HGNC Approved Gene Symbol:USF1
Cytogenetic location:1q23.3 Genomic coordinates(GRCh38) :1:161,039,251-161,045,977 (from NCBI)
Upstream stimulatory factor (USF) is a ubiquitously expressed cellular transcription factor. Purified USF consists of 2 related polypeptides, USF1, of 43 kD, and USF2 (600390), of 44 kD. USF1 belongs to the MYC (190080) family of DNA-binding proteins (Gregor et al., 1990;Viollet et al., 1996).
Gregor et al. (1990) cloned USF1 by microsequence analysis of purified USF protein. USF1 contains a C-terminal DNA-binding domain that includes a helix-loop-helix motif and a leucine repeat.Gregor et al. (1990) also identified alternatively spliced USF1 variants.
Sirito et al. (1994) cloned mouse Usf1. Northern blot analysis detected Usf1 expression in all mouse tissues examined.
Gregor et al. (1990) found that USF1 interacted with its target DNA as a dimer. The leucine repeat of USF1 was required for efficient DNA binding and USF1 dimerization, but the isolated helix-loop-helix domain also bound DNA.
Sirito et al. (1994) found that mouse Usf1 and Usf2 had similar DNA binding properties.
Viollet et al. (1996) found that USF1/USF2a heterodimers represented more than 66% of the USF-binding activity in vivo, whereas USF1 and USF2a homodimers represented less that 10%. USF1/USF2b heterodimers accounted for almost 15% of the USF species in some cell lines. The preferential heterodimerization of USF subunits was reproduced ex vivo, but in vitro cotranslated subunits or recombinant USF proteins dimerized randomly. In transiently transfected HeLa or hepatoma cells, USF2a and USF1 homodimers transactivated a minimal promoter with similar efficiency, whereas USF2b was a poor transactivator of the minimal promoter. USF1, USF2a, and USF2b homodimers were equally efficient in transactivating the liver-specific pyruvate kinase gene (609712) promoter.
By transfection experiments,Roy et al. (1997) found that USF1 can act synergistically with GTF2I (601679) to activate transcription through both pyrimidine-rich initiator (Inr) elements and E-box elements of the adenovirus major late promoter. By mutation analysis, they determined that this synergistic action requires both the activation and dimerization domains of USF1. By in vitro cotranslation followed by coimmunoprecipitation studies, they confirmed direct protein interaction between GTF2I and USF1.
Iynedjian (1998) demonstrated that mammalian USF1 activated reporter gene expression from the E box within the promoter of the liver-specific glucokinase gene (GCK;138079). Expression of a truncated form of USF1 lacking the transcription activation domain and the basic region decreased reporter activity by a dominant-negative effect.
Hosts and pathogens evolve various responses for controlling infection and evading destruction, respectively. Using column chromatography,Zhong et al. (2001) identified a factor in Chlamydia trachomatis, the causative organism of trachoma and chronic urogenital infection, that degrades the transcription factors RFX5 (601863) and USF1. The degradation of these host factors correlates with the suppression of MHC class I and class II antigen expression in infected cells, thereby suppressing the host immune response.
Resting human lymphocytes do not have telomerase activity, but activation by a variety of stimuli induces TERT (187270) expression and telomerase activity.Yago et al. (2002) found that activated human T and B lymphocytes expressed USF1 and the full-length isoform of USF2, and that dimers of these proteins bound E boxes in the TERT promoter and activated TERT expression. In contrast, resting human T and B lymphocytes expressed both the N-terminally truncated isoform of USF2 and full-length USF2, and the truncated isoform had a dominant-negative effect on TERT expression induced by full-length USF2.
Shieh et al. (1993) assigned the USF1 gene to 1q22-q23 by study of mouse/human somatic cell hybrids and by in situ hybridization. With the isolation of the Usf1 cDNA in the mouse by RT-PCR,Henrion et al. (1995) could use isotopic in situ hybridization to map the gene to bands 1H and 11C-E in the mouse. Since chromosome 1 of the mouse is homologous to the region of human chromosome 1 where USF1 is located,Henrion et al. (1995) suggested that the sequence on chromosome 11 is a pseudogene or a related gene. In the mouse,Steingrimsson et al. (1995) mapped this and 4 other bHLH-ZIP transcription factors by interspecific backcross analysis. Usf1 had previously been mapped to mouse chromosome 1 by in situ hybridization, but its position on the meiotic linkage map had not been determined. Its location was consistent with the location of the human gene.
