MicroRNA-194 is a target of transcription factor 1 (Tcf1, HNF1α) in adult liver and controls expression of frizzled-6

Authors

  • Jan Krützfeldt,

    1. Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
    2. Competence Center for Systems Biology and Metabolic Diseases, ETH Zurich, Zurich, Switzerland
    3. Division of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital of Berne Inselspital, Berne, Switzerland
    Current affiliation:
    1. University Hospital Zurich, Division of Endocrinology, Diabetes and Clinical Nutrition, Rämistrasse 100, CH 8091 Zurich, Switzerland
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  • Nora Rösch,

    1. Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
    2. Competence Center for Systems Biology and Metabolic Diseases, ETH Zurich, Zurich, Switzerland
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  • Jean Hausser,

    1. Biozentrum Basel, Basel, Switzerland
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  • Muthiah Manoharan,

    1. Alnylam Pharmaceuticals Inc., Cambridge, MA, USA
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  • Mihaela Zavolan,

    1. Biozentrum Basel, Basel, Switzerland
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  • Markus Stoffel

    Corresponding author
    1. Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
    2. Competence Center for Systems Biology and Metabolic Diseases, ETH Zurich, Zurich, Switzerland
    • Swiss Institute of Technology (ETH Zurich), Institute of Molecular Systems Biology, HPT E73, Wolfgang Pauli Str. 16, CH-8093 Zurich Switzerland
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    • fax: +41 44 633 1051


  • Potential conflict of interest: Nothing to report.

  • Supported in part by the Swiss National Science Foundation (LiverX) and ERC grant Metabolomirs (to M.S.).

Abstract

Transcription factor 1 (Tcf1; hepatocyte nuclear factor 1α [HNF1α]) is critical for hepatocyte development and function. Whether Tcf1 also regulates hepatic microRNAs (miRNAs) has not been investigated yet. Here we analyzed Tcf1-dependent miRNA expression in adult mice in which this transcription factor had been genetically deleted (Tcf1−/−) using miRNA microarray analysis. The miR-192/-194 cluster was markedly down-regulated in liver of Tcf1−/− mice. MiR-192/-194 levels were also decreased in two other tissues that express Tcf1, kidney and small intestine, although to a lesser extent than in liver. In order to identify targets of miR-192/-194 in vivo we combined Affymetrix gene analysis of liver in which miR-192/-194 had been silenced or overexpressed, respectively, and tested regulated messenger RNAs (mRNAs) with multiple binding sites for these miRNAs. This approach revealed frizzled-6 (Fzd6) as a robust endogenous target of miR-194. MiR-194 also targets human FZD6 and expression of miR-194 and Fzd6 are inversely correlated in a mouse model of hepatocellular carcinoma (Dgcr8flox/flox p53flox/flox × Alb-Cre). Conclusion: Our results support a role of miR-194 in liver tumorigenesis through its endogenous target Fzd6. These results may have important implications for Tcf1-mediated liver proliferation. (HEPATOLOGY 2012;55:98–107)

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