USF1 (upstream transcription factor 1)

2010-04-01   Adrie JM Verhoeven 

Cardiovascular Research School (COEUR), Department of Biochemistry, Erasmus MC, Rotterdam, Netherlands




Atlas Image
Human USF1 gene diagram. Exons 1 through 11 are depicted by boxes, the open reading frames of the USF1 protein and the splice variant are shown by dark and light green colour code, respectively. The approximate positions of two functional SNPs are also indicated.


The human USF1 gene on chromosome 1q23 spans 6.73 kb and 11 exons.


The mRNA is about 1870 nt. Translation is from a start codon in exon 2 and ends at a stop codon in exon 11, and results in a 310 amino acid protein product. In a splice variant, an alternative donor splice site within exon 4 is used; translation from this variant mRNA is from an in-frame start codon in exon 5, and results in a 251 amino acid protein product (Saito et al., 2003).


Atlas Image
Functional domains of the USF1 protein. The A1 domain is important for E-box dependent transactivation, the USR (USF-specific region) and A2 domains are important for E-box and initiator element (Inr)-dependent transactivation (Roy et al., 1997). Post-translational modifications that affect USF1 function are indicated. The protein product of the splice variant lacks the first 59 amino acids, dimerizes with full-length USF1 protein, which results in its inactivation (Saito et al., 2003).


USF1 belongs to the bHLH-Zip class of transcription factors. The bHLH-ZIP domains are important for DNA binding and dimerization. USF homo- and heterodimers activate transcription of target genes through binding either at distal E-box elements or at pyrimidine-rich Inr elements in the core promoter (Roy et al., 1997). Whole genome ChIP-chip analysis in human hepatoma HepG2 cells showed that USF1 and USF2 bind predominantly to CACGTGAC elements (Rada-Iglesias et al., 2008). In addition, USF2 but not USF1 binds to pyrimidine rich elements, suggesting that transactivation through Inr elements is mainly through USF2. Transactivation activity critically depends on post-translational modification of USF1. DNA binding to the E-box element is increased by phosphorylation of USF1 by the cdk1, p38 stress-activated kinase, protein kinase A and protein kinase C pathway (Corre and Galibert, 2005), whereas phosphorylation through the PI3Kinase pathway leads to loss of DNA binding activity to the ApoAV promoter (Nowak et al., 2005). Cellular stress stimuli such as DNA damage, oxidative stress and heavy metal exposure, induce p38-mediated phosphorylation at T153 and increased USF1 transactivation activity. Upon increased and/or prolonged stress exposure, USF1 phosphorylated at T153 becomes acetylated at K199 with concomitant loss of transactivation activity (Corre et al., 2009). In fasting-refeeding cycles, insulin increases the transactivation activity of USF1 via DNA-PK mediated phosphorylation of residue S262 and subsequent acetylation at K237 (Wong et al., 2009).


The USF1 gene is ubiquitously expressed (Sirito et al., 1994).


The USF1 protein is located in the nucleus.


