T-cell factor 4 and β-catenin chromatin occupancies pattern zonal liver metabolism in mice.
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.
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.
Angélique
A
Gougelet
Cyril
C
Torre
Philippe
P
Veber
Chiara
C
Sartor
Laura
L
Bachelot
Pierre-Damien
PD
Denechaud
Cécile
C
Godard
Marthe
M
Moldes
Anne-Françoise
AF
Burnol
Céline
C
Dubuquoy
Benoit
B
Terris
François
F
Guillonneau
Tao
T
Ye
Michael
M
Schwarz
Albert
A
Braeuning
Christine
C
Perret
Sabine
S
Colnot
D000818:Animals; D002843:Chromatin / Q000378:metabolism; D053263:Gene Regulatory Networks; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020239:Receptor Cross-Talk; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D002843:Chromatin; D051557:Hepatocyte Nuclear Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin