Liu, Shiyang, Haghani, Sara, Petretto, Enrico, Madan, Babita, Harmston, Nathan and Virshup, David M.
2026.
Identification of Wnt‐regulated genes that are repressed by, or independent of, β‐catenin.
The FEBS Journal
10.1111/febs.70417
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Abstract
Wnt signaling regulates metazoan development and homeostasis, in part by β-catenin-dependent activation and repression of a large number of genes. However, Wnt signaling also regulates genes independent of β-catenin, genes that are less well-characterized. In this study, using a pan-Wnt inhibitor, we performed a comprehensive transcriptome analysis in a Wnt-addicted orthotopic cancer model to delineate the β-catenin-dependent and independent arms of Wnt signaling. We find that while a large percentage of Wnt-regulated genes are regulated by β-catenin, 10% of these genes are regulated independent of β-catenin. Interestingly, a large proportion of these β-catenin-independent genes are Wnt-repressed. Among the β-catenin-dependent genes, more than half are repressed by β-catenin. We used this dataset to investigate the mechanisms by which Wnt/β-catenin signaling represses gene expression, revealing the role of a cis-regulatory motif, the negative regulatory element (NRE). The NRE motif is enriched in the promoters of β-catenin repressed genes and is required for their repression. This provides a comprehensive analysis of the β-catenin-independent arm of the Wnt signaling pathway in a cancer model and suggests that a cis-regulatory grammar may determine Wnt-dependent gene activation versus repression.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | In Press |
| Schools: | Schools > Biosciences |
| Additional Information: | RRS policy applied |
| Publisher: | Wiley |
| ISSN: | 1742-464X |
| Date of First Compliant Deposit: | 12 February 2026 |
| Date of Acceptance: | 16 January 2026 |
| Last Modified: | 12 Feb 2026 12:15 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/184553 |
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