IP, siRNA and overexpression in HUVECs, Ptp4a1 KO and transgenic mice, phospho-site specific analysis","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus Co-IP plus phospho-site (S309) identification plus in vivo KO model; single lab, multiple methods","pmids":["36534975"],"is_preprint":false},{"year":2024,"finding":"USF1 transcriptionally activates USP14 by binding its promoter (confirmed by ChIP and dual-luciferase assay), which promotes deubiquitination and stabilization of NLRC5, leading to Smad2/3 pathway activation and endothelial-to-mesenchymal transition (EndMT) driving atherosclerosis.","method":"Dual-luciferase reporter, ChIP, Co-IP (USP14/NLRC5), siRNA knockdown, ApoE −/− mouse atherosclerosis model","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter confirm USF1→USP14 binding, Co-IP shows USP14/NLRC5 interaction, in vivo model; single lab","pmids":["38424494"],"is_preprint":false},{"year":2016,"finding":"Inhibition of HDAC2/3 by apicidin increases USF1 acetylation, enhances USF1 association with HDAC2/3 and with the ADAM10 promoter, and up-regulates ADAM10 expression via an ERK-dependent mechanism; USF1 knockdown prevents apicidin-induced ADAM10 up-regulation.","method":"Luciferase reporter assay, USF1 knockdown (siRNA), USF1 acetylation assay, Co-immunoprecipitation (USF1/HDAC2/3), ChIP, ERK inhibitor (U0126)","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus functional reporter plus siRNA; single lab, multiple methods","pmids":["28003340"],"is_preprint":false},{"year":2009,"finding":"The rs1867277 A allele in the FOXE1 5' UTR recruits USF1/USF2 as a complex (demonstrated by DNA-binding assays); only the A allele (not the G allele) forms a USF1/USF2 complex, leading to allele-dependent transcriptional regulation of FOXE1.","method":"DNA-binding (EMSA/pull-down) assays, allele-specific binding, transfection reporter assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — allele-specific EMSA/pull-down plus reporter; single lab","pmids":["19730683"],"is_preprint":false},{"year":2024,"finding":"Knockdown of USF1 or MYC in human monocyte-derived macrophages decreases phagocytosis and chemotaxis, increases cell size, alters morphology, and reduces actin content; these phenotypes concordantly reflect the functional decline seen in macrophages from older donors, identifying USF1 as a driver of macrophage age-related functional decline.","method":"siRNA knockdown of USF1 in human MDMs, phagocytosis assay, chemotaxis assay, morphology/actin quantification, transcriptomic analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined siRNA knockdown with multiple functional readouts (phagocytosis, chemotaxis, actin, morphology); single lab","pmids":["38578825"],"is_preprint":false},{"year":2000,"finding":"USF1 and USF2 are the major transcription factors binding the FMR1 promoter in brain and testis extracts; methylation of the promoter reduces USF1/USF2 binding and abolishes α-Pal/Nrf-1 binding, providing a mechanism by which CpG methylation silences FMR1 transcription beyond histone deacetylase recruitment.","method":"EMSA with brain and testis nuclear extracts, antibody supershift, methylation interference, site mutagenesis, reporter gene assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA with defined antibody supershifts in tissue extracts plus methylation interference plus reporter; single lab","pmids":["11058604"],"is_preprint":false}],"current_model":"USF1 is a ubiquitous bHLH-LZ transcription factor that binds E-box (CANNTG) elements as homodimers or USF1/USF2 heterodimers to activate or repress a broad range of target genes (FAS, HOXB4, HO-1, iNOS, POMC, MC1R, Tyrosinase, PAI-1, APC, FMR1, CIITA PIV, and many others); its activity is tuned by multiple post-translational modifications—phosphorylation by p38 (activating, on Thr-153), cyclin-CDK complexes, PKC, PKA, AKT, and CK2 (on Thr-100, suppressing heterodimerization), and dephosphorylation by PTP4A1 (on Ser-309, activating)—where p38-mediated Thr-153 phosphorylation additionally primes stress-dependent acetylation that redirects USF1 target-gene specificity; USF1 recruits chromatin-modifying complexes (PRMT1/PCAF/SRC-1 for active histone marks at insulators; hSET1A for H3K4me3 at developmental loci) and interacts with co-regulators including TFII-I, Ets-1, Stat1, NF-Y, PDX-1, ERα, Pea3, and HDAC1-containing complexes; in the DNA-damage response, USF1 stabilizes p53 by blocking MDM2-mediated degradation through a non-transcriptional mechanism; USF1 also regulates brown adipose thermogenesis, spermatogonial stem cell quiescence, macrophage phagocytosis/chemotaxis, and nucleotide excision repair gene expression."},"narrative":{"mechanistic_narrative":"USF1 is a ubiquitous basic helix-loop-helix-leucine zipper transcription factor that binds E-box (CANNTG) elements as USF1 homodimers or USF1/USF2 heterodimers to activate or repress a broad spectrum of target genes across metabolism, stress responses, development, and immunity [PMID:7499393, PMID:15242350]. Its specificity is achieved largely through combinatorial protein-protein cooperation at composite promoters: USF1 synergizes with TFII-I at Inr/E-box elements [PMID:9384587], with Stat1 at the CIITA GAS/E-box module during IFNγ signaling [PMID:9491997], with Ets-1 at the HIV-1 LTR [PMID:9501094], and with NF-Y, Sp1, ERα, and Pea3 at other loci [PMID:12791656, PMID:15111769, PMID:15466854], while also acting as a repressor that competes with the AhR/Arnt complex at the CYP1A1 XRE [PMID:9374477] and with CLOCK:BMAL1 at circadian E-boxes [PMID:23580255]. USF1 nucleates chromatin-modifying activity, recruiting PRMT1/PCAF/SRC-1 to establish active histone marks and barrier function at the β-globin insulator [PMID:17846119] and the hSET1A H3K4 methyltransferase complex to developmental loci such as HoxB4 to license differentiation [PMID:23754954]. USF1 activity is extensively tuned by post-translational modification: p38 phosphorylates Thr-153 in response to UV/oxidative stress, which both activates USF1 and primes a downstream acetylation event that redirects its target-gene output away from pigmentation and cell-cycle genes [PMID:11532965, PMID:19389701]; cyclin-CDK complexes, PKC, PKA, and AKT enhance its DNA binding [PMID:10548544, PMID:12063293, PMID:30183375]; CK2 phosphorylates Thr-100 to suppress USF1/USF2 heterodimerization in a promoter-selective manner [PMID:25194820]; and PTP4A1 dephosphorylates Ser-309 to boost its transcriptional activity [PMID:36534975]. Beyond transcription, USF1 stabilizes p53 through a non-transcriptional mechanism, physically blocking MDM2-mediated degradation [PMID:24831529]. At the physiological level, USF1 regulates lipogenic (FAS) and nutrient-responsive gene expression [PMID:7499393, PMID:24511897], negatively controls brown adipose thermogenesis [PMID:26819196], drives UV-induced nucleotide excision repair gene expression [PMID:22291606], maintains spermatogonial stem cell quiescence [PMID:30759202], and sustains macrophage phagocytosis and chemotaxis [PMID:38578825].","teleology":[{"year":1995,"claim":"Established USF1 as a physiological E-box-binding regulator of a metabolic gene, showing its protein level itself is nutritionally regulated rather than constant.","evidence":"UV cross-linking, antibody supershift, and immunoblotting at the FAS insulin response sequence across fasted/refed rat liver","pmids":["7499393"],"confidence":"High","gaps":["Mechanism linking nutritional state to USF1 protein abundance not defined","Identity/relevance of the 17 kDa USF1-related fasted-state protein unresolved"]},{"year":1997,"claim":"Showed USF1 does not act alone but synergizes with a partner factor (TFII-I) at composite Inr/E-box promoters, introducing the combinatorial-cooperation theme.","evidence":"cDNA cloning, in vivo transcription assays, and domain deletion mapping on the adenovirus major late promoter","pmids":["9384587"],"confidence":"High","gaps":["Structural basis of the USF1-TFII-I contact not resolved","Generality across cellular promoters not established at the time"]},{"year":1998,"claim":"Defined USF1 as a cooperative DNA-binding partner whose recruitment of Stat1 to an adjacent GAS site couples IFNγ signaling to CIITA induction, and established direct DBD-DBD contacts with Ets-1 as a transactivation requirement.","evidence":"EMSA cooperative binding, promoter mutagenesis, reporter assays (CIITA PIV); yeast one-hybrid, Co-IP, dominant-negative analysis (Ets-1/HIV-1 LTR)","pmids":["9491997","9501094"],"confidence":"High","gaps":["Whether the same surfaces mediate all USF1 partner interactions unknown","Stoichiometry of multiprotein complexes on composite promoters not determined"]},{"year":1999,"claim":"Identified phosphorylation as a direct switch on USF1 DNA-binding affinity, mapping cyclin-CDK-responsive sites to the USF-specific region outside the DBD.","evidence":"In vitro kinase assays with cyclin A2/B1-p34(cdc2), EMSA, and deletion mutagenesis of recombinant USF1","pmids":["10548544"],"confidence":"High","gaps":["Exact phospho-residues within 143-197 not pinpointed","In vivo cell-cycle relevance not demonstrated"]},{"year":2001,"claim":"Connected stress signaling to USF1 by showing p38 directly phosphorylates and activates it, making USF1 the effector of UV-induced pigmentation gene activation.","evidence":"In vitro kinase assay, reporter assays, and USF1-/- mouse melanocytes under UV irradiation; parallel demonstration of zinc-responsive MT-I cooperation with MTF-1 in null embryos","pmids":["11532965","11230134"],"confidence":"High","gaps":["Phosphorylation site not yet mapped at this stage","How p38-USF1 selects pigmentation targets unresolved"]},{"year":2004,"claim":"Extended the p38-USF1 stress axis to the melanocortin pathway (POMC, MC1R) using loss-of-function genetics, establishing USF1 as a node coordinating the UV photoprotective response.","evidence":"USF1-/- mouse melanocytes, UV irradiation, reporter assays, and RT-PCR","pmids":["15358786"],"confidence":"High","gaps":["Direct vs indirect occupancy at POMC/MC1R E-boxes not fully delineated","Crosstalk with other UV-responsive factors unaddressed"]},{"year":2007,"claim":"Revealed USF1 as a recruiter of histone-modifying