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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review USF1 (upstream transcription factor 1) Adrie JM Verhoeven Cardiovascular Research School (COEUR), Department of Biochemistry, Erasmus MC, Rotterdam, Netherlands (AJMV) Published in Atlas Database: April 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/USF1ID45856ch1q23.html DOI: 10.4267/2042/44944 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology homologous bHLH-ZIP transcription factor. USF1 and USF2 homo- and heterodimers are similarly active in affecting transcription of most target genes. USF2 homodimers may have additional effects. Identity Other names: bHLHb11, FCHL, FCHL1, HYPLIP1, MLTF, MLTF1, UEF HGNC (Hugo): USF1 Location: 1q23.3 Local order: From centromere to telomere: F11R (F11 receptor) (on reverse strand), TSTD1 (thiosulfate sulfurtransferase (rhodanese)-like domain containing 1) (on reverse strand), USF1 (upstream transcription factor 1) (on reverse strand), ARHGAP30 (Rho GTPase activating protein 30) (on reverse strand), PVRL4 (poliovirus receptor-related 4) (on reverse strand), KLHDC9 (kelch domain containing 9) (on plus strand), PFDN2 (prefoldin subunit 2) (on reverse strand). Note USF1 is a bHLH-ZIP transcription factor which forms homo-dimers or heterodimers with USF2, a highly DNA/RNA Description The human USF1 gene on chromosome 1q23 spans 6.73 kb and 11 exons. Transcription 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). 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. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1) 73 USF1 (upstream transcription factor 1) Verhoeven AJM 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). 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; Protein Description 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 stressactivated 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 T 153 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). Expression The USF1 gene is ubiquitously expressed (Sirito et al., 1994). Localisation The USF1 protein is located in the nucleus. Function 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 Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1) 74 USF1 (upstream transcription factor 1) Verhoeven AJM 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). 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. Homology The USF1 gene is widely conserved with orthologs identified in Ciona intestinalis and Drosophila melanogaster. Mutations Note 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 antilipolytic activity (Kantartzis et al., 2007). References Sirito M, Lin Q, Maity T, Sawadogo M. Ubiquitous expression of the 43- and 44-kDa forms of transcription factor USF in mammalian cells. Nucleic Acids Res. 1994 Feb 11;22(3):42733 Cogswell JP, Godlevski MM, Bonham M, Bisi J, Babiss L. Upstream stimulatory factor regulates expression of the cell cycle-dependent cyclin B1 gene promoter. Mol Cell Biol. 1995 May;15(5):2782-90 Luo X, Sawadogo M. Antiproliferative properties of the USF family of helix-loop-helix transcription factors. Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1308-13 Roy AL, Du H, Gregor PD, Novina CD, Martinez E, Roeder RG. Cloning of an inr- and E-box-binding protein, TFII-I, that interacts physically and functionally with USF1. EMBO J. 1997 Dec 1;16(23):7091-104 Implicated in Carcinogenesis Sirito M, Lin Q, Deng JM, Behringer RR, Sawadogo M. Overlapping roles and asymmetrical cross-regulation of the USF proteins in mice. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3758-63 Note 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). Vallet VS, Casado M, Henrion AA, Bucchini D, Raymondjean M, Kahn A, Vaulont S. Differential roles of upstream stimulatory factors 1 and 2 in the transcriptional response of liver genes to glucose. J Biol Chem. 1998 Aug 7;273(32):20175-9 Ismail PM, Lu T, Sawadogo M. Loss of USF transcriptional activity in breast cancer cell lines. Oncogene. 1999 Sep 30;18(40):5582-91 McMurray HR, McCance DJ. Human papillomavirus type 16 E6 activates TERT gene transcription through induction of c-Myc and release of USF-mediated repression. J Virol. 2003 Sep;77(18):9852-61 Saito T, Oishi T, Yanai K, Shimamoto Y, Fukamizu A. Cloning and characterization of a novel splicing isoform of USF1. Int J Mol Med. 2003 Aug;12(2):161-7 Familial combined hyperlipidemia (FCHL) Pajukanta P, Lilja HE, Sinsheimer JS, Cantor RM, Lusis AJ, Gentile M, Duan XJ, Soro-Paavonen A, Naukkarinen J, Saarela J, Laakso M, Ehnholm C, Taskinen MR, Peltonen L. Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat Genet. 2004 Apr;36(4):371-6 Disease FCHL is the most common genetic form of hyperlipidemia and is associated with increased risk of premature cardiovascular disease. Affected persons Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1) Chang JT, Yang HT, Wang TC, Cheng AJ. Upstream stimulatory factor (USF) as a transcriptional suppressor of 75 USF1 (upstream transcription factor 1) Verhoeven AJM human telomerase reverse transcriptase (hTERT) in oral cancer cells. Mol Carcinog. 2005 Nov;44(3):183-92 Kantartzis K, Fritsche A, Machicao F, Stumvoll M, Machann J, Schick F, Häring HU, Stefan N. Upstream transcription factor 1 gene polymorphisms are associated with high antilipolytic insulin sensitivity and show gene-gene interactions. J Mol Med. 2007 Jan;85(1):55-61 Corre S, Galibert MD. Upstream stimulating factors: highly versatile stress-responsive transcription factors. Pigment Cell Res. 2005 Oct;18(5):337-48 Naukkarinen J, Gentile M, Soro-Paavonen A, Saarela J, Koistinen HA, Pajukanta P, Taskinen MR, Peltonen L. USF1 and dyslipidemias: converging evidence for a functional intronic variant. Hum Mol Genet. 2005 Sep 1;14(17):2595-605 Pezzolesi MG, Zbuk KM, Waite KA, Eng C. Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional Ebox motif deleted in Cowden syndrome. Hum Mol Genet. 2007 May 1;16(9):1058-71 Nowak M, Helleboid-Chapman A, Jakel H, Martin G, DuranSandoval D, Staels B, Rubin EM, Pennacchio LA, Taskinen MR, Fruchart-Najib J, Fruchart JC. Insulin-mediated downregulation of apolipoprotein A5 gene expression through the phosphatidylinositol 3-kinase pathway: role of upstream stimulatory factor. Mol Cell Biol. 2005 Feb;25(4):1537-48 Rada-Iglesias A, Ameur A, Kapranov P, Enroth S, Komorowski J, Gingeras TR, Wadelius C. 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. Genome Res. 2008 Mar;18(3):38092 Naukkarinen J, Ehnholm C, Peltonen L. Genetics of familial combined hyperlipidemia. Curr Opin Lipidol. 2006 Jun;17(3):285-90 Corre S, Primot A, Baron Y, Le Seyec J, Goding C, Galibert MD. Target gene specificity of USF-1 is directed via p38mediated phosphorylation-dependent acetylation. J Biol Chem. 2009 Jul 10;284(28):18851-62 Bu Y, Gelman IH. v-Src-mediated down-regulation of SSeCKS metastasis suppressor gene promoter by the recruitment of HDAC1 into a USF1-Sp1-Sp3 complex. J Biol Chem. 2007 Sep 14;282(37):26725-39 Naukkarinen J, Nilsson E, Koistinen HA, Söderlund S, Lyssenko V, Vaag A, Poulsen P, Groop L, Taskinen MR, Peltonen L. Functional variant disrupts insulin induction of USF1: mechanism for USF1-associated dyslipidemias. Circ Cardiovasc Genet. 2009 Oct;2(5):522-9 Huang S, Li X, Yusufzai TM, Qiu Y, Felsenfeld G. USF1 recruits histone modification complexes and is critical for maintenance of a chromatin barrier. Mol Cell Biol. 2007 Nov;27(22):7991-8002 Wong RH, Chang I, Hudak CS, Hyun S, Kwan HY, Sul HS. A role of DNA-PK for the metabolic gene regulation in response to insulin. Cell. 2009 Mar 20;136(6):1056-72 Jung HS, Kim KS, Chung YJ, Chung HK, Min YK, Lee MS, Lee MK, Kim KW, Chung JH. USF inhibits cell proliferation through delay in G2/M phase in FRTL-5 cells. Endocr J. 2007 Apr;54(2):275-85 Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1) This article should be referenced as such: Verhoeven AJM. USF1 (upstream transcription factor 1). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1):73-76. 76