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Cited by 190Wnt/β-catenin signaling in development and cancerLiver physiology and pathologyColorectal Cancer Treatments and Studies

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

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Gougelet, Angélique, Torre, Cyril, Veber, Philippe, Sartor, Chiara, Bachelot, Laura, Denechaud, Pierre-Damien, Godard, Cécile, Moldes, Marthe +9 more·2014·Hepatology
DOI 10.1002/hep.26924
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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. (Hepatology 2014;59:2344–2357)

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  • Indirect regulation of hepatocyte identity is mediated by competition of HNF4α and β-catenin for binding to TCF. Without nuclear β-catenin, the HNF4α/TCF complex promotes periportal gene expression, whereas nuclear translocation of β-catenin forms a β-catenin/TCF complex that favours pericentral gene expression.

    “This indirect regulation of hepatocyte identity is mediated by the competition of HNF4α and β-catenin for binding to TCF. Without nuclear β-catenin, the HNF4α/TCF complex promotes periportal gene expression, whereas nuclear translocation of β-catenin forms a β-catenin/TCF complex that favours pericentral gene expression.52”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [52]

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Authors
Gougelet, A., Torre, C., Veber, P., Sartor, C., Bachelot, L., Denechaud, P.-D., Godard, C., Moldes, M., Burnol, A.-F., Dubuquoy, C., Terris, B., Guillonneau, F., Ye, T., Schwarz, M., Braeuning, A., Perret, C., & Colnot, S.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • University of Tübingen (DE)
Corresponding author
Colnot, Sabine
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2014-06
Volume
59
Issue
6
Pages
2344-2357
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.26924
OpenAlex
W2069092694
Cited by
190
References
40
Citations by year
2026: 6 · 2025: 20 · 2024: 25 · 2023: 21 · 2022: 9 · 2021: 13 · 2020: 16 · 2019: 18 · 2018: 12 · 2017: 15 · 2016: 14 · 2015: 12 · 2014: 8 · 2013: 1
FWCI
5.22
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 457 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
Agence Nationale de la Recherche (ANR-11-LABX-0071, ANR-11-IDEX-0005)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords
β-catenin signaling, TCF4, HNF4α, HNF4, drug metabolism, bile metabolism, lipid metabolism, hepatocellular carcinoma, chromatin occupancy, transcriptional repression
MeSH terms
Animals, Chromatin, Humans, Liver, Liver Neoplasms, Male, Mice, Knockout, Receptor Cross-Talk, Hepatocytes, Lipid Metabolism, beta Catenin, Mice, Hepatocyte Nuclear Factor 4, Gene Regulatory Networks, Transcription Factor 7-Like 2 Protein

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