USF1 has been shown to play an important role in transcriptional regulation of a huge number of seemingly unrelated genes (Corre and Galibert, 2005; Rada-Iglesias et al., 2008), consistent with the abundant distribution of E-box like elements in the genome. Whole-genome ChIP analysis in HepG2 cells identified 2518 USF1 binding sites in chromatin context, of which 41 % were located within 1 kb of a transcription start site (Rade-Iglesias et al., 2008). USF1 binding signals strongly correlate with target gene expression levels, suggesting that USF1 plays an important role in transcription activation. USF1 physically interacts with histone modifying enzymes, transcription preinitiation complex factors, coactivator and corepressor proteins (Corre and Galibert, 2005; Huang et al., 2007; Corre et al., 2009; Wong et al., 2009). In addition, USF1 interacts with other transcription factors to achieve cooperative transcriptional activation of individual genes (Corre and Galibert, 2005). USF1 also plays a crucial role in chromatin barrier insulator function, in which euchromatin regions are protected from heterochromatin-induced gene silencing (Huang et al., 2007). USFs recruit histone modifying enzymes to the insulator element, which modify the adjacent nucleosomes thereby maintaining chromatin in an open state and preventing heterochromatin spread. Similarly, USFs main function at enhancer elements may be to render the adjacent region accessible for binding of other, bona fide transcription factors, by the recruitment of histone modifying enzymes (Huang et al., 2007).
Tumor suppression: Several lines of evidence support the hypothesis that USF1 may act as a tumor suppressor. First, USF1 is involved in the transcriptional activation of several tumor suppressor genes (e.g. p53, APC, BRCA2, PTEN, SSeCKS) (Corre and Galibert, 2005; Pezzolesi et al., 2007; Bu and Gelman, 2007), and represses expression of human telomerase reverse transcriptase TERT (McMurray and McCance, 2003; Chang et al., 2005). Second, USF1 is involved in cell cycle control (Cogswell et al., 1995) and overexpression of USF1 slows G2/M transition in thyrocytes and thyroid carcinoma cells (Jung et al., 2007). Third, USF1 overexpression leads to a strong reduction in cell proliferation in Ha-Ras/c-Myc transformed fibroblasts (Luo and Sawadogo, 1996). Fourth, USF1 transactivation activity is completely lost in three out of six transformed breast cell lines (Ismail et al., 1999). Fifth, USF1 antagonizes some activities of the oncoprotein c-Myc, possibly by competing for the same DNA binding sites (Luo and Sawadogo, 1996; McMurray and McCance, 2003). Definitive proof that USF1 is a tumor suppressor protein, e.g. showing that USF1 knockdown increases cell proliferation and tumor formation, however, is still missing. This proof may be hard to gain, as USF2 may compensate for USF1 loss, and USF2 appears to have a broader antiproliferative function than USF1 (Luo and Sadawogo, 1996; Sirito et al., 1998; Vallet et al., 1998).


The USF1 gene is widely conserved with orthologs identified in Ciona intestinalis and Drosophila melanogaster.



Of the 121 SNPs in the USF1 gene collected in the dbSNP database, only the rs4126997 T>C polymorphism causes a non-synchronous mutation (V15A missense), but data on allele frequency or functional effects are not available. The two SNPs that are shown to be functional, rs2073658 A>G in intron 7 (heterozygosity 0.296) and rs3737787 C>T in the 3-UTR (heterozygosity 0.309), are in almost complete linkage disequilibrium. The minor allele is accompanied by normal USF1 expression in human muscle and fat tissue but loss of insulin-induced upregulation of USF1 mRNA and known USF1 target genes (Naukkarinen et al., 2005; Naukkarinen et al., 2009), as well as reduced insulin-mediated anti-lipolytic activity (Kantartzis et al., 2007).

Implicated in

Entity name
Given the suggestive evidence for a role of USF1 in tumor suppression, one may anticipate that carcinogenesis will evolve from loss of USF1 transactivation activity, either as a result of mutations in the USF1 gene or of posttranslational modification of USF1 protein. This has not been reported yet. Alternatively, tumor suppressor genes may lose responsivity to USF1 by mutations in the DNA binding element or by changes in local DNA methylation. This is exemplified by the observation of a classic Cowden syndrome patient with early onset breast cancer and reduced PTEN activity, which appears to be due to a specific germline mutation of an E-box element in the PTEN gene and loss of USF1 binding (Pezzolesi et al., 2007).
Entity name
Familial combined hyperlipidemia (FCHL)
FCHL is the most common genetic form of hyperlipidemia and is associated with increased risk of premature cardiovascular disease. Affected persons characteristically show elevation of both cholesterol and triglycerides in the blood, which is due to increased VLDL and LDL levels. This is often accompanied by elevated apoB100 and low HDL levels, and a preponderance of small dense LDL particles (Naukkarinen et al., 2006). FCHL is genetically heterogeneous. One of the loci that is linked to FCHL is 1q21-q23. Pajukanta et al. (2004) showed that the dyslipidemia observed in FCHL is linked to the USF1 gene. The disease is associated with a common haplotype of non-coding SNPs within the USF1 gene. Carriers of the risk allele show lack of insulin-induced increase of USF1 expression in skeletal muscle and fat tissue (Naukkarinen et al., 2009). As USF1 is involved in regulation of numerous genes of glucose and lipid metabolism (Corre and Galibert, 2005), non-responsive USF1 expression may lead to increased production and reduced metabolism of plasma lipids and lipoproteins.


