Regulation of fibrinogen production by microRNAs

Fort, Alexandre; Borel, Christelle; Migliavacca, Eugenia; Antonarakis, Stylianos; Fish, Richard; Neerman Arbez, Marguerite

doi:10.1182/blood-2010-02-268011

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Title		Regulation of fibrinogen production by microRNAs
Authors		Fort, Alexandre Borel, Christelle Migliavacca, Eugenia Antonarakis, Stylianos Fish, Richard Neerman Arbez, Marguerite
Published in		Blood. 2010, vol. 116, no. 14, p. 2608-2615
Abstract		Elevated levels of fibrinogen are associated with increased risk of cardiovascular disease, whereas low fibrinogen can lead to a bleeding disorder. We investigated whether microRNAs (miRNAs), known to act as post-transcriptional regulators of gene expression, regulate fibrinogen production. Using transfection of a library of 470 annotated human miRNA precursor molecules in HuH7 hepatoma cells and quantitative measurements of fibrinogen production, we identified 23 miRNAs with down-regulating (up to 64% decrease) and 4 with up-regulating effects (up to 129% increase) on fibrinogen production. Among the down-regulating miRNAs, we investigated the mechanism of action of 3 hsa-miR-29 family members and hsa-miR-409-3p. Overexpression of hsa-miR-29 members led to decreased steady-state levels of all fibrinogen gene (FGA, FGB, and FGG) transcripts in HuH7 cells. Luciferase reporter gene assays demonstrated that this was independent of miRNA-fibrinogen 3'-untranslated region interactions. In contrast, overexpression of hsa-miR-409-3p specifically lowered fibrinogen Bbeta mRNA levels, and this effect was dependent on a target site in the fibrinogen Bbeta mRNA 3'-untranslated region. This study adds to the known mechanisms that control fibrinogen production, points toward a potential cause of variable circulating fibrinogen levels, and demonstrates that a screening approach can identify miRNAs that regulate clinically important proteins.
Keywords		3' Untranslated Regions — Cell Line — Cell Line, Tumor — Fibrinogen/genetics/metabolism — Gene Expression Regulation — Genes, Reporter — Humans — MicroRNAs/*genetics
Identifiers		DOI: 10.1182/blood-2010-02-268011 PMID: 20570858
Full text		Article - Limited access to UNIGE Other version: http://bloodjournal.hematologylibrary.org/content/116/14/2608.full.pdf
Structures		Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement
Research groups		Endothélium vasculaire (11) Pathologie Moléculaire de la Trisomie 21 et le Génome Humain (248) Recherche translationnelle : anomalies de l'hémostase et thromboses (504)
Citation (ISO format)		FORT, Alexandre et al. Regulation of fibrinogen production by microRNAs. In: Blood, 2010, vol. 116, n° 14, p. 2608-2615. doi: 10.1182/blood-2010-02-268011 https://archive-ouverte.unige.ch/unige:20943