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

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