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Hepatology. 2014 Jun;59(6):2344-57. doi: 10.1002/hep.26924. Epub 2014 Apr 14.

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

Author information

1
Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Paris, France.

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.

PMID:
24214913
DOI:
10.1002/hep.26924
[Indexed for MEDLINE]

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