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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatin / metabolism
  • Gene Regulatory Networks
  • Hepatocyte Nuclear Factor 4 / metabolism*
  • Hepatocytes / metabolism*
  • Humans
  • Lipid Metabolism
  • Liver / metabolism
  • Liver Neoplasms / etiology*
  • Male
  • Mice
  • Mice, Knockout
  • Receptor Cross-Talk
  • Transcription Factor 7-Like 2 Protein / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • CTNNB1 protein, mouse
  • Chromatin
  • Hepatocyte Nuclear Factor 4
  • Transcription Factor 7-Like 2 Protein
  • beta Catenin