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).

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).