Pajukanta et al. (2004) showed that familial combined hyperlipidemia (FCHL1;602491) was linked and associated with the USF1 gene in 60 extended Finnish families, including 721 genotyped individuals (p = 0.00002), especially in males with high triglycerides (p = 0.0000009). They identified several SNPs in tight linkage disequilibrium and a common SNP haplotype defining the disease-associated USF1 allele. They also identified a new putative regulatory element in USF1 flanking the susceptibility haplotype.
Shoulders (2004) diagrammed a theoretical scenario whereby the use of a putative promoter in intron 7 of USF1 might lead to the generation of a mini-USF1 protein lacking the transactivation domain. Because mini-USF proteins in vitro behave as transdominant inhibitors (Lefrancois-Martinez et al., 1995;Viollet et al., 1996), whether the putative promoter identified byPajukanta et al. (2004) might operate in vivo to downregulate USF1 activity should be established.
USF1 is a transcription factor controlling expression of several genes involved in lipid and glucose homeostasis and colocalizes with FCHL and type 2 diabetes (see125853) on chromosome 1q22-q23.Putt et al. (2004) identified 3 common polymorphisms in USF1 and examined their association with fasting and postprandial lipids and with response to an oral glucose tolerance test (OGTT) in the European Atherosclerosis Research Study II offspring study. In haplotype analysis, 475C/1748T showed significantly higher and 475T/1748T showed lower peak glucose during the OGTT. There was significant case-control heterogeneity in the interaction of genotype with body mass index (BMI) and fasting low density lipoprotein (LDL) with 306A-G and 1748C-T, respectively. The interaction of BMI and 475C-T on fasting glucose levels achieved case-control heterogeneity of borderline significance. Furthermore, 475C-T showed interaction with polymorphisms in both hormone-sensitive lipase (HSL;151750) and APOC3 (107720) on area under the curve (AUC) triglycerides and plasma apoE levels, respectively.Putt et al. (2004) concluded that in these healthy young men, variation in USF1 was the influencing feature of both glucose and lipid homeostasis, showing case-control heterogeneity.
Coon et al. (2005) reported an association between the 2 USF1 SNPs identified byPajukanta et al. (2004) and FCHL, LDL cholesterol, and triglycerides in a large sample of 2,195 individuals from 87 Utah pedigrees. The pedigrees were ascertained for traits related to FCHL, including early death due to coronary heart disease, early strokes, or early-onset hypertension.
By analyzing the glucose responsiveness of Usf knockout mice,Vallet et al. (1998) determined that normal responsiveness required either Usf1/Usf2 heterodimers or Usf2 homodimers, even in mice with total Usf binding activity reduced by half. Usf1 homodimers gave rise to delayed glucose responsiveness.
Casado et al. (1999) stated that the E box within the FASN (600212) promoter is regulated by USF1, USF2, and SREBP1 (184756). They analyzed the glucose responsiveness of hepatic Fasn gene expression in Usf1 and Usf2 knockout mice and found that in both types of mutant mice, induction of the Fasn gene by refeeding a carbohydrate-rich diet was severely delayed. In contrast, expression of Srebp1 was almost normal, and insulin response was unchanged.Casado et al. (1999) concluded that the USF transactivators, and especially USF1/USF2 heterodimers, are essential to sustain the dietary induction of the FASN gene in liver.