machinery, directly binding PRMT1 and assembling a PCAF/SRC-1 complex that maintains insulator barrier function.","evidence":"Co-IP, ChIP, siRNA knockdown, and dominant-negative peptide interference at the β-globin insulator","pmids":["17846119"],"confidence":"High","gaps":["Order of complex assembly on chromatin not established","Whether PRMT1 recruitment generalizes beyond the insulator unknown"]},{"year":2009,"claim":"Resolved the p38-USF1 mechanism by mapping Thr-153 phosphorylation as the prerequisite for stress-induced acetylation that redirects USF1 target specificity while preserving nuclear DNA binding.","evidence":"In vitro kinase assay, phospho-specific antibodies, T153A mutagenesis, acetylation and reporter assays","pmids":["19389701"],"confidence":"High","gaps":["Acetyltransferase and acetylated lysine(s) not identified","Genome-wide consequences of the phospho-acetyl switch not mapped"]},{"year":2013,"claim":"Established two distinct chromatin/developmental roles: USF1 recruits hSET1A for H3K4me3 to license ESC differentiation, and competes with CLOCK:BMAL1 for E-boxes to modulate circadian behavior.","evidence":"ChIP, Co-IP, siRNA, dominant-negative, ESC differentiation assays (HoxB4); genetic suppressor mapping, saturation binding, and genome-wide ChIP (circadian)","pmids":["23754954","23580255"],"confidence":"High","gaps":["How USF1 vs CLOCK:BMAL1 occupancy is balanced in normal physiology unclear","Determinants of USF1-hSET1A locus selectivity unknown"]},{"year":2014,"claim":"Uncovered a non-transcriptional function: USF1 stabilizes p53 by blocking MDM2 binding, decoupling a transcription factor from its DNA-binding activity.","evidence":"Co-IP, USF1-/- and USF1-deficient melanoma cells, DBD/transactivation-less truncation rescue, Nutlin-3 controls","pmids":["24831529"],"confidence":"High","gaps":["Structural basis of USF1-p53/MDM2 interplay not defined","Stoichiometry and subcellular site of the protective complex unknown"]},{"year":2014,"claim":"Defined CK2 phosphorylation of Thr-100 as a dimerization switch that selectively gates USF1 output at metabolic (glucokinase, FAS) versus stress (HO-1) promoters.","evidence":"In vitro kinase, point mutagenesis, Co-IP for USF1-USF2 dimerization, reporter assays with CK2 inhibitors","pmids":["25194820"],"confidence":"High","gaps":["How loss of heterodimerization yields promoter-specific outcomes mechanistically unresolved","In vivo CK2-USF1 axis not tested"]},{"year":2016,"claim":"Placed USF1 at the center of energy metabolism, showing it negatively regulates brown adipose thermogenesis and positively drives adipogenic FAS expression.","evidence":"USF1-/- mice, BAT sympathectomy, diet-induced obesity, siRNA in brown adipocytes, LPL assays (BAT); ChIP, siRNA, overexpression in adipogenesis (FAS)","pmids":["26819196","24511897"],"confidence":"High","gaps":["Direct BAT target genes of USF1 not enumerated","Reconciliation of pro-adipogenic vs anti-thermogenic roles incomplete"]},{"year":2019,"claim":"Demonstrated pathogen subversion of USF1 and a stem-cell maintenance role: H. pylori delocalizes USF1/p53 to drive p53 degradation and gastric carcinogenesis, while USF1 maintains spermatogonial stem cell quiescence.","evidence":"Immunofluorescence, Co-IP, USF1-/- mice, H. pylori infection (gastric); USF1-/- mice with histology and SSC marker staining (testis)","pmids":["31822580","30759202"],"confidence":"Medium","gaps":["H. pylori factor and signaling that relocalize USF1 not identified","Direct USF1 targets governing SSC quiescence unknown"]},{"year":2023,"claim":"Identified PTP4A1-mediated Ser-309 dephosphorylation as an activating modification driving anti-inflammatory transcription (TNFAIP3/A20) and NF-κB suppression in endothelium.","evidence":"ChIP, luciferase reporter, Co-IP, phospho-site analysis in HUVECs and Ptp4a1 KO/transgenic mice","pmids":["36534975"],"confidence":"Medium","gaps":["Kinase that phosphorylates S309 in this context not identified","Single lab; reciprocal validation of PTP4A1-USF1 axis limited"]},{"year":2024,"claim":"Extended USF1 into vascular disease and immune aging, driving USP14-dependent NLRC5 stabilization in atherosclerotic EndMT and sustaining macrophage phagocytosis and chemotaxis.","evidence":"ChIP, dual-luciferase, Co-IP, ApoE-/- mice (USP14/NLRC5/EndMT); siRNA in human monocyte-derived macrophages with functional and transcriptomic readouts","pmids":["38424494","38578825"],"confidence":"Medium","gaps":["Direct vs indirect control of the actin/morphology program in macrophages unresolved","Single-lab findings without independent replication"]},{"year":null,"claim":"How the layered post-translational code (p38/Thr-153, CK2/Thr-100, AKT, CDK, PTP4A1/Ser-309) is integrated to select among the hundreds of E-box targets in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking specific modifications to genome-wide target selection","Structural basis of partner-dependent specificity uncharacterized","Endogenous full-length occupancy maps across modification states lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,7,17,29,35]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[7,8,9,29,31]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[5,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,11,24,31]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,7,29]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5,12]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,14,35]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[9]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[30]}],"complexes":[],"partners":["USF2","TFII-I","STAT1","ETS-1","PRMT1","NF-Y","PDX-1","P53"],"other_free_text":[]}},"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":307,"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":174,"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. USF1 is regulated.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7499393","citation_count":104,"is_preprint":false},{"pmid":"17846119","id":"PMC_17846119","title":"USF1 recruits histone modification complexes and is critical for maintenance of a chromatin barrier.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17846119","citation_count":102,"is_preprint":false},{"pmid":"15358786","id":"PMC_15358786","title":"UV-induced expression of key component of the tanning process, the POMC and MC1R genes, is dependent on the p-38-activated upstream stimulating factor-1 (USF-1).","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15358786","citation_count":101,"is_preprint":false},{"pmid":"18230803","id":"PMC_18230803","title":"Whole-genome maps of USF1 and USF2 binding and histone H3 acetylation reveal new aspects of promoter structure and candidate genes for common human disorders.","date":"2008","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/18230803","citation_count":86,"is_preprint":false},{"pmid":"11230134","id":"PMC_11230134","title":"The transcription factors MTF-1 and USF1 cooperate to regulate mouse metallothionein-I expression in response to the essential metal zinc in visceral endoderm cells during early development.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11230134","citation_count":83,"is_preprint":false},{"pmid":"11058604","id":"PMC_11058604","title":"Interaction of the transcription factors USF1, USF2, and alpha -Pal/Nrf-1 with the FMR1 promoter. 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":"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":"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":"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. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/30743215","citation_count":51,"is_preprint":false},{"pmid":"38578825","id":"PMC_38578825","title":"Aging-related defects in macrophage function are driven by MYC and USF1 transcriptional programs.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38578825","citation_count":50,"is_preprint":false},{"pmid":"9287355","id":"PMC_9287355","title":"The basic helix-loop-helix-zipper transcription factor USF1 regulates expression of the surfactant protein-A gene.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9287355","citation_count":48,"is_preprint":false},{"pmid":"16699592","id":"PMC_16699592","title":"Risk alleles of USF1 gene predict cardiovascular disease of women in two prospective studies.","date":"2006","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16699592","citation_count":46,"is_preprint":false},{"pmid":"10548544","id":"PMC_10548544","title":"DNA-binding activity of the transcription factor upstream stimulatory factor 1 (USF-1) is regulated by cyclin-dependent phosphorylation.","date":"1999","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10548544","citation_count":45,"is_preprint":false},{"pmid":"36307901","id":"PMC_36307901","title":"Upregulation of Superenhancer-Driven LncRNA FASRL by USF1 Promotes De Novo Fatty Acid Biosynthesis to Exacerbate Hepatocellular Carcinoma.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36307901","citation_count":44,"is_preprint":false},{"pmid":"28701916","id":"PMC_28701916","title":"The Role of HOTAIR/miR-148b-3p/USF1 on Regulating the Permeability of BTB.","date":"2017","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28701916","citation_count":43,"is_preprint":false},{"pmid":"12235287","id":"PMC_12235287","title":"Epithelial monolayer wounding stimulates binding of USF-1 to an E-box motif in the plasminogen activator inhibitor type 1 gene.","date":"2002","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/12235287","citation_count":43,"is_preprint":false},{"pmid":"30931936","id":"PMC_30931936","title":"USF1-induced upregulation of LINC01048 promotes cell proliferation and apoptosis in cutaneous squamous cell carcinoma by binding to TAF15 to transcriptionally activate YAP1.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30931936","citation_count":42,"is_preprint":false},{"pmid":"9374477","id":"PMC_9374477","title":"Inhibition of the transcription of CYP1A1 gene by the upstream stimulatory factor 1 in rabbits. Competitive binding of USF1 with AhR.Arnt complex.