TCF/LEF dependent and independent transcriptional regulation of Wnt/β-catenin target genes

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Canonical Wnt signaling primarily involves nuclear beta-catenin (β-catenin) activity mediated by TCF/LEF transcription factors.
• The precise mechanisms and extent of β-catenin's transcriptional regulation are still being elucidated.

Purpose of the Study:

• To investigate whether β-catenin can regulate gene expression independently of TCF/LEF transcription factors.
• To characterize novel modes of β-catenin transcriptional activity.

Main Methods:

• CRISPR/Cas9 genome editing was used to generate HEK 293T cell lines lacking all four TCF/LEF genes.
• Unbiased whole transcriptome sequencing and genome-wide analysis were performed to assess β-catenin targets and genomic occupancy.

Main Results:

• A subset of β-catenin transcriptional targets were identified that do not require TCF/LEF factors.
• β-catenin was found to occupy specific genomic regions even in the absence of TCF/LEF.
• A novel transcriptional activity, termed β-catenin-GHOST response, was revealed, which is active when TCF/LEF factors are absent.

Conclusions:

• β-catenin possesses a previously unrecognized mechanism of action that bypasses TCF/LEF transcription factors.
• This discovery expands our understanding of Wnt signaling pathway regulation and β-catenin's role.
• The β-catenin-GHOST response represents a new avenue for studying gene regulation in various biological contexts.