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unige:31577 
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A novel regulatory element between the human FGA and FGG genes |
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| Authors | ||
| Published in | Thrombosis and Haemostasis. 2012, vol. 108, no. 3, p. 427-34 | |
| Abstract | High circulating fibrinogen levels correlate with cardiovascular disease (CVD) risk. Fibrinogen levels vary between people and also change in response to physiological and environmental stimuli. A modest proportion of the variation in fibrinogen levels can be explained by genotype, inferring that variation in genomic sequences that regulate the fibrinogen genes ( FGA , FGB and FGG ) may affect hepatic fibrinogen production and perhaps CVD risk. We previously identified a conserved liver enhancer in the fibrinogen gene cluster (CNC12), between FGB and FGA . Genome-wide Chromatin immunoprecipitation-sequencing (ChIP-seq) demonstrated that transcription factors which bind fibrinogen gene promoters also interact with CNC12, as well as two potential fibrinogen enhancers (PFE), between FGA and FGG . Here we show that one of the PFE sequences has potent hepatocyte enhancer activity. Using a luciferase reporter gene system, we found that PFE2 enhances minimal promoter- and FGA promoter-driven gene expression in hepatoma cells, regardless of its orientation with respect to the promoters. A region within PFE2 bears a short series of conserved nucleotides which maintain enhancer activity without flanking sequence. We also demonstrate that PFE2 is a liver enhancer in vivo, driving enhanced green fluorescent protein expression in transgenic zebrafish larval livers. Our study shows that combining public domain ChIP-seq data with in vitro and in vivo functional tests can identify novel fibrinogen gene cluster regulatory sequences. Variation in such elements could affect fibrinogen production and influence CVD risk. | |
| Keywords | Animals — Animals, Genetically Modified — Carcinoma, Hepatocellular/pathology — Cell Line, Tumor/metabolism — Chromatin Immunoprecipitation — Chromosome Mapping — Conserved Sequence — Enhancer Elements, Genetic/genetics — Fibrinogen/genetics — Gene Expression Regulation — Genes, Reporter — Genes, Synthetic — Green Fluorescent Proteins/biosynthesis/genetics — HEK293 Cells/metabolism — Hep G2 Cells/metabolism — Hepatocytes/metabolism — Humans — Larva — Liver Neoplasms/pathology — Luciferases/biosynthesis/genetics — Mice — Recombinant Fusion Proteins/biosynthesis/genetics — Transgenes — Zebrafish/growth & development | |
| Identifiers | DOI: 10.1160/TH12-04-0274 PMID: 22836734 | |
| Note | special issue | |
| Full text | ||
| Structures | ||
| Project | FNS: 31003A-134967 | |
| Citation (ISO format) | FISH, Richard, NEERMAN ARBEZ, Marguerite. A novel regulatory element between the human FGA and FGG genes. In: Thrombosis and Haemostasis, 2012, vol. 108, n° 3, p. 427-34. https://archive-ouverte.unige.ch/unige:31577 |
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