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9374477","citation_count":41,"is_preprint":false},{"pmid":"30214629","id":"PMC_30214629","title":"Suppression of metastasis through inhibition of chitinase 3-like 1 expression by miR-125a-3p-mediated up-regulation of USF1.","date":"2018","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/30214629","citation_count":40,"is_preprint":false},{"pmid":"19910639","id":"PMC_19910639","title":"Genetic association and interaction analysis of USF1 and APOA5 on lipid levels and atherosclerosis.","date":"2009","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19910639","citation_count":39,"is_preprint":false},{"pmid":"19389701","id":"PMC_19389701","title":"Target gene specificity of USF-1 is directed via p38-mediated phosphorylation-dependent acetylation.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19389701","citation_count":39,"is_preprint":false},{"pmid":"11085749","id":"PMC_11085749","title":"Hematopoietic expression of HOXB4 is regulated in normal and leukemic stem cells through transcriptional activation of the HOXB4 promoter by upstream stimulating factor (USF)-1 and USF-2.","date":"2000","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11085749","citation_count":39,"is_preprint":false},{"pmid":"18625721","id":"PMC_18625721","title":"Retinoic acid utilizes CREB and USF1 in a transcriptional feed-forward loop in order to stimulate MKP1 expression in human immunodeficiency virus-infected podocytes.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18625721","citation_count":38,"is_preprint":false},{"pmid":"17289164","id":"PMC_17289164","title":"Regulation of IL-10 expression by upstream stimulating factor (USF-1) in glioma-associated microglia.","date":"2007","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/17289164","citation_count":36,"is_preprint":false},{"pmid":"11583573","id":"PMC_11583573","title":"Promoter I of the ovine acetyl-CoA carboxylase-alpha gene: an E-box motif at -114 in the proximal promoter binds upstream stimulatory factor (USF)-1 and USF-2 and acts as an insulin-response sequence in differentiating adipocytes.","date":"2001","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/11583573","citation_count":35,"is_preprint":false},{"pmid":"24831529","id":"PMC_24831529","title":"p53 requires the stress sensor USF1 to direct appropriate cell fate decision.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24831529","citation_count":34,"is_preprint":false},{"pmid":"17626016","id":"PMC_17626016","title":"v-Src-mediated down-regulation of SSeCKS metastasis suppressor gene promoter by the recruitment of HDAC1 into a USF1-Sp1-Sp3 complex.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17626016","citation_count":34,"is_preprint":false},{"pmid":"15111769","id":"PMC_15111769","title":"Regulation of the estrogen receptor alpha minimal promoter by Sp1, USF-1 and ERalpha.","date":"2004","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/15111769","citation_count":34,"is_preprint":false},{"pmid":"21873430","id":"PMC_21873430","title":"The E-box binding factors Max/Mnt, MITF, and USF1 act coordinately with FoxO to regulate expression of proapoptotic and cell cycle control genes by phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3 signaling.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21873430","citation_count":33,"is_preprint":false},{"pmid":"32776110","id":"PMC_32776110","title":"The transcription factor USF1 promotes glioma cell invasion and migration by activating lncRNA HAS2-AS1.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32776110","citation_count":31,"is_preprint":false},{"pmid":"15242350","id":"PMC_15242350","title":"Upstream stimulatory factors, USF1 and USF2, bind to the human haem oxygenase-1 proximal promoter in vivo and regulate its transcription.","date":"2004","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15242350","citation_count":31,"is_preprint":false},{"pmid":"8875887","id":"PMC_8875887","title":"Mouse USF1 gene cloning: comparative organization within the c-myc gene family.","date":"1996","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/8875887","citation_count":30,"is_preprint":false},{"pmid":"12063293","id":"PMC_12063293","title":"Role of USF1 phosphorylation on cardiac alpha-myosin heavy chain promoter activity.","date":"2002","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12063293","citation_count":29,"is_preprint":false},{"pmid":"21543418","id":"PMC_21543418","title":"Role of the USF1 transcription factor in diabetic kidney disease.","date":"2011","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21543418","citation_count":28,"is_preprint":false},{"pmid":"15691871","id":"PMC_15691871","title":"Role of USF1 and USF2 as potential repressor proteins for human intestinal monocarboxylate transporter 1 promoter.","date":"2005","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15691871","citation_count":28,"is_preprint":false},{"pmid":"34140779","id":"PMC_34140779","title":"miR-210-3p Promotes Lung Cancer Development and Progression by Modulating USF1 and PCGF3.","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34140779","citation_count":26,"is_preprint":false},{"pmid":"28003340","id":"PMC_28003340","title":"Histone deacetylase inhibitor apicidin increases expression of the α-secretase ADAM10 through transcription factor USF1-mediated mechanisms.","date":"2016","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/28003340","citation_count":26,"is_preprint":false},{"pmid":"18276913","id":"PMC_18276913","title":"Association analysis of allelic variants of USF1 in coronary atherosclerosis.","date":"2008","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18276913","citation_count":26,"is_preprint":false},{"pmid":"25308402","id":"PMC_25308402","title":"Association of USF1 and APOA5 polymorphisms with familial combined hyperlipidemia in an Italian population.","date":"2014","source":"Molecular and cellular probes","url":"https://pubmed.ncbi.nlm.nih.gov/25308402","citation_count":25,"is_preprint":false},{"pmid":"38424494","id":"PMC_38424494","title":"USF1 transcriptionally activates USP14 to drive atherosclerosis by promoting EndMT through NLRC5/Smad2/3 axis.","date":"2024","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/38424494","citation_count":24,"is_preprint":false},{"pmid":"30995827","id":"PMC_30995827","title":"Transcriptional Regulation Factors of the Human Mitochondrial Aspartate/Glutamate Carrier Gene, Isoform 2 (SLC25A13): USF1 as Basal Factor and FOXA2 as Activator in Liver Cells.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30995827","citation_count":24,"is_preprint":false},{"pmid":"15479157","id":"PMC_15479157","title":"The roles of Sp1, Sp3, USF1/USF2 and NRF-1 in the regulation and three-dimensional structure of the Fragile X mental retardation gene promoter.","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15479157","citation_count":24,"is_preprint":false},{"pmid":"35414770","id":"PMC_35414770","title":"USF1-ATRAP-PBX3 Axis Promote Breast Cancer Glycolysis and Malignant Phenotype by Activating AKT/mTOR Signaling.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35414770","citation_count":23,"is_preprint":false},{"pmid":"35287174","id":"PMC_35287174","title":"USF1/CD90 signaling in maintaining glioblastoma stem cells and tumor-associated macrophages adhesion.","date":"2022","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35287174","citation_count":23,"is_preprint":false},{"pmid":"17885212","id":"PMC_17885212","title":"USF1 gene variants, cardiovascular risk, and mortality in European Americans: analysis of two US cohort studies.","date":"2007","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17885212","citation_count":23,"is_preprint":false},{"pmid":"15466854","id":"PMC_15466854","title":"Pea3 transcription factor cooperates with USF-1 in regulation of the murine bax transcription without binding to an Ets-binding site.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15466854","citation_count":23,"is_preprint":false},{"pmid":"18593823","id":"PMC_18593823","title":"Genetic variants in the USF1 gene are associated with low-density lipoprotein cholesterol levels and incident type 2 diabetes mellitus in women: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002.","date":"2008","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18593823","citation_count":22,"is_preprint":false},{"pmid":"18768914","id":"PMC_18768914","title":"USF1/2 transcription factor DNA-binding activity is induced during rat Sertoli cell differentiation.","date":"2008","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/18768914","citation_count":21,"is_preprint":false},{"pmid":"32275336","id":"PMC_32275336","title":"USF1-induced overexpression of long noncoding RNA WDFY3-AS2 promotes lung adenocarcinoma progression via targeting miR-491-5p/ZNF703 axis.","date":"2020","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/32275336","citation_count":21,"is_preprint":false},{"pmid":"15473256","id":"PMC_15473256","title":"A promoter polymorphism in the central MHC gene, IKBL, influences the binding of transcription factors USF1 and E47 on disease-associated haplotypes.","date":"2004","source":"Gene expression","url":"https://pubmed.ncbi.nlm.nih.gov/15473256","citation_count":21,"is_preprint":false},{"pmid":"18445538","id":"PMC_18445538","title":"Upstream transcription factor 1 (USF1) in risk of type 2 diabetes: association study in 2000 Dutch Caucasians.","date":"2008","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/18445538","citation_count":21,"is_preprint":false},{"pmid":"16186412","id":"PMC_16186412","title":"Common polymorphisms in the USF1 gene are not associated with type 2 diabetes in French Caucasians.","date":"2005","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/16186412","citation_count":20,"is_preprint":false},{"pmid":"11180124","id":"PMC_11180124","title":"A complex composed of USF1 and USF2 activates the human FcepsilonRI alpha chain expression via a CAGCTG element in the first intron.","date":"2001","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11180124","citation_count":19,"is_preprint":false},{"pmid":"36534975","id":"PMC_36534975","title":"Endothelial PTP4A1 mitigates vascular inflammation via USF1/A20 axis-mediated NF-κB inactivation.","date":"2023","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/36534975","citation_count":18,"is_preprint":false},{"pmid":"24722012","id":"PMC_24722012","title":"Upstream Transcription Factor 1 (USF1) allelic variants regulate lipoprotein metabolism in women and USF1 expression in atherosclerotic plaque.","date":"2014","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/24722012","citation_count":18,"is_preprint":false},{"pmid":"12225970","id":"PMC_12225970","title":"USF-1 and USF-2 trans-repress IL-1beta-induced iNOS transcription in mesangial cells.","date":"2002","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12225970","citation_count":18,"is_preprint":false},{"pmid":"22291606","id":"PMC_22291606","title":"USF-1 is critical for maintaining genome integrity in response to UV-induced DNA photolesions.