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Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif

Aravinda-Bharathi Ramakrishnan1, Lisheng Chen1, Peter E Burby1

  • 1Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109 USA.

Nucleic Acids Research
|August 6, 2021
PubMed

Insights

Wnt signaling regulation involves more than just beta-catenin and TCF transcription factors (TFs). This study reveals a TCF/CDX complex and novel CAG DNA motifs are crucial for Wnt-responsive element activation.

Area of Science:

  • Molecular Biology
  • Genetics
  • Developmental Biology

Background:

  • Wnt signaling is crucial for development and disease.
  • Transcriptional regulation is primarily attributed to beta-catenin and TCF transcription factors (TFs).
  • The roles of additional TFs in Wnt target gene regulation remain largely uncharacterized.

Purpose of the Study:

  • To investigate the mechanism of Wnt-responsive element (WRE) activation.
  • To identify novel factors and DNA motifs involved in Wnt signaling.
  • To elucidate the complex interactions governing signal-dependent enhancer activity.

Main Methods:

  • Characterization of a Wnt-responsive element (WRE) downstream of the Axin2 gene.
  • Systematic mutagenesis of the WRE.
  • Use of a separation-of-function TCF mutant.
  • Computational and experimental analyses.

Main Results:

  • TCF and Caudal type homeobox (CDX) proteins are required for WRE activation.
  • WRE activity necessitates the formation of a TCF/CDX complex.
  • Novel CAG DNA motifs were identified as essential for Wnt signaling activation.
  • The TCF/CDX/CAG regulatory mode is prevalent across multiple WREs.

Conclusions:

  • Wnt target gene regulation is more complex than previously understood.
  • TCF/CDX complex formation and novel DNA motifs are critical for Wnt-responsive enhancer function.
  • This study highlights intricate cis- and trans- interactions in signal-dependent gene regulation.

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