Wu et al. (2010) reported that overexpression of human USF1 in both transgenic mice and mice with transient liver-specific overexpression influenced metabolic trait phenotypes, including obesity, total cholesterol level, LDL and VLDL cholesterol level, and glucose/insulin ratio. Additional analyses of trait and hepatic gene expression data from an F2 population derived from C57BL/6J and C3H/HeJ strains in which there is a naturally occurring variation in Usf1 expression supported a causal role for Usf1 for relevant metabolic traits. Gene network and pathway analyses of the liver gene expression signatures in the F2 population and the hepatic overexpression model suggested the involvement of Usf1 in immune responses and metabolism, including an Igfbp2 (146731)-centered module. In all 3 mouse model settings, notable sex specificity was observed, consistent with human studies showing differences in association with USF1 gene polymorphisms between sexes.
Pajukanta et al. (2004) identified 2 SNPs of the USF1 gene, usf1s1 (rs3737787) and usf1s2 (191523.0002), that were associated with familial combined hyperlipidemia mapping to a locus on 1q21-q23 (FCHL1;602491). The usf1s1 SNP is located in the 3-prime untranslated region (Naukkarinen et al., 2005). The common alleles (1-1) of the 2 SNPs define an at-risk haplotype. Allelic associations of the at-risk haplotype were found with triglycerides, apoB (107730), total cholesterol, and LDL peak particle size, supporting the concept that USF1 affects the complex lipid phenotype of FCHL and not only 1 lipid trait.
The usf1s2 SNP (rs2073658), which was associated with susceptibility to familial combined hyperlipidemia (FCHL1;602491) byPajukanta et al. (2004), is located in intron 7; see191523.0001.
Naukkarinen et al. (2005) identified a 20-bp DNA sequence in intron 7 of the USF1 gene, containingrs2073658, that bound nuclear proteins and likely represented a transcriptional regulatory element. This functional role was further supported by the differential expression of USF1-regulated genes in fat biopsy between individuals carrying different allelic variants of USF1. Apolipoprotein E (APOE;107741) was the most downregulated gene in the at-risk individuals, linking the potential risk alleles of USF1 with the impaired APOE-dependent catabolism of atherogenic lipoprotein particles.
Casado, M., Vallet, V. S., Kahn, A., Vaulont, S.Essential role in vivo of upstream stimulatory factors for a normal dietary response of the fatty acid synthase gene in the liver. J. Biol. Chem. 274: 2009-2013, 1999. [PubMed:9890958,related citations] [Full Text]
Coon, H., Xin, Y., Hopkins, P. N., Cawthon, R. M., Hasstedt, S. J., Hunt, S. C.Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides. Hum. Genet. 117: 444-451, 2005. [PubMed:15959806,related citations] [Full Text]
Gregor, P. D., Sawadogo, M., Roeder, R. G.The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer. Genes Dev. 4: 1730-1740, 1990. [PubMed:2249772,related citations] [Full Text]
Henrion, A. A., Martinez, A., Mattei, M.-G., Kahn, A., Raymondjean, M.Structure, sequence, and chromosomal location of the gene for USF2 transcription factors in mouse. Genomics 25: 36-43, 1995. [PubMed:7774954,related citations] [Full Text]
Iynedjian, P. B.Identification of upstream stimulatory factor as transcriptional activator of the liver promoter of the glucokinase gene. Biochem. J. 333: 705-712, 1998. [PubMed:9677331,related citations] [Full Text]
Lefrancois-Martinez, A.-M., Martinez, A., Antoine, B., Raymondjean, M., Kahn, A.Upstream stimulatory factor proteins are major components of the glucose response complex of the L-type pyruvate kinase gene promoter. J. Biol. Chem. 270: 2640-2643, 1995. [PubMed:7852331,related citations] [Full Text]
Naukkarinen, J., Gentile, M., Soro-Paavonen, A., Saarela, J., Koistinen, H. A., Pajukanta, P., Taskinen, M.-R., Peltonen, L.USF1 and dyslipidemias: converging evidence for a functional intronic variant. Hum. Molec. Genet. 14: 2595-2605, 2005. [PubMed:16076849,related citations] [Full Text]
Pajukanta, P., Lilja, H. E., Sinsheimer, J. S., Cantor, R. M., Lusis, A. J., Gentile, M., Duan, X. J., Soro-Paavonen, A., Naukkarinen, J., Saarela, J., Laakso, M., Ehnholm, C., Taskinen, M.-R., Peltonen, L.Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nature Genet. 36: 371-376, 2004. [PubMed:14991056,related citations] [Full Text]
Putt, W., Palmen, J., Nicaud, V., Tregouet, D.-A., Tahri-Daizadeh, N., Flavell, D. M., Humphries, S. E., Talmud, P. J.Variation in USF1 shows haplotype effects, gene:gene and gene:environment associations with glucose and lipid parameters in the European Atherosclerosis Research Study II. Hum. Molec. Genet. 13: 1587-1597, 2004. [PubMed:15175273,related citations] [Full Text]
Roy, A. L., Du, H., Gregor, P. D., Novina, C. D., Martinez, E., Roeder, R. G.Cloning of an Inr- and E-box binding protein, TFII-I, that interacts physically and functionally with USF1. EMBO J. 16: 7091-7104, 1997. [PubMed:9384587,related citations] [Full Text]
Shieh, B.-H., Sparkes, R. S., Gaynor, R. B., Lusis, A. J.Localization of the gene-encoding upstream stimulatory factor (USF) to human chromosome 1q22-q23. Genomics 16: 266-268, 1993. [PubMed:8486371,related citations] [Full Text]
Shoulders, C. C.USF1 on trial. Nature Genet. 36: 322-323, 2004. [PubMed:15054483,related citations] [Full Text]
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. 22: 427-433, 1994. [PubMed:8127680,related citations] [Full Text]
Steingrimsson, E., Sawadogo, M., Gilbert, D. J., Zervos, A. S., Brent, R., Blanar, M. A., Fisher, D. E., Copeland, N. G., Jenkins, N. A.Murine chromosomal location of five bHLH-Zip transcription factor genes. Genomics 28: 179-183, 1995. [PubMed:8530024,related citations] [Full Text]
Vallet, V. S., Casado, M., Henrion, A. A., 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. 273: 20175-20179, 1998. [PubMed:9685363,related citations] [Full Text]
Viollet, B., Lefrancois-Martinez, A.-M., Henrion, A., Kahn, A., Raymondjean, M., Martinez, A.Immunochemical characterization and transacting properties of upstream stimulatory factor isoforms. J. Biol. Chem. 271: 1405-1415, 1996. [PubMed:8576131,related citations] [Full Text]
Wu, S., Mar-Heyming, R., Dugum, E. Z., Kolaitis, N. A., Qi, H., Pajukanta, P., Castellani, L. W., Lusis, A. J., Drake, T. A.Upstream transcription factor 1 influences plasma lipid and metabolic traits in mice. Hum. Molec. Genet. 19: 597-608, 2010. [PubMed:19995791,images,related citations] [Full Text]
Yago, M., Ohki, R., Hatakeyama, S., Fujita, T., Ishikawa, F.Variant forms of upstream stimulatory factors (USFs) control the promoter activity of hTERT, the human gene encoding the catalytic subunit of telomerase. FEBS Lett. 520: 40-46, 2002. [PubMed:12044867,related citations] [Full Text]
Zhong, G., Fan, P., Ji, H., Dong, F., Huang, Y.Identification of a chlamydial protease-like activity factor responsible for the degradation of host transcription factors. J. Exp. Med. 193: 935-942, 2001. [PubMed:11304554,images,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: USF1
Cytogenetic location: 1q23.3 Genomic coordinates(GRCh38) : 1:161,039,251-161,045,977(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | {Hyperlipidemia, familial combined, susceptibility to} | 602491 | 3 |
Upstream stimulatory factor (USF) is a ubiquitously expressed cellular transcription factor. Purified USF consists of 2 related polypeptides, USF1, of 43 kD, and USF2 (600390), of 44 kD. USF1 belongs to the MYC (190080) family of DNA-binding proteins (Gregor et al., 1990; Viollet et al., 1996).
Gregor et al. (1990) cloned USF1 by microsequence analysis of purified USF protein. USF1 contains a C-terminal DNA-binding domain that includes a helix-loop-helix motif and a leucine repeat. Gregor et al. (1990) also identified alternatively spliced USF1 variants.
Sirito et al. (1994) cloned mouse Usf1. Northern blot analysis detected Usf1 expression in all mouse tissues examined.
Gregor et al. (1990) found that USF1 interacted with its target DNA as a dimer. The leucine repeat of USF1 was required for efficient DNA binding and USF1 dimerization, but the isolated helix-loop-helix domain also bound DNA.
Sirito et al. (1994) found that mouse Usf1 and Usf2 had similar DNA binding properties.
Viollet et al. (1996) found that USF1/USF2a heterodimers represented more than 66% of the USF-binding activity in vivo, whereas USF1 and USF2a homodimers represented less that 10%. USF1/USF2b heterodimers accounted for almost 15% of the USF species in some cell lines. The preferential heterodimerization of USF subunits was reproduced ex vivo, but in vitro cotranslated subunits or recombinant USF proteins dimerized randomly. In transiently transfected HeLa or hepatoma cells, USF2a and USF1 homodimers transactivated a minimal promoter with similar efficiency, whereas USF2b was a poor transactivator of the minimal promoter. USF1, USF2a, and USF2b homodimers were equally efficient in transactivating the liver-specific pyruvate kinase gene (609712) promoter.
By transfection experiments, Roy et al. (1997) found that USF1 can act synergistically with GTF2I (601679) to activate transcription through both pyrimidine-rich initiator (Inr) elements and E-box elements of the adenovirus major late promoter. By mutation analysis, they determined that this synergistic action requires both the activation and dimerization domains of USF1. By in vitro cotranslation followed by coimmunoprecipitation studies, they confirmed direct protein interaction between GTF2I and USF1.
Iynedjian (1998) demonstrated that mammalian USF1 activated reporter gene expression from the E box within the promoter of the liver-specific glucokinase gene (GCK; 138079). Expression of a truncated form of USF1 lacking the transcription activation domain and the basic region decreased reporter activity by a dominant-negative effect.
Hosts and pathogens evolve various responses for controlling infection and evading destruction, respectively. Using column chromatography, Zhong et al. (2001) identified a factor in Chlamydia trachomatis, the causative organism of trachoma and chronic urogenital infection, that degrades the transcription factors RFX5 (601863) and USF1. The degradation of these host factors correlates with the suppression of MHC class I and class II antigen expression in infected cells, thereby suppressing the host immune response.
Resting human lymphocytes do not have telomerase activity, but activation by a variety of stimuli induces TERT (187270) expression and telomerase activity. Yago et al. (2002) found that activated human T and B lymphocytes expressed USF1 and the full-length isoform of USF2, and that dimers of these proteins bound E boxes in the TERT promoter and activated TERT expression. In contrast, resting human T and B lymphocytes expressed both the N-terminally truncated isoform of USF2 and full-length USF2, and the truncated isoform had a dominant-negative effect on TERT expression induced by full-length USF2.
Shieh et al. (1993) assigned the USF1 gene to 1q22-q23 by study of mouse/human somatic cell hybrids and by in situ hybridization. With the isolation of the Usf1 cDNA in the mouse by RT-PCR, Henrion et al. (1995) could use isotopic in situ hybridization to map the gene to bands 1H and 11C-E in the mouse. Since chromosome 1 of the mouse is homologous to the region of human chromosome 1 where USF1 is located, Henrion et al. (1995) suggested that the sequence on chromosome 11 is a pseudogene or a related gene. In the mouse, Steingrimsson et al. (1995) mapped this and 4 other bHLH-ZIP transcription factors by interspecific backcross analysis. Usf1 had previously been mapped to mouse chromosome 1 by in situ hybridization, but its position on the meiotic linkage map had not been determined. Its location was consistent with the location of the human gene.
Pajukanta et al. (2004) showed that familial combined hyperlipidemia (FCHL1; 602491) was linked and associated with the USF1 gene in 60 extended Finnish families, including 721 genotyped individuals (p = 0.00002), especially in males with high triglycerides (p = 0.0000009). They identified several SNPs in tight linkage disequilibrium and a common SNP haplotype defining the disease-associated USF1 allele. They also identified a new putative regulatory element in USF1 flanking the susceptibility haplotype.
Shoulders (2004) diagrammed a theoretical scenario whereby the use of a putative promoter in intron 7 of USF1 might lead to the generation of a mini-USF1 protein lacking the transactivation domain. Because mini-USF proteins in vitro behave as transdominant inhibitors (Lefrancois-Martinez et al., 1995; Viollet et al., 1996), whether the putative promoter identified by Pajukanta et al. (2004) might operate in vivo to downregulate USF1 activity should be established.
USF1 is a transcription factor controlling expression of several genes involved in lipid and glucose homeostasis and colocalizes with FCHL and type 2 diabetes (see 125853) on chromosome 1q22-q23. Putt et al. (2004) identified 3 common polymorphisms in USF1 and examined their association with fasting and postprandial lipids and with response to an oral glucose tolerance test (OGTT) in the European Atherosclerosis Research Study II offspring study. In haplotype analysis, 475C/1748T showed significantly higher and 475T/1748T showed lower peak glucose during the OGTT. There was significant case-control heterogeneity in the interaction of genotype with body mass index (BMI) and fasting low density lipoprotein (LDL) with 306A-G and 1748C-T, respectively. The interaction of BMI and 475C-T on fasting glucose levels achieved case-control heterogeneity of borderline significance. Furthermore, 475C-T showed interaction with polymorphisms in both hormone-sensitive lipase (HSL; 151750) and APOC3 (107720) on area under the curve (AUC) triglycerides and plasma apoE levels, respectively. Putt et al. (2004) concluded that in these healthy young men, variation in USF1 was the influencing feature of both glucose and lipid homeostasis, showing case-control heterogeneity.
Coon et al. (2005) reported an association between the 2 USF1 SNPs identified by Pajukanta et al. (2004) and FCHL, LDL cholesterol, and triglycerides in a large sample of 2,195 individuals from 87 Utah pedigrees. The pedigrees were ascertained for traits related to FCHL, including early death due to coronary heart disease, early strokes, or early-onset hypertension.
By analyzing the glucose responsiveness of Usf knockout mice, Vallet et al. (1998) determined that normal responsiveness required either Usf1/Usf2 heterodimers or Usf2 homodimers, even in mice with total Usf binding activity reduced by half. Usf1 homodimers gave rise to delayed glucose responsiveness.
Casado et al. (1999) stated that the E box within the FASN (600212) promoter is regulated by USF1, USF2, and SREBP1 (184756). They analyzed the glucose responsiveness of hepatic Fasn gene expression in Usf1 and Usf2 knockout mice and found that in both types of mutant mice, induction of the Fasn gene by refeeding a carbohydrate-rich diet was severely delayed. In contrast, expression of Srebp1 was almost normal, and insulin response was unchanged. Casado et al. (1999) concluded that the USF transactivators, and especially USF1/USF2 heterodimers, are essential to sustain the dietary induction of the FASN gene in liver.
Wu et al. (2010) reported that overexpression of human USF1 in both transgenic mice and mice with transient liver-specific overexpression influenced metabolic trait phenotypes, including obesity, total cholesterol level, LDL and VLDL cholesterol level, and glucose/insulin ratio. Additional analyses of trait and hepatic gene expression data from an F2 population derived from C57BL/6J and C3H/HeJ strains in which there is a naturally occurring variation in Usf1 expression supported a causal role for Usf1 for relevant metabolic traits. Gene network and pathway analyses of the liver gene expression signatures in the F2 population and the hepatic overexpression model suggested the involvement of Usf1 in immune responses and metabolism, including an Igfbp2 (146731)-centered module. In all 3 mouse model settings, notable sex specificity was observed, consistent with human studies showing differences in association with USF1 gene polymorphisms between sexes.
Pajukanta et al. (2004) identified 2 SNPs of the USF1 gene, usf1s1 (rs3737787) and usf1s2 (191523.0002), that were associated with familial combined hyperlipidemia mapping to a locus on 1q21-q23 (FCHL1; 602491). The usf1s1 SNP is located in the 3-prime untranslated region (Naukkarinen et al., 2005). The common alleles (1-1) of the 2 SNPs define an at-risk haplotype. Allelic associations of the at-risk haplotype were found with triglycerides, apoB (107730), total cholesterol, and LDL peak particle size, supporting the concept that USF1 affects the complex lipid phenotype of FCHL and not only 1 lipid trait.
The usf1s2 SNP (rs2073658), which was associated with susceptibility to familial combined hyperlipidemia (FCHL1; 602491) by Pajukanta et al. (2004), is located in intron 7; see 191523.0001.
Naukkarinen et al. (2005) identified a 20-bp DNA sequence in intron 7 of the USF1 gene, containing rs2073658, that bound nuclear proteins and likely represented a transcriptional regulatory element. This functional role was further supported by the differential expression of USF1-regulated genes in fat biopsy between individuals carrying different allelic variants of USF1. Apolipoprotein E (APOE; 107741) was the most downregulated gene in the at-risk individuals, linking the potential risk alleles of USF1 with the impaired APOE-dependent catabolism of atherogenic lipoprotein particles.
Casado, M., Vallet, V. S., Kahn, A., Vaulont, S.Essential role in vivo of upstream stimulatory factors for a normal dietary response of the fatty acid synthase gene in the liver. J. Biol. Chem. 274: 2009-2013, 1999. [PubMed: 9890958] [Full Text: https://doi.org/10.1074/jbc.274.4.2009]
Coon, H., Xin, Y., Hopkins, P. N., Cawthon, R. M., Hasstedt, S. J., Hunt, S. C.Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides. Hum. Genet. 117: 444-451, 2005. [PubMed: 15959806] [Full Text: https://doi.org/10.1007/s00439-005-1340-x]
Gregor, P. D., Sawadogo, M., Roeder, R. G.The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer. Genes Dev. 4: 1730-1740, 1990. [PubMed: 2249772] [Full Text: https://doi.org/10.1101/gad.4.10.1730]
Henrion, A. A., Martinez, A., Mattei, M.-G., Kahn, A., Raymondjean, M.Structure, sequence, and chromosomal location of the gene for USF2 transcription factors in mouse. Genomics 25: 36-43, 1995. [PubMed: 7774954] [Full Text: https://doi.org/10.1016/0888-7543(95)80107-w]
Iynedjian, P. B.Identification of upstream stimulatory factor as transcriptional activator of the liver promoter of the glucokinase gene. Biochem. J. 333: 705-712, 1998. [PubMed: 9677331] [Full Text: https://doi.org/10.1042/bj3330705]
Lefrancois-Martinez, A.-M., Martinez, A., Antoine, B., Raymondjean, M., Kahn, A.Upstream stimulatory factor proteins are major components of the glucose response complex of the L-type pyruvate kinase gene promoter. J. Biol. Chem. 270: 2640-2643, 1995. [PubMed: 7852331] [Full Text: https://doi.org/10.1074/jbc.270.6.2640]
Naukkarinen, J., Gentile, M., Soro-Paavonen, A., Saarela, J., Koistinen, H. A., Pajukanta, P., Taskinen, M.-R., Peltonen, L.USF1 and dyslipidemias: converging evidence for a functional intronic variant. Hum. Molec. Genet. 14: 2595-2605, 2005. [PubMed: 16076849] [Full Text: https://doi.org/10.1093/hmg/ddi294]
Pajukanta, P., Lilja, H. E., Sinsheimer, J. S., Cantor, R. M., Lusis, A. J., Gentile, M., Duan, X. J., Soro-Paavonen, A., Naukkarinen, J., Saarela, J., Laakso, M., Ehnholm, C., Taskinen, M.-R., Peltonen, L.Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nature Genet. 36: 371-376, 2004. [PubMed: 14991056] [Full Text: https://doi.org/10.1038/ng1320]