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22291606","citation_count":18,"is_preprint":false},{"pmid":"11010817","id":"PMC_11010817","title":"Growth state-dependent binding of USF-1 to a proximal promoter E box element in the rat plasminogen activator inhibitor type 1 gene.","date":"2000","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/11010817","citation_count":18,"is_preprint":false},{"pmid":"32269179","id":"PMC_32269179","title":"USF1-mediated upregulation of lncRNA GAS6-AS2 facilitates osteosarcoma progression through miR-934/BCAT1 axis.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32269179","citation_count":17,"is_preprint":false},{"pmid":"29180680","id":"PMC_29180680","title":"Functional interplay between the transcription factors USF1 and PDX-1 and protein kinase CK2 in pancreatic β-cells.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29180680","citation_count":17,"is_preprint":false},{"pmid":"18097648","id":"PMC_18097648","title":"USF1 gene variants contribute to metabolic traits in men in a longitudinal 32-year follow-up study.","date":"2007","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/18097648","citation_count":17,"is_preprint":false},{"pmid":"30183375","id":"PMC_30183375","title":"Phosphorylation of E-box binding USF-1 by PI3K/AKT enhances its transcriptional activation of the WBP2 oncogene in breast cancer cells.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30183375","citation_count":17,"is_preprint":false},{"pmid":"17309647","id":"PMC_17309647","title":"Associations between USF1 gene variants and cardiovascular risk factors in the Quebec Family Study.","date":"2007","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17309647","citation_count":16,"is_preprint":false},{"pmid":"25385722","id":"PMC_25385722","title":"Requirement of the transcription factor USF1 in bovine oocyte and early embryonic development.","date":"2014","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25385722","citation_count":16,"is_preprint":false},{"pmid":"22390463","id":"PMC_22390463","title":"Upstream transcription factor 1 (USF1) polymorphisms associate with Alzheimer's disease-related neuropathological lesions: Tampere Autopsy Study.","date":"2012","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/22390463","citation_count":16,"is_preprint":false},{"pmid":"30759202","id":"PMC_30759202","title":"Transcription Factor USF1 Is Required for Maintenance of Germline Stem Cells in Male Mice.","date":"2019","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30759202","citation_count":15,"is_preprint":false},{"pmid":"12851711","id":"PMC_12851711","title":"Cloning and characterization of a novel splicing isoform of USF1.","date":"2003","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12851711","citation_count":15,"is_preprint":false},{"pmid":"24511897","id":"PMC_24511897","title":"Suppression of adipogenesis by valproic acid through repression of USF1-activated fatty acid synthesis in adipocytes.","date":"2014","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/24511897","citation_count":15,"is_preprint":false},{"pmid":"12697323","id":"PMC_12697323","title":"HOXB7 expression is regulated by the transcription factors NF-Y, YY1, Sp1 and USF-1.","date":"2003","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/12697323","citation_count":15,"is_preprint":false},{"pmid":"9295342","id":"PMC_9295342","title":"Characterization of UEF-4, a DNA-binding protein required for transcriptional synergism between two AP-1 sites in the human urokinase enhancer.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9295342","citation_count":14,"is_preprint":false},{"pmid":"20054229","id":"PMC_20054229","title":"Gene-gene interaction between APOA5 and USF1: two candidate genes for the metabolic syndrome.","date":"2009","source":"Obesity facts","url":"https://pubmed.ncbi.nlm.nih.gov/20054229","citation_count":14,"is_preprint":false},{"pmid":"30545366","id":"PMC_30545366","title":"USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages.","date":"2018","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/30545366","citation_count":14,"is_preprint":false},{"pmid":"34766130","id":"PMC_34766130","title":"TUG1 long non-coding RNA enlists the USF1 transcription factor to overexpress ROMO1 leading to hepatocellular carcinoma growth and metastasis.","date":"2020","source":"MedComm","url":"https://pubmed.ncbi.nlm.nih.gov/34766130","citation_count":14,"is_preprint":false},{"pmid":"9388470","id":"PMC_9388470","title":"Upstream stimulatory factor 1 (USF1) suppresses induction of CYP1A1 mRNA by 3-methylcholanthrene (MC) in HepG2 cells.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9388470","citation_count":14,"is_preprint":false},{"pmid":"25194820","id":"PMC_25194820","title":"The upstream stimulatory factor USF1 is regulated by protein kinase CK2 phosphorylation.","date":"2014","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/25194820","citation_count":13,"is_preprint":false},{"pmid":"27649659","id":"PMC_27649659","title":"USF1 prompt melanoma through upregulating TGF-β signaling pathway.","date":"2016","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27649659","citation_count":13,"is_preprint":false},{"pmid":"23666615","id":"PMC_23666615","title":"Molecular characterization, expression patterns, and association analysis with carcass traits of porcine USF1 gene.","date":"2013","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/23666615","citation_count":13,"is_preprint":false},{"pmid":"21078375","id":"PMC_21078375","title":"NF-Y and USF1 transcription factor binding to CCAAT-box and E-box elements activates the CP27 promoter.","date":"2010","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/21078375","citation_count":12,"is_preprint":false},{"pmid":"27693430","id":"PMC_27693430","title":"miR-483 is a self-regulating microRNA and can activate its own expression via USF1 in HeLa cells.","date":"2016","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27693430","citation_count":12,"is_preprint":false},{"pmid":"24417972","id":"PMC_24417972","title":"Leishmania donovani activates uncoupling protein 2 transcription to suppress mitochondrial oxidative burst through differential modulation of SREBP2, Sp1 and USF1 transcription factors.","date":"2014","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24417972","citation_count":11,"is_preprint":false},{"pmid":"18782566","id":"PMC_18782566","title":"Interaction of USF1/USF2 and alpha-Pal/Nrf1 to Fmr-1 promoter increases in mouse brain during aging.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18782566","citation_count":11,"is_preprint":false},{"pmid":"29441861","id":"PMC_29441861","title":"Upstream stimulating factor1 (USF1) enhances the proliferation of glioblastoma stem cells mainly by activating the transcription of mucin13 (MUC13).","date":"2017","source":"Die Pharmazie","url":"https://pubmed.ncbi.nlm.nih.gov/29441861","citation_count":11,"is_preprint":false},{"pmid":"29871931","id":"PMC_29871931","title":"Interleukin-like EMT inducer (ILEI) promotes melanoma invasiveness and is transcriptionally up-regulated by upstream stimulatory factor-1 (USF-1).","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29871931","citation_count":11,"is_preprint":false},{"pmid":"2204028","id":"PMC_2204028","title":"A yeast homolog of the human UEF stimulates transcription from the adenovirus 2 major late promoter in yeast and in mammalian cell-free systems.","date":"1990","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2204028","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51441,"output_tokens":11064,"usd":0.160141,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21727,"output_tokens":5295,"usd":0.120505,"stage2_stop_reason":"end_turn"},"total_usd":0.280646,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"USF-1 binds cooperatively with Stat1 to an adjacent GAS/E-box motif on the CIITA promoter IV (PIV) to activate CIITA transcription in response to IFNγ; both Stat1 and USF-1 are essential, and Stat1 only binds the GAS site in the presence of USF-1 at the E box.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), cooperative binding assays, functional promoter deletion/mutagenesis, transfection reporter assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — EMSA cooperative binding plus functional mutagenesis of cis elements plus transient transfection, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9491997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"TFII-I (a 120 kDa transcription factor) interacts physically and functionally with USF1; TFII-I stimulates USF1 binding to both Inr and E-box elements and the two proteins act synergistically to activate transcription through both elements of the adenovirus major late promoter in vivo. Domains of USF1 required for independent and synergistic activation functions were identified.\",\n      \"method\": \"cDNA cloning, ectopic expression, in vivo transcription assays, domain deletion analysis, cooperative DNA-binding assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal functional assays with domain mapping and in vivo transactivation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"9384587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"USF-1 is phosphorylated and activated by the stress-responsive p38 kinase; this modification is required for UV-induced activation of the Tyrosinase promoter in pigment cells, while Mitf regulates basal Tyrosinase expression.