T-cell factor 4 and β-catenin chromatin occupancies pattern zonal liver metabolism in mice

Authors

  • Angélique Gougelet,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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    • These authors contributed equally to this work.

  • Cyril Torre,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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    • These authors contributed equally to this work.

  • Philippe Veber,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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  • Chiara Sartor,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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  • Laura Bachelot,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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  • Pierre-Damien Denechaud,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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  • Cécile Godard,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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  • Marthe Moldes,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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  • Anne-Françoise Burnol,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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  • Céline Dubuquoy,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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  • Benoit Terris,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Service d'Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Cochin, Université Paris Descartes, Paris, France
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  • François Guillonneau,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. 3P5 proteomics facility, Paris, France
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  • Tao Ye,

    1. Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, INSERM U 596, Université de Strasbourg, Illkirch, France
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  • Michael Schwarz,

    1. Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany
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  • Albert Braeuning,

    1. Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Tübingen, Germany
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  • Christine Perret,

    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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  • Sabine Colnot

    Corresponding author
    1. Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
    • Address reprint requests to: Sabine Colnot, Ph.D., Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, 24 rue du Faubourg Saint Jacques, 75014 Paris, France. E-mail: sabine.colnot@inserm.fr; fax: +33 144412421.

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  • See Editorial on Page 2080

  • Potential conflict of interest: Nothing to report.

  • This work was supported by the Ligue Nationale Contre le Cancer (Labellisation Programme 2011-2013), the Agence Nationale de la Recherche (WNT-METABOLIV, 2011-2013), and, in part, by the French Laboratory of Excellence program, Who am I (no. ANR-11-LABX-0071), included in the Investments for the Future program no. ANR-11-IDEX-0005-01. Cancersys EU FP7 programme (2008-2010) also funded experimental work and fellowships for P.V., A.G., P.D.D., and L.B. C.T. held a fellowship from the Ministère de la Recherche et de la Technologie.

Abstract

β-catenin signaling can be both a physiological and oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20%-40% of hepatocellular carcinomas (HCCs) with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by T-cell factor (Tcf)−4 and β-catenin, transcriptome, and metabolome. We find that Tcf-4 DNA bindings depend on β-catenin. Tcf-4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf-4 on hepatocyte nuclear factor 4 (Hnf-4)-responsive elements. β-Catenin, Tcf-4, and Hnf-4α interact, dictating β-catenin transcription, which is antagonistic to that elicited by Hnf-4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. Conclusions: β-catenin patterns the zonal liver together with Tcf-4, Hnf-4α, and xenobiotic nuclear receptors. This network represses lipid metabolism and exacerbates glutamine, drug, and bile metabolism, mirroring HCCs with β-catenin mutational activation. (Hepatology 2014;59:2344–2357)

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