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T‐cell factor 4 and β‐catenin chromatin occupancies pattern zonal liver metabolism in mice
Author(s) -
Gougelet Angélique,
Torre Cyril,
Veber Philippe,
Sartor Chiara,
Bachelot Laura,
Denechaud PierreDamien,
Godard Cécile,
Moldes Marthe,
Burnol AnneFrançoise,
Dubuquoy Céline,
Terris Benoit,
Guillonneau François,
Ye Tao,
Schwarz Michael,
Braeuning Albert,
Perret Christine,
Colnot Sabine
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26924
Subject(s) - transcription factor , hccs , hepatocyte nuclear factors , biology , chromatin , wnt signaling pathway , catenin , microbiology and biotechnology , hepatocyte nuclear factor 4 , nuclear receptor , signal transduction , cancer research , gene , biochemistry
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. (H epatology 2014;59:2344–2357)