\",\n      \"method\": \"In vitro kinase assay, reporter gene assays, USF-1 −/− mouse melanocytes, UV irradiation model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro phosphorylation assay plus loss-of-function (KO cells) with specific promoter readout, two orthogonal approaches\",\n      \"pmids\": [\"11532965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"UV-induced activation of the POMC and MC1R promoters is mediated by p38 stress-activated kinase signaling to USF-1; melanocytes from USF-1 −/− mice fail to up-regulate POMC and MC1R in response to UV irradiation.\",\n      \"method\": \"Loss-of-function mouse model (USF-1 −/−), reporter gene assays, UV irradiation, RT-PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with specific gene-expression readout plus reporter assays, replicated finding from same lab extending prior p38 paper\",\n      \"pmids\": [\"15358786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"USF-1 is phosphorylated on Thr-153 by p38 in response to UV/DNA damage/oxidative stress, and this phosphorylation is a prerequisite for subsequent acetylation of USF-1; phospho-acetylated USF-1 is nuclear, binds DNA, but displays altered (reduced) transcriptional activation toward pigmentation and cell-cycle genes.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibodies, acetylation assays, mutagenesis (T153A), reporter gene assays, nuclear localization studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted phosphorylation-dependent acetylation with mutagenesis, functional readout on target promoters, multiple orthogonal methods\",\n      \"pmids\": [\"19389701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"USF1 recruits histone modification complexes to the β-globin locus insulator: USF1 interacts directly with histone H4R3-specific methyltransferase PRMT1, and together with PCAF and SRC-1 forms a complex with both HMT and HAT activities. siRNA knockdown of USF1 causes localized loss of H4R3 methylation and other euchromatin marks at the insulator; a dominant-negative USF1 peptide abolishes insulator barrier function.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, dominant-negative peptide interference, histone modification assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct protein interaction (Co-IP), siRNA loss-of-function with defined histone-mark readout, dominant-negative functional assay; multiple orthogonal methods\",\n      \"pmids\": [\"17846119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"USF-1 directly interacts with Ets-1 through their respective DNA-binding domains; the USF-1/Ets-1 complex binds adjacent E-box and Ets sites on the HIV-1 LTR enhancer and the two factors synergize for transactivation. A dominant-negative Ets-1 that lacks DNA binding but retains the USF-1 interaction surface inhibits USF-1-mediated transactivation, demonstrating the importance of direct protein–protein contact.\",\n      \"method\": \"Yeast one-hybrid screen, Co-immunoprecipitation, EMSA, reporter gene assays, dominant-negative mutant analysis, domain mapping\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — yeast screen + Co-IP + EMSA + functional reporter assays + domain mapping + dominant-negative, multiple orthogonal methods\",\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; the amount of the 43 kDa USF1 protein is dramatically increased in liver of refed rats, while a 17 kDa USF1-related protein is high in fasted rats and decreases upon refeeding, indicating nutritional regulation of USF1 expression.\",\n      \"method\": \"Competition gel-shift assay, antibody supershift, UV cross-linking, immunoblotting of fasted/refed rat liver\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — UV cross-linking and antibody supershift identify USF1 at the FAS IRS; protein-level changes confirmed by Western blot across nutritional states; multiple orthogonal methods\",\n      \"pmids\": [\"7499393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The DNA-binding affinity of recombinant USF-1 is greatly increased by phosphorylation with cyclin A2-p34(cdc2) or cyclin B1-p34(cdc2) complexes; the phosphorylation site(s) map to amino acids 143–197, outside the minimal DNA-binding domain but within the USF-specific region, and deletion studies show this region regulates DNA binding in a phosphorylation-dependent manner.\",\n      \"method\": \"In vitro kinase assay with cyclin–CDK complexes, recombinant USF-1, EMSA, deletion mutagenesis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined kinase complexes plus deletion mutagenesis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10548544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USF1 competes with the CLOCK:BMAL1 complex for E-box sites in circadian target genes; a SNP in the Usf1 promoter elevates Usf1 transcript and protein, increasing USF1 occupancy genome-wide and suppressing the ClockΔ19 behavioral phenotype. Saturation binding experiments show reduced affinity of the CLOCKΔ19:BMAL1 complex for E-box sites, permitting this increased USF1 occupancy.\",\n      \"method\": \"Genetic mapping, quantitative saturation binding, genome-wide ChIP, promoter-SNP analysis, behavioral circadian assays in mice\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic epistasis (suppressor mapping), in vitro binding affinity measurements, genome-wide ChIP; multiple orthogonal methods\",\n      \"pmids\": [\"23580255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USF1 stabilizes the p53 protein by preventing p53-MDM2 complex formation and MDM2-mediated degradation of p53; in USF1-deficient cells, MDM2–p53 interaction is enhanced and p53 levels drop. A USF1 truncated protein lacking DNA-binding and transactivation domains can still restore p53 induction, indicating a non-transcriptional mechanism of USF1 in p53 stabilization.\",\n      \"method\": \"Co-immunoprecipitation (p53/MDM2), Usf1 −/− mouse and USF1-deficient melanoma cells, dominant-negative and truncation constructs, Nutlin-3 rescue, Western blotting\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing altered USF1-p53-MDM2 complex plus genetic KO readout plus truncation mutagenesis; multiple orthogonal methods\",\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 USF1/p53 nuclear complex formation, and relocates USF1/p53 complexes to the cytoplasm, thereby impairing their transcriptional function and promoting proteasomal degradation of p53; Usf1 −/− mice show accelerated gastric carcinogenesis.\",\n      \"method\": \"Immunofluorescence localization, co-immunoprecipitation (USF1/p53), Usf1 −/− mouse model, H. pylori infection of gastric cell lines, camptothecin DNA-damage model\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP of USF1/p53 complex, subcellular localization imaging, genetic KO in vivo model; multiple orthogonal approaches\",\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 deposition and transcriptional preinitiation complex assembly; dominant-negative AUSF1 or siRNA knockdown of hSET1A reduces mesoderm markers and inhibits lineage differentiation from ESCs.\",\n      \"method\": \"ChIP, Co-immunoprecipitation, siRNA knockdown, dominant-negative overexpression, ESC differentiation assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP (H3K4me3), Co-IP, loss-of-function with specific histone-mark and differentiation readouts; multiple orthogonal methods\",\n      \"pmids\": [\"23754954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"USF1 cooperates with MTF-1 to activate the metallothionein-I (MT-I) gene in visceral endoderm cells in response to zinc; USF1 binds an E-box1 element at -223 bp in the MT-I promoter and is required for optimal (but not basal) zinc-responsive MT-I expression, as shown by embryo genetics and promoter binding.\",\n      \"method\": \"MTF-1 and USF1 null mouse embryo genetics, EMSA, promoter mutagenesis, maternal zinc manipulation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (KO embryos) plus EMSA plus mutagenesis; replicated in multiple approaches\",\n      \"pmids\": [\"11230134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USF1 deficiency in mice activates brown adipose tissue (BAT) thermogenesis, increases energy expenditure, and directs triglycerides from circulation to BAT via a lipoprotein lipase-dependent mechanism. In brown adipocytes, Usf1 silencing amplifies adrenergic response, indicating a direct negative regulatory role of USF1 in BAT activation.\",\n      \"method\": \"Usf1 −/− mice, BAT sympathectomy, diet-induced obesity model, siRNA silencing in brown adipocytes, adrenergic stimulation assays, lipoprotein lipase activity measurements\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with specific BAT/thermogenesis phenotype, siRNA in primary adipocytes, LPL mechanism; multiple orthogonal methods\",\n      \"pmids\": [\"26819196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CK2 phosphorylates USF1 on Thr-100 (identified by deletion and point mutagenesis); CK2 phosphorylation of USF1 inhibits USF1-USF2 heterodimerization, and inhibition of CK2 stimulates transcription from glucokinase and FAS promoters but not HO-1 promoter, demonstrating promoter-specific regulation by CK2-mediated USF1 phosphorylation.\",\n      \"method\": \"In vitro kinase assay, deletion and point mutants, co-immunoprecipitation (USF1-USF2 interaction), reporter gene assays, CK2 inhibitors\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted phosphorylation with mutagenesis plus Co-IP for dimerization plus functional reporter assays; multiple orthogonal methods\",\n      \"pmids\": [\"25194820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CK2 phosphorylates USF1 and strengthens USF1-PDX-1 interaction; USF1 transrepresses the PDX-1 promoter in a CK2-dependent manner, and this repression is abrogated by elevated glucose or CK2 inhibition. A phospho-mutant of USF1 reduces PDX-1 promoter binding, indicating that CK2-mediated USF1 phosphorylation modulates both PDX-1 transcription and USF1-PDX-1 protein interaction.