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A novel regulatory element between the human FGA and FGG genes.
Journal article

A novel regulatory element between the human FGA and FGG genes.

  • Fish RJ Department of Genetic Medicine and Development, University of Geneva Medical Centre, Geneva, Switzerland. Richard.Fish@unige.ch
  • Neerman-Arbez M
  • 2012-07-28
Published in:
  • Thrombosis and haemostasis. - 2012
Animals
Animals, Genetically Modified
Carcinoma, Hepatocellular
Cell Line, Tumor
Chromatin Immunoprecipitation
Chromosome Mapping
Conserved Sequence
Enhancer Elements, Genetic
Fibrinogen
Gene Expression Regulation
Genes, Reporter
Genes, Synthetic
Green Fluorescent Proteins
HEK293 Cells
Hep G2 Cells
Hepatocytes
Humans
Larva
Liver Neoplasms
Luciferases
Mice
Recombinant Fusion Proteins
Transgenes
Zebrafish
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/62219
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