Pubmed IDLast YearTitleAuthors
176260162007v-Src-mediated down-regulation of SSeCKS metastasis suppressor gene promoter by the recruitment of HDAC1 into a USF1-Sp1-Sp3 complex.Bu Y et al
160106902005Upstream stimulatory factor (USF) as a transcriptional suppressor of human telomerase reverse transcriptase (hTERT) in oral cancer cells.Chang JT et al
77395591995Upstream stimulatory factor regulates expression of the cell cycle-dependent cyclin B1 gene promoter.Cogswell JP et al
161621742005Upstream stimulating factors: highly versatile stress-responsive transcription factors.Corre S et al
193897012009Target gene specificity of USF-1 is directed via p38-mediated phosphorylation-dependent acetylation.Corre S et al
178461192007USF1 recruits histone modification complexes and is critical for maintenance of a chromatin barrier.Huang S et al
105238351999Loss of USF transcriptional activity in breast cancer cell lines.Ismail PM et al
173799622007USF inhibits cell proliferation through delay in G2/M phase in FRTL-5 cells.Jung HS et al
170166912007Upstream transcription factor 1 gene polymorphisms are associated with high antilipolytic insulin sensitivity and show gene-gene interactions.Kantartzis K et al
85777601996Antiproliferative properties of the USF family of helix-loop-helix transcription factors.Luo X et al
129418942003Human papillomavirus type 16 E6 activates TERT gene transcription through induction of c-Myc and release of USF-mediated repression.McMurray HR et al
200316292009Functional variant disrupts insulin induction of USF1: mechanism for USF1-associated dyslipidemias.Naukkarinen J et al
156844022005Insulin-mediated down-regulation of apolipoprotein A5 gene expression through the phosphatidylinositol 3-kinase pathway: role of upstream stimulatory factor.Nowak M et al
149910562004Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1).Pajukanta P et al
173414832007Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome.Pezzolesi MG et al
182308032008Whole-genome maps of USF1 and USF2 binding and histone H3 acetylation reveal new aspects of promoter structure and candidate genes for common human disorders.Rada-Iglesias A et al
93845871997Cloning of an inr- and E-box-binding protein, TFII-I, that interacts physically and functionally with USF1.Roy AL et al
128517112003Cloning and characterization of a novel splicing isoform of USF1.Saito T et al
95204401998Overlapping roles and asymmetrical cross-regulation of the USF proteins in mice.Sirito M et al
96853631998Differential roles of upstream stimulatory factors 1 and 2 in the transcriptional response of liver genes to glucose.Vallet VS et al
193038492009A role of DNA-PK for the metabolic gene regulation in response to insulin.Wong RH et al

Other Information

Locus ID:

NCBI: 7391
MIM: 191523
HGNC: 12593
Ensembl: ENSG00000158773


dbSNP: 7391
ClinVar: 7391
TCGA: ENSG00000158773


Gene IDTranscript IDUniprot

Expression (GTEx)


Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
206826872010Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program.88
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
197500042009A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia.77
149910562004Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1).69
149910562004Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1).69
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
129707522003Regulation of telomerase reverse transcriptase gene activity by upstream stimulatory factor.44
189748422008Gender differences in genetic risk profiles for cardiovascular disease.33
169434252006Antagonistic regulation of beta-globin gene expression by helix-loop-helix proteins USF and TFII-I.28
197208312009Hepatocyte growth factor family negatively regulates hepatic gluconeogenesis via induction of orphan nuclear receptor small heterodimer partner in primary hepatocytes.28


Adrie JM Verhoeven

USF1 (upstream transcription factor 1)

Atlas Genet Cytogenet Oncol Haematol. 2010-04-01

Online version: