Scientific article

A novel regulatory element between the human FGA and FGG genes

Published inThrombosis and haemostasis, vol. 108, no. 3, p. 427-434
Publication date2012

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.

  • 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
Notespecial issue
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. 427–434. doi: 10.1160/TH12-04-0274
Main files (1)
Article (Accepted version)
ISSN of the journal0340-6245

Technical informations

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