USF1

The upstream stimulatory factor (USF) gene encodes a transcription factor USF that belongs to the proto-oncogene MYC family and features a basic helix-loop-helix leucine zipper (bHLH-LZ) motif in the protein structure. USF was originally identified as regulating the major late promoters of adenovirus, and recent research has further revealed its role in tissue protection. In the context of insulin and glucose-induced USF activities, those E-box motifs can act as a glucose-responsive element (GRE) and a part of the carbohydrate response element (ChoRE) to interact with transcription factors. Both USF1 and USF2 transcripts comprise 10 exons and can undergo exon 4-excision during alternative splicing. From an auto-regulation perspective, these exon 4-excision products act as dominant negative regulators and are found to suppress USF-dependent gene expression. == Protein ==

Although USF1 and USF2 share 70% of the amino acid sequence in their bHLH-LZ region, only 40% similarity is found in their full-length proteins. In addition, USF1 and USF2 exhibit different protein abundances in a cell type-specific manner. Despite the ubiquitous expression of both isoforms, USF1 and USF2 mediate different biological processes and functions in cells. While USF1 modulates metabolism, immune response, and tissue protection, USF2 primarily controls embryonic development, brain function, iron metabolism, and fertility. Structurally, the highly conserved bHLH-LZ structure on the C-terminus of USF yields high binding specificity and promotes the formation of USF1 homodimers or USF1-USF2 heterodimers for DNA binding. The USF-specific region (USR) on the N-terminal region, on the other hand, facilitates the nuclear translocation and activation of USF1. == Function ==

The USF1 gene encodes a member of the basic helix-loop-helix leucine zipper family and can function as a cellular transcription factor. The encoded protein can activate transcription through pyrimidine-rich initiator (Inr) elements and E-box motifs. This gene has been linked to familial combined hyperlipidemia (FCHL). Two transcript variants encoding distinct isoforms have been identified for this gene. == Regulation ==

Modulation of DNA binding affinity The symmetrical E-box motif is the main target of bHLH-LZ transcription factors, and USF1 has a high binding affinity for the core sequence CACGTG in the motif. • ERK1 (also known as MAPK3) and ERK2 (also known as MAPK1) phosphorylate USF1 in response to TFG-β signaling in vascular smooth muscle cells. Gene transcription • Transforming growth factor β 1 (TGF beta 1) is encoded by the TFGB1 gene, which contains an E-box within the promoter region and has been implicated in excessive extracellular matrix accumulation under a high-glucose condition. cJun-cJun / cJun-cFos dimers preferentially bind to the phorbol 12-O-Tetradecanoylphorbol-13-acetate (TPA)-responsive element (TRE region, TGACTCA), whereas cJun-ATF dimers and ATF homodimers preferentially bind to the cAMP-responsive element (CRE, TGACGTCA). Heterochromatin is required for genome stability and gene expression regulation. However, it can spread into neighboring DNA regions and inactivate gene expression. Chromosome boundary elements are thus necessary to block such stochastic spreads of heterochromatin and maintain stable gene expression. USF1 and USF2 have been found to recruit various histone-modifying complexes, including the histone H3 methyltransferase Set1 complex and the H4 arginine 3 methyltransferase PRMT1, with the latter known to establish active chromatin domains. Lipogenic pathways • In response to insulin elevation, DNA-protein kinase (DNA-PK) involved in DNA damage repair becomes dephosphorylated and activated. USF1 siRNA knockout has been shown to compromise the blastocyst rate and deregulate the transcripts of twist-related protein 2 (increased) and growth differentiation factor-9 and follistatin (decreased) by affecting their promoter-binding element E-box region during oocyte maturation. == Clinical significance ==

Diabetic kidney disease Diabetic kidney disease (DKD) (or diabetic nephropathy) is a progressive microalbuminuria disease with a slight loss of albumin in the urine (30–300 mg per day); DKD has been viewed as a diabetic complication-related microvascular disorder in a renal manifestation. In kidney biopsy, DKD is characterized by glomerular and tubular basement thickening, mesangial expansion, glomerulosclerosis, podocyte effacement and nephron loss. DKD occurs in 30%-50% of the diabetic patient population and leads to kidney failures in up to 20% of the type 1 diabetic patients. Especially, APOL1 is known to complex with APOA-I and HDL to facilitate cell autophagy in response to injuries and to prevent glomerular diseases; however, an APOL1 risk variant specific to podocyte inhibits cell autophagy and can trigger kidney disease. FASN-mediated de novo lipid synthesis accounts for more than 93% of triglycerides in tumor cells. In prostate cancer cells and promyelocytic leukemia cells, USF1 activation also attains a high-level of PAI-1 expression and inhibits spontaneous or camptothecin-induced apoptosis. Among gastric cancer patients, 88% of the patients are diagnosed with H. pylori infection, and half of the patients show lower USF1 expression in tumor tissues. Mechanistically, H. pylori induces DNA hypermethylation in the promoter regions of USF1 and USF2 and inhibits expression. Decreased expression reduces the interaction between USF1 and p53 when DNA damage occurs, rendering p53 to associate more frequently with the E3-ubiquitin ligase HDM2 (also known as MDM2) and increasing p53 instability in cancer cells. The core FCHL lipid profiles feature high serum cholesterol/triglyceride, apolipoprotein B (APOB), and LDL levels. Genetic evidence has suggested a FCHL-related locus on the human chromosome 1q21-q23, which is linked to metabolic syndromes. Fine-mapping of those linked regions identifies USF1 as the first positionally cloned gene for FCHL and a target for FCHL treatment. In addition, hepatocyte nuclear factor 4 alpha (HNF4A) is also implicated in high lipid levels and metabolic syndromes. Cooperative effects of USF1 and HNF4A have been shown to regulate the expression of apolipoprotein A-II (APOA2) and apolipoprotein C-III (APOC3). Mutations in USF1, HNF4A, and apolipoproteins also increase patients' susceptibility to FCHL. Additional genes subjected to USF1 regulation and involved in glucose/lipid metabolism include apolipoprotein A5 (APOA5), apolipoprotein E (APOE), hormone-sensitive lipase (LIPE), hepatic lipase (LIPC), glucokinase (GCK), islet-specific glucose-6-phosphatase catalytic-subunit-related protein (IGRP), insulin, glucagon receptor (GCGR) and ATP-binding cassette transporter A1 (ABCA1). == Interactions ==

USF1 (human gene) has been shown to interact with USF2, FOSL1, and GTF2I. == References ==