\",\n      \"method\": \"Promoter luciferase assays, Co-immunoprecipitation (USF1-PDX-1), CK2 inhibitor treatment, USF1 phospho-mutant, primary islet insulin secretion assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of USF1-PDX-1 plus functional reporter plus phospho-mutant; single lab, consistent methods\",\n      \"pmids\": [\"29180680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"USF1 and USF2 trans-repress the iNOS gene in mesangial cells by binding an E-box at -893/-888; mutation of this E-box augments IL-1β-induced iNOS promoter activity. Cotransfection of USF-1 and USF-2 suppresses IL-1β-stimulated iNOS promoter activity, and dominant-negative USF-2 or cis-element decoys augment it.\",\n      \"method\": \"Site-directed mutagenesis of iNOS promoter E-box, EMSA, antibody supershift, cotransfection reporter assays, dominant-negative USF-2 constructs\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-directed mutagenesis of binding site plus dominant-negative plus EMSA; multiple orthogonal methods in one study\",\n      \"pmids\": [\"12225970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"USF1 binds the PAI-1 proximal promoter E-box (CACGTG at -160 to -165) in a growth-state-dependent manner; phosphorylated USF1 (isolated by promoter-DNA affinity chromatography) is the predominant E-box-binding form in wound-stimulated cells. Wounding induces USF1 nuclear accumulation and E-box binding within 2 h, correlating with PAI-1 transcriptional induction.\",\n      \"method\": \"EMSA, UV cross-linking, deoxyoligonucleotide affinity chromatography, immunocytochemistry, Western blotting, in vitro wound model\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (affinity chromatography, EMSA, UV cross-linking) identifying phospho-USF1 as wound-responsive E-box binder; single lab\",\n      \"pmids\": [\"12235287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Purified rat USF1 is phosphorylated in vitro by PKC and PKA (but not casein kinase II); phosphorylated USF1 by either kinase shows increased DNA-binding activity to the cardiac α-MHC HME E-box, and PKC phosphorylation additionally promotes USF1 multimer formation. In vivo, USF1 is found in at least two phosphorylated forms in ventricular myocytes.\",\n      \"method\": \"In vitro kinase assay (PKC, PKA, CK2), EMSA, 2D gel electrophoresis of in vivo phosphorylated nuclear proteins\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted phosphorylation assay by defined kinases plus in vivo 2D gel confirmation; multiple orthogonal approaches\",\n      \"pmids\": [\"12063293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A USF1/USF2 heterodimer binds a CAGCTG (E-box) element in the first intron of the FcεRI α-chain gene and activates its expression; overexpression of antisense USF2 represses FcεRI α-chain promoter activity and decreases α-chain mRNA in mast cell lines.\",\n      \"method\": \"EMSA with antibodies and in vitro-translated proteins, cotransfection reporter assays, antisense USF2 knockdown\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA with defined proteins plus functional reporter plus antisense knockdown; single lab, consistent approaches\",\n      \"pmids\": [\"11180124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"USF1 and USF2 bind the HOXB4 promoter E-box (HXRE-2) in vitro and in K562 cells; cotransfection assays show USF-1 and USF-2 (but not MITF) induce the HOXB4 promoter in K562 and CD34+ cells via MAPK pathway activation.\",\n      \"method\": \"Yeast one-hybrid screen, EMSA, cotransfection reporter assays in K562 and CD34+ cells, HXRE-2 mutagenesis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast one-hybrid identifies USF2, EMSA confirms USF1/2, functional reporter assays; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"11085749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NF-Y and USF1/2 interact biochemically on the HOXB4 promoter (identified by Co-IP), and the NF-Y/USF1/2 complex is required for full HOXB4 promoter activity in hematopoietic cells; ChIP shows reduced NF-Y occupancy in more differentiated granulocytic cells consistent with lower HOXB4 expression.\",\n      \"method\": \"Co-immunoprecipitation (NF-Y/USF1-2 interaction), ChIP, cotransfection reporter assays, E-box mutagenesis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of protein complex plus ChIP for in vivo occupancy plus functional reporter; single lab\",\n      \"pmids\": [\"12791656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"v-Src down-regulates the SSeCKS/AKAP12 alpha promoter by recruiting HDAC1 into a USF1-Sp1-Sp3 complex; v-Src does not alter USF1 binding to the E-box but increases Sp1/Sp3 binding. HDAC1 recruitment is necessary and sufficient for promoter repression; TSA (HDAC inhibitor) restores SSeCKS levels.\",\n      \"method\": \"Promoter deletion analysis, chromatin immunoprecipitation, cotransfection reporter assays, TSA and 5-azacytidine treatment, protein expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating HDAC1 recruitment, functional reporter with mutagenesis, pharmacological rescue; single lab\",\n      \"pmids\": [\"17626016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USF1 is required for TGF-β1 and renin gene expression in diabetic kidney disease; high glucose inhibits AMPK activity and increases USF1 nuclear translocation in mesangial cells. Activation of AMPK with AICAR stimulates AMPK and reduces nuclear USF1 accumulation, indicating AMPK regulates USF1 nuclear localization.\",\n      \"method\": \"USF1 −/− mice crossed with Akita diabetic mice, mesangial cell culture, AMPK activation with AICAR, nuclear fractionation, Western blotting\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with disease phenotype plus pharmacological AMPK manipulation with subcellular localization readout; single lab\",\n      \"pmids\": [\"21543418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USF1 is activated downstream of PI3K/Akt/GSK3 signaling; GSK3 phosphorylates USF1 on the previously described activating site Thr-153 as well as on a newly identified site Ser-186. USF1 (together with MITF) drives transcription of proapoptotic and cell-cycle arrest genes when PI3K is inhibited, coordinately with FoxO.\",\n      \"method\": \"ChIP, siRNA knockdown, pharmacological PI3K inhibition, identification of GSK3 phosphorylation sites on USF1, gene expression profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus siRNA plus phosphorylation site identification; single lab, multiple methods\",\n      \"pmids\": [\"21873430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Retinoic acid triggers a feed-forward loop in which CREB (activated directly by PKA) induces USF1 expression, and the induced USF1 then binds the MKP1 promoter E-box to drive the late phase of MKP1 transcription; both CREB and USF1 binding to the MKP1 promoter were confirmed by ChIP.\",\n      \"method\": \"ChIP (CREB and USF1 binding to MKP1 promoter), gel-shift assay, siRNA knockdown of CREB and USF1, MKP1 promoter reporter with CRE/E-box mutations\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus EMSA plus siRNA knockdown plus mutant reporter; single lab\",\n      \"pmids\": [\"18625721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"H. pylori activates COX-2 gene transcription via a proximal CRE/E-box element at -56 to -48 in the cox-2 promoter; USF1/2 and CREB transcription factors binding to this element transmit H. pylori-dependent COX-2 transcription, and this is mediated by MEK/ERK1/2 signaling activated by bacterial virulence factors outside the cagPAI.\",\n      \"method\": \"Promoter deletion analysis, EMSA (USF1/2 and CREB binding), MEK/ERK inhibitor experiments, reporter assays, mRNA/protein quantification\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus functional promoter analysis plus signaling pathway inhibitor; single lab, consistent methods\",\n      \"pmids\": [\"14531897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"USF-1 and ERα form a multi-protein complex with Sp1 at the ERα minimal promoter; Sp1 and USF-1 bind directly to the promoter (shown by EMSA), while ERα interacts with USF-1 in vitro (GST pull-down) without directly binding DNA, and combined overexpression causes synergistic transactivation.\",\n      \"method\": \"EMSA, GST pull-down, cotransfection reporter assays\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — GST pull-down plus EMSA plus functional reporter; single lab\",\n      \"pmids\": [\"15111769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"USF1 and USF2 constitutively bind an E-box in the proximal promoter of the human HO-1 gene in vivo (confirmed by ChIP and DMS footprinting); overexpression of USF1 or USF2 enhances basal HO-1 expression, and a dominant-negative USF reduces it, showing USFs are required for high-level HO-1 expression.\",\n      \"method\": \"ChIP, DMS in vivo footprinting, EMSA, dominant-negative USF overexpression, reporter assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vivo DMS footprinting plus ChIP plus dominant-negative loss-of-function plus reporter assays; multiple orthogonal methods\",\n      \"pmids\": [\"15242350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"USF-1 up-regulates CSA and HR23A gene expression in response to UV irradiation, which are key players in TCR and GGR sub-pathways of nucleotide excision repair, through a p53-independent mechanism; Usf1 −/− mice show compromised UV-induced DNA repair.\",\n      \"method\": \"In vitro and in vivo UV irradiation assays, Usf1 −/− mouse model, mRNA quantification, NER activity assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with NER readout plus gene expression analysis; single lab\",\n      \"pmids\": [\"22291606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A novel alternative splicing isoform of USF1, termed USF1/BD, lacks the N-terminal transactivation domain; it localizes to the nucleus, retains DNA-binding activity as both homodimer and heterodimer with wild-type USF1, and represses the angiotensinogen gene promoter when transfected into cells.\",\n      \"method\": \"cDNA cloning, nuclear localization assay (ectopic expression), in vitro translation DNA-binding assay, reporter gene assay\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab with in vitro binding and reporter assay; limited mechanistic follow-up\",\n      \"pmids\": [\"12851711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"USF1 suppresses CYP1A1 induction by competing with the AhR·Arnt complex for binding to the XRE, which overlaps with a USF1 E-box binding site; transfection of USF1 into HepG2 cells prevents AhR·Arnt–XRE interaction and depresses MC-induced CYP1A1 mRNA induction.\",\n      \"method\": \"EMSA, antibody supershift, XRE-TK/Luc reporter cotransfection, S1 nuclease protection assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA competition plus reporter gene functional assay plus mRNA quantification; single lab, multiple consistent methods\",\n      \"pmids\": [\"9374477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Pea3 cooperates with USF-1 for transactivation of the bax promoter without directly binding DNA; E-boxes in the minimal bax promoter are required for Pea3 transactivation potential, and USF-1 can form a ternary complex with Pea3 and DNA (shown by antibody-mediated EMSA supershift).\",\n      \"method\": \"Pea3 overexpression and siRNA, reporter gene assays, EMSA with antibody supershift demonstrating ternary complex\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — EMSA ternary-complex evidence plus functional reporter; single lab\",\n      \"pmids\": [\"15466854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USF1 is required for maintenance of spermatogonial stem cells (SSCs) in mice; Usf1 −/− mice show SSC over-proliferation and age-dependent depletion of SSCs leading to progressive spermatogenic decline, testicular atrophy, and reduced sperm production, demonstrating a direct role in maintaining SSC quiescence.\",\n      \"method\": \"Usf1 −/− mouse model, histology, immunostaining for SSC and Sertoli markers, spermatogenesis assessment\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with specific SSC-proliferation phenotype; single lab\",\n      \"pmids\": [\"30759202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USF1 (and USF2) binding to the FAS gene E-box promoter element drives FAS transcription in adipocytes; knockdown of USF1 represses adipogenesis along with decreased FAS expression, while USF1 overexpression enhances adipogenesis and FAS expression; valproic acid suppresses adipogenesis partly by down-regulating USF1.\",\n      \"method\": \"ChIP (USF1 binding to FAS promoter E-box), siRNA knockdown, overexpression, luciferase reporter assay, adipogenesis quantification\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus siRNA and overexpression with phenotypic readout; single lab\",\n      \"pmids\": [\"24511897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AKT phosphorylates USF-1 in response to insulin/PI3K signaling, enhancing USF-1 binding to the WBP2 promoter E-box and increasing WBP2 transcription; this was identified by yeast one-hybrid, confirmed by ChIP and tandem mass spectrometry, and the phosphorylation-dependent E-box binding demonstrated by reporter assay.\",\n      \"method\": \"Yeast one-hybrid, ChIP, tandem mass spectrometry (phosphorylation site), luciferase reporter with E-box mutation, AKT inhibitor treatment\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast one-hybrid plus ChIP plus mass-spec phosphorylation plus reporter; single lab\",\n      \"pmids\": [\"30183375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTP4A1 increases the transcriptional activity of USF1 by dephosphorylating its S309 residue, which in turn drives transcription of TNFAIP3/A20 and thereby inhibits NF-κB activity and vascular inflammation; shown by ChIP, luciferase reporter, and Co-IP assays.\",\n      \"method\": \"ChIP, luciferase reporter, Co-IP, siRNA and overexpression in HUVECs, Ptp4a1 KO and transgenic mice, phospho-site specific analysis\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus Co-IP plus phospho-site (S309) identification plus in vivo KO model; single lab, multiple methods\",\n      \"pmids\": [\"36534975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USF1 transcriptionally activates USP14 by binding its promoter (confirmed by ChIP and dual-luciferase assay), which promotes deubiquitination and stabilization of NLRC5, leading to Smad2/3 pathway activation and endothelial-to-mesenchymal transition (EndMT) driving atherosclerosis.\",\n      \"method\": \"Dual-luciferase reporter, ChIP, Co-IP (USP14/NLRC5), siRNA knockdown, ApoE −/− mouse atherosclerosis model\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter confirm USF1→USP14 binding, Co-IP shows USP14/NLRC5 interaction, in vivo model; single lab\",\n      \"pmids\": [\"38424494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Inhibition of HDAC2/3 by apicidin increases USF1 acetylation, enhances USF1 association with HDAC2/3 and with the ADAM10 promoter, and up-regulates ADAM10 expression via an ERK-dependent mechanism; USF1 knockdown prevents apicidin-induced ADAM10 up-regulation.\",\n      \"method\": \"Luciferase reporter assay, USF1 knockdown (siRNA), USF1 acetylation assay, Co-immunoprecipitation (USF1/HDAC2/3), ChIP, ERK inhibitor (U0126)\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus functional reporter plus siRNA; single lab, multiple methods\",\n      \"pmids\": [\"28003340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The rs1867277 A allele in the FOXE1 5' UTR recruits USF1/USF2 as a complex (demonstrated by DNA-binding assays); only the A allele (not the G allele) forms a USF1/USF2 complex, leading to allele-dependent transcriptional regulation of FOXE1.\",\n      \"method\": \"DNA-binding (EMSA/pull-down) assays, allele-specific binding, transfection reporter assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — allele-specific EMSA/pull-down plus reporter; single lab\",\n      \"pmids\": [\"19730683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of USF1 or MYC in human monocyte-derived macrophages decreases phagocytosis and chemotaxis, increases cell size, alters morphology, and reduces actin content; these phenotypes concordantly reflect the functional decline seen in macrophages from older donors, identifying USF1 as a driver of macrophage age-related functional decline.\",\n      \"method\": \"siRNA knockdown of USF1 in human MDMs, phagocytosis assay, chemotaxis assay, morphology/actin quantification, transcriptomic analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined siRNA knockdown with multiple functional readouts (phagocytosis, chemotaxis, actin, morphology); single lab\",\n      \"pmids\": [\"38578825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"USF1 and USF2 are the major transcription factors binding the FMR1 promoter in brain and testis extracts; methylation of the promoter reduces USF1/USF2 binding and abolishes α-Pal/Nrf-1 binding, providing a mechanism by which CpG methylation silences FMR1 transcription beyond histone deacetylase recruitment.\",\n      \"method\": \"EMSA with brain and testis nuclear extracts, antibody supershift, methylation interference, site mutagenesis, reporter gene assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA with defined antibody supershifts in tissue extracts plus methylation interference plus reporter; single lab\",\n      \"pmids\": [\"11058604\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USF1 is a ubiquitous bHLH-LZ transcription factor that binds E-box (CANNTG) elements as homodimers or USF1/USF2 heterodimers to activate or repress a broad range of target genes (FAS, HOXB4, HO-1, iNOS, POMC, MC1R, Tyrosinase, PAI-1, APC, FMR1, CIITA PIV, and many others); its activity is tuned by multiple post-translational modifications—phosphorylation by p38 (activating, on Thr-153), cyclin-CDK complexes, PKC, PKA, AKT, and CK2 (on Thr-100, suppressing heterodimerization), and dephosphorylation by PTP4A1 (on Ser-309, activating)—where p38-mediated Thr-153 phosphorylation additionally primes stress-dependent acetylation that redirects USF1 target-gene specificity; USF1 recruits chromatin-modifying complexes (PRMT1/PCAF/SRC-1 for active histone marks at insulators; hSET1A for H3K4me3 at developmental loci) and interacts with co-regulators including TFII-I, Ets-1, Stat1, NF-Y, PDX-1, ERα, Pea3, and HDAC1-containing complexes; in the DNA-damage response, USF1 stabilizes p53 by blocking MDM2-mediated degradation through a non-transcriptional mechanism; USF1 also regulates brown adipose thermogenesis, spermatogonial stem cell quiescence, macrophage phagocytosis/chemotaxis, and nucleotide excision repair gene expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"USF1 is a ubiquitous basic helix-loop-helix-leucine zipper transcription factor that binds E-box (CANNTG) elements as USF1 homodimers or USF1/USF2 heterodimers to activate or repress a broad spectrum of target genes across metabolism, stress responses, development, and immunity [#7, #29]. Its specificity is achieved largely through combinatorial protein-protein cooperation at composite promoters: USF1 synergizes with TFII-I at Inr/E-box elements [#1], with Stat1 at the CIITA GAS/E-box module during IFN\\u03b3 signaling [#0], with Ets-1 at the HIV-1 LTR [#6], and with NF-Y, Sp1, ER\\u03b1, and Pea3 at other loci [#22, #28, #33], while also acting as a repressor that competes with the AhR/Arnt complex at the CYP1A1 XRE [#32] and with CLOCK:BMAL1 at circadian E-boxes [#9]. USF1 nucleates chromatin-modifying activity, recruiting PRMT1/PCAF/SRC-1 to establish active histone marks and barrier function at the \\u03b2-globin insulator [#5] and the hSET1A H3K4 methyltransferase complex to developmental loci such as HoxB4 to license differentiation [#12]. USF1 activity is extensively tuned by post-translational modification: p38 phosphorylates Thr-153 in response to UV/oxidative stress, which both activates USF1 and primes a downstream acetylation event that redirects its target-gene output away from pigmentation and cell-cycle genes [#2, #4]; cyclin-CDK complexes, PKC, PKA, and AKT enhance its DNA binding [#8, #19, #36]; CK2 phosphorylates Thr-100 to suppress USF1/USF2 heterodimerization in a promoter-selective manner [#15]; and PTP4A1 dephosphorylates Ser-309 to boost its transcriptional activity [#37]. Beyond transcription, USF1 stabilizes p53 through a non-transcriptional mechanism, physically blocking MDM2-mediated degradation [#10]. At the physiological level, USF1 regulates lipogenic (FAS) and nutrient-responsive gene expression [#7, #35], negatively controls brown adipose thermogenesis [#14], drives UV-induced nucleotide excision repair gene expression [#30], maintains spermatogonial stem cell quiescence [#34], and sustains macrophage phagocytosis and chemotaxis [#41].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established USF1 as a physiological E-box-binding regulator of a metabolic gene, showing its protein level itself is nutritionally regulated rather than constant.\",\n      \"evidence\": \"UV cross-linking, antibody supershift, and immunoblotting at the FAS insulin response sequence across fasted/refed rat liver\",\n      \"pmids\": [\"7499393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking nutritional state to USF1 protein abundance not defined\", \"Identity/relevance of the 17 kDa USF1-related fasted-state protein unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed USF1 does not act alone but synergizes with a partner factor (TFII-I) at composite Inr/E-box promoters, introducing the combinatorial-cooperation theme.\",\n      \"evidence\": \"cDNA cloning, in vivo transcription assays, and domain deletion mapping on the adenovirus major late promoter\",\n      \"pmids\": [\"9384587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the USF1-TFII-I contact not resolved\", \"Generality across cellular promoters not established at the time\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined USF1 as a cooperative DNA-binding partner whose recruitment of Stat1 to an adjacent GAS site couples IFN\\u03b3 signaling to CIITA induction, and established direct DBD-DBD contacts with Ets-1 as a transactivation requirement.\",\n      \"evidence\": \"EMSA cooperative binding, promoter mutagenesis, reporter assays (CIITA PIV); yeast one-hybrid, Co-IP, dominant-negative analysis (Ets-1/HIV-1 LTR)\",\n      \"pmids\": [\"9491997\", \"9501094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same surfaces mediate all USF1 partner interactions unknown\", \"Stoichiometry of multiprotein complexes on composite promoters not determined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified phosphorylation as a direct switch on USF1 DNA-binding affinity, mapping cyclin-CDK-responsive sites to the USF-specific region outside the DBD.\",\n      \"evidence\": \"In vitro kinase assays with cyclin A2/B1-p34(cdc2), EMSA, and deletion mutagenesis of recombinant USF1\",\n      \"pmids\": [\"10548544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact phospho-residues within 143-197 not pinpointed\", \"In vivo cell-cycle relevance not demonstrated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected stress signaling to USF1 by showing p38 directly phosphorylates and activates it, making USF1 the effector of UV-induced pigmentation gene activation.\",\n      \"evidence\": \"In vitro kinase assay, reporter assays, and USF1-/- mouse melanocytes under UV irradiation; parallel demonstration of zinc-responsive MT-I cooperation with MTF-1 in null embryos\",\n      \"pmids\": [\"11532965\", \"11230134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation site not yet mapped at this stage\", \"How p38-USF1 selects pigmentation targets unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended the p38-USF1 stress axis to the melanocortin pathway (POMC, MC1R) using loss-of-function genetics, establishing USF1 as a node coordinating the UV photoprotective response.\",\n      \"evidence\": \"USF1-/- mouse melanocytes, UV irradiation, reporter assays, and RT-PCR\",\n      \"pmids\": [\"15358786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect occupancy at POMC/MC1R E-boxes not fully delineated\", \"Crosstalk with other UV-responsive factors unaddressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed USF1 as a recruiter of histone-modifying machinery, directly binding PRMT1 and assembling a PCAF/SRC-1 complex that maintains insulator barrier function.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA knockdown, and dominant-negative peptide interference at the \\u03b2-globin insulator\",\n      \"pmids\": [\"17846119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of complex assembly on chromatin not established\", \"Whether PRMT1 recruitment generalizes beyond the insulator unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the p38-USF1 mechanism by mapping Thr-153 phosphorylation as the prerequisite for stress-induced acetylation that redirects USF1 target specificity while preserving nuclear DNA binding.\",\n      \"evidence\": \"In vitro kinase assay, phospho-specific antibodies, T153A mutagenesis, acetylation and reporter assays\",\n      \"pmids\": [\"19389701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase and acetylated lysine(s) not identified\", \"Genome-wide consequences of the phospho-acetyl switch not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established two distinct chromatin/developmental roles: USF1 recruits hSET1A for H3K4me3 to license ESC differentiation, and competes with CLOCK:BMAL1 for E-boxes to modulate circadian behavior.\",\n      \"evidence\": \"ChIP, Co-IP, siRNA, dominant-negative, ESC differentiation assays (HoxB4); genetic suppressor mapping, saturation binding, and genome-wide ChIP (circadian)\",\n      \"pmids\": [\"23754954\", \"23580255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USF1 vs CLOCK:BMAL1 occupancy is balanced in normal physiology unclear\", \"Determinants of USF1-hSET1A locus selectivity unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Uncovered a non-transcriptional function: USF1 stabilizes p53 by blocking MDM2 binding, decoupling a transcription factor from its DNA-binding activity.\",\n      \"evidence\": \"Co-IP, USF1-/- and USF1-deficient melanoma cells, DBD/transactivation-less truncation rescue, Nutlin-3 controls\",\n      \"pmids\": [\"24831529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of USF1-p53/MDM2 interplay not defined\", \"Stoichiometry and subcellular site of the protective complex unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined CK2 phosphorylation of Thr-100 as a dimerization switch that selectively gates USF1 output at metabolic (glucokinase, FAS) versus stress (HO-1) promoters.\",\n      \"evidence\": \"In vitro kinase, point mutagenesis, Co-IP for USF1-USF2 dimerization, reporter assays with CK2 inhibitors\",\n      \"pmids\": [\"25194820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How loss of heterodimerization yields promoter-specific outcomes mechanistically unresolved\", \"In vivo CK2-USF1 axis not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed USF1 at the center of energy metabolism, showing it negatively regulates brown adipose thermogenesis and positively drives adipogenic FAS expression.\",\n      \"evidence\": \"USF1-/- mice, BAT sympathectomy, diet-induced obesity, siRNA in brown adipocytes, LPL assays (BAT); ChIP, siRNA, overexpression in adipogenesis (FAS)\",\n      \"pmids\": [\"26819196\", \"24511897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct BAT target genes of USF1 not enumerated\", \"Reconciliation of pro-adipogenic vs anti-thermogenic roles incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated pathogen subversion of USF1 and a stem-cell maintenance role: H. pylori delocalizes USF1/p53 to drive p53 degradation and gastric carcinogenesis, while USF1 maintains spermatogonial stem cell quiescence.\",\n      \"evidence\": \"Immunofluorescence, Co-IP, USF1-/- mice, H. pylori infection (gastric); USF1-/- mice with histology and SSC marker staining (testis)\",\n      \"pmids\": [\"31822580\", \"30759202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"H. pylori factor and signaling that relocalize USF1 not identified\", \"Direct USF1 targets governing SSC quiescence unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified PTP4A1-mediated Ser-309 dephosphorylation as an activating modification driving anti-inflammatory transcription (TNFAIP3/A20) and NF-\\u03baB suppression in endothelium.\",\n      \"evidence\": \"ChIP, luciferase reporter, Co-IP, phospho-site analysis in HUVECs and Ptp4a1 KO/transgenic mice\",\n      \"pmids\": [\"36534975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase that phosphorylates S309 in this context not identified\", \"Single lab; reciprocal validation of PTP4A1-USF1 axis limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended USF1 into vascular disease and immune aging, driving USP14-dependent NLRC5 stabilization in atherosclerotic EndMT and sustaining macrophage phagocytosis and chemotaxis.\",\n      \"evidence\": \"ChIP, dual-luciferase, Co-IP, ApoE-/- mice (USP14/NLRC5/EndMT); siRNA in human monocyte-derived macrophages with functional and transcriptomic readouts\",\n      \"pmids\": [\"38424494\", \"38578825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect control of the actin/morphology program in macrophages unresolved\", \"Single-lab findings without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the layered post-translational code (p38/Thr-153, CK2/Thr-100, AKT, CDK, PTP4A1/Ser-309) is integrated to select among the hundreds of E-box targets in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking specific modifications to genome-wide target selection\", \"Structural basis of partner-dependent specificity uncharacterized\", \"Endogenous full-length occupancy maps across modification states lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 7, 17, 29, 35]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [7, 8, 9, 29, 31]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [5, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 11, 24, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 7, 29]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 14, 35]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [30]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"USF2\", \"TFII-I\", \"Stat1\", \"Ets-1\", \"PRMT1\", \"NF-Y\", \"PDX-1\", \"p53\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}