PUBLICATION
A liver enhancer in the fibrinogen gene cluster
- Authors
- Fort, A., Fish, R.J., Attanasio, C., Dosch, R., Visel, A., and Neerman-Arbez, M.
- ID
- ZDB-PUB-101011-47
- Date
- 2011
- Source
- Blood 117(1): 276-282 (Journal)
- Registered Authors
- Dosch, Roland
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Carcinoma, Hepatocellular/genetics*
- Carcinoma, Hepatocellular/metabolism
- Cells, Cultured
- Conserved Sequence
- Embryo, Mammalian/cytology
- Embryo, Mammalian/metabolism
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/metabolism
- Enhancer Elements, Genetic/genetics*
- Fibrinogen/genetics*
- Green Fluorescent Proteins/metabolism
- Humans
- In Situ Hybridization
- Kidney/cytology
- Kidney/metabolism
- Liver Neoplasms/genetics*
- Liver Neoplasms/metabolism
- Mice
- Multigene Family*
- Regulatory Sequences, Nucleic Acid*
- Zebrafish/embryology
- Zebrafish/metabolism
- PubMed
- 20921339 Full text @ Blood
Citation
Fort, A., Fish, R.J., Attanasio, C., Dosch, R., Visel, A., and Neerman-Arbez, M. (2011) A liver enhancer in the fibrinogen gene cluster. Blood. 117(1):276-282.
Abstract
The plasma concentration of fibrinogen varies in the healthy human population between 1.5-3.5 g/L. Understanding the basis of this variability has clinical importance because elevated fibrinogen levels are associated with increased cardiovascular disease risk. To identify novel regulatory elements involved in the control of fibrinogen expression, we used sequence conservation and in silico-predicted regulatory potential to select 14 conserved non-coding sequences (CNCs) within the conserved block of synteny containing the fibrinogen locus. The regulatory potential of each CNC was tested in vitro using a luciferase reporter gene assay in fibrinogen-expressing hepatoma cell lines (HuH7 and HepG2). Four potential enhancers were tested for their ability to direct enhanced green fluorescent protein (EGFP) expression in zebrafish embryos. CNC12, a sequence equidistant from the human fibrinogen alpha and beta chain genes, activates strong liver EGFP expression in injected embryos and their transgenic progeny. A transgenic assay in E14.5 mouse embryos confirmed the ability of CNC12 to activate transcription in the liver. While additional experiments are necessary to prove the role of CNC12 in the regulation of fibrinogen, our study reveals a novel regulatory element in the fibrinogen locus which is active in the liver and may contribute to variable fibrinogen expression in humans.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping