T-cell Factor 4 and ß-Catenin Chromatin Occupancies Pattern Zonal Liver Metabolism in Mice

beta-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 beta-catenin-dependent zonal transcription using mice with beta-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by T-cell factor (Tcf)-4 and beta-catenin, transcriptome, and metabolome. We find that Tcf-4 DNA bindings depend on beta-catenin. Tcf-4/beta-catenin binds Wnt-responsive elements preferentially around beta-catenin-induced genes. In contrast, genes repressed by beta-catenin bind Tcf-4 on hepatocyte nuclear factor 4 (Hnf-4)-responsive elements. beta-Catenin, Tcf-4, and Hnf-4 interact, dictating beta-catenin transcription, which is antagonistic to that elicited by Hnf-4. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by beta-catenin, partly through xenobiotic nuclear receptors. Conclusions: beta-catenin patterns the zonal liver together with Tcf-4, Hnf-4, and xenobiotic nuclear receptors. This network represses lipid metabolism and exacerbates glutamine, drug, and bile metabolism, mirroring HCCs with beta-catenin mutational activation.