Putt, W., Palmen, J., Nicaud, V., Tregouet, D.-A., Tahri-Daizadeh, N., Flavell, D. M., Humphries, S. E., Talmud, P. J.Variation in USF1 shows haplotype effects, gene:gene and gene:environment associations with glucose and lipid parameters in the European Atherosclerosis Research Study II. Hum. Molec. Genet. 13: 1587-1597, 2004. [PubMed: 15175273] [Full Text: https://doi.org/10.1093/hmg/ddh168]
Roy, A. L., Du, H., Gregor, P. D., Novina, C. D., Martinez, E., Roeder, R. G.Cloning of an Inr- and E-box binding protein, TFII-I, that interacts physically and functionally with USF1. EMBO J. 16: 7091-7104, 1997. [PubMed: 9384587] [Full Text: https://doi.org/10.1093/emboj/16.23.7091]
Shieh, B.-H., Sparkes, R. S., Gaynor, R. B., Lusis, A. J.Localization of the gene-encoding upstream stimulatory factor (USF) to human chromosome 1q22-q23. Genomics 16: 266-268, 1993. [PubMed: 8486371] [Full Text: https://doi.org/10.1006/geno.1993.1174]
Shoulders, C. C.USF1 on trial. Nature Genet. 36: 322-323, 2004. [PubMed: 15054483] [Full Text: https://doi.org/10.1038/ng0404-322]
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. 22: 427-433, 1994. [PubMed: 8127680] [Full Text: https://doi.org/10.1093/nar/22.3.427]
Steingrimsson, E., Sawadogo, M., Gilbert, D. J., Zervos, A. S., Brent, R., Blanar, M. A., Fisher, D. E., Copeland, N. G., Jenkins, N. A.Murine chromosomal location of five bHLH-Zip transcription factor genes. Genomics 28: 179-183, 1995. [PubMed: 8530024] [Full Text: https://doi.org/10.1006/geno.1995.1129]
Vallet, V. S., Casado, M., Henrion, A. A., 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. 273: 20175-20179, 1998. [PubMed: 9685363] [Full Text: https://doi.org/10.1074/jbc.273.32.20175]
Viollet, B., Lefrancois-Martinez, A.-M., Henrion, A., Kahn, A., Raymondjean, M., Martinez, A.Immunochemical characterization and transacting properties of upstream stimulatory factor isoforms. J. Biol. Chem. 271: 1405-1415, 1996. [PubMed: 8576131] [Full Text: https://doi.org/10.1074/jbc.271.3.1405]
Wu, S., Mar-Heyming, R., Dugum, E. Z., Kolaitis, N. A., Qi, H., Pajukanta, P., Castellani, L. W., Lusis, A. J., Drake, T. A.Upstream transcription factor 1 influences plasma lipid and metabolic traits in mice. Hum. Molec. Genet. 19: 597-608, 2010. [PubMed: 19995791] [Full Text: https://doi.org/10.1093/hmg/ddp526]
Yago, M., Ohki, R., Hatakeyama, S., Fujita, T., Ishikawa, F.Variant forms of upstream stimulatory factors (USFs) control the promoter activity of hTERT, the human gene encoding the catalytic subunit of telomerase. FEBS Lett. 520: 40-46, 2002. [PubMed: 12044867] [Full Text: https://doi.org/10.1016/s0014-5793(02)02757-6]
Zhong, G., Fan, P., Ji, H., Dong, F., Huang, Y.Identification of a chlamydial protease-like activity factor responsible for the degradation of host transcription factors. J. Exp. Med. 193: 935-942, 2001. [PubMed: 11304554] [Full Text: https://doi.org/10.1084/jem.193.8.935]
Dear OMIM User,
To ensure long-term funding for the OMIM project, we have diversified our revenue stream. We are determined to keep this website freely accessible. Unfortunately, it is not free to produce. Expert curators review the literature and organize it to facilitate your work. Over 90% of the OMIM's operating expenses go to salary support for MD and PhD science writers and biocurators. Please join your colleagues by making a donation now and again in the future. Donations are an important component of our efforts to ensure long-term funding to provide you the information that you need at your fingertips.
Thank you in advance for your generous support,
Ada Hamosh, MD, MPH
Scientific Director, OMIM