Finding a Needle in a Genomic Haystack

Cadigan

2017

F1000Res

Self Cite

Wnt/β-catenin signaling is highly conserved throughout metazoans, is required for numerous essential events in development, and serves as a stem cell niche signal in many contexts. Misregulation of the pathway is linked to several human pathologies, most notably cancer. Wnt stimulation results in stabilization and nuclear import of β-catenin, which then acts as a transcriptional co-activator. Transcription factors of the T-cell family (TCF) are the best-characterized nuclear binding partners of β-catenin and mediators of Wnt gene regulation. This review provides an update on what is known about the transcriptional activation of Wnt target genes, highlighting recent work that modifies the conventional model. Wnt/β-catenin signaling regulates genes in a highly context-dependent manner, and the role of other signaling pathways and TCF co-factors in this process will be discussed. Understanding Wnt gene regulation has served to elucidate many biological roles of the pathway, and we will use examples from stem cell biology, metabolism, and evolution to illustrate some of the rich Wnt biology that has been uncovered.

Section: Tcfs and Wnt Target Locationsupporting

confidence: 65%

Wnt target genes and where to find them

Cadigan

2017

F1000Res

Self Cite

“…Correlative experiments using chromatin immunoprecipitation (ChIP) based techniques have identified several TFs that show significant levels of chromatin co-occupancy with TCFs (Bhambhani and Cadigan, 2014; Söderholm and Cantù, 2021). Some of these TFs also directly interact with TCFs, suggesting that they could be part of a Wnt/TCF TF collective.…”

Section: Introductionmentioning

confidence: 99%

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

Chen

Burby

et al. 2021

Preprint

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Transcriptional regulation by Wnt signalling is primarily thought to be accomplished by a complex of β-catenin and TCF family transcription factors (TFs). Although numerous studies have suggested that additional TFs play roles in regulating Wnt target genes, their mechanisms of action have not been investigated in detail. We characterised a Wnt-responsive element (WRE) downstream of the Wnt target gene Axin2 and found that TCFs and Caudal-related homeodomain (CDX) proteins were required for its activation. Using a new separation-of-function TCF mutant, we found that WRE activity requires the formation of a TCF/CDX complex. Our systematic mutagenesis of this enhancer identified other sequences essential for activation by Wnt signalling, including several copies of a novel CAG DNA motif. Computational and experimental evidence indicates that the TCF/CDX/CAG mode of regulation is prevalent in multiple WREs. Put together, our results demonstrate the complex nature of cis- and trans- interactions required for signal-dependent enhancer activity.

“…Correlative experiments using chromatin immunoprecipitation (ChIP) based techniques have identified several TFs that show significant levels of chromatin co-occupancy with TCFs ( 6 , 30 ). Some of these TFs also directly interact with TCFs, suggesting that they could be part of a Wnt/TCF TF collective.…”

Section: Introductionmentioning

confidence: 99%

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

Chen

Burby

et al. 2021

Nucleic Acids Research

Transcriptional regulation by Wnt signalling is primarily thought to be accomplished by a complex of β-catenin and TCF family transcription factors (TFs). Although numerous studies have suggested that additional TFs play roles in regulating Wnt target genes, their mechanisms of action have not been investigated in detail. We characterised a Wnt-responsive element (WRE) downstream of the Wnt target gene Axin2 and found that TCFs and Caudal type homeobox (CDX) proteins were required for its activation. Using a new separation-of-function TCF mutant, we found that WRE activity requires the formation of a TCF/CDX complex. Our systematic mutagenesis of this enhancer identified other sequences essential for activation by Wnt signalling, including several copies of a novel CAG DNA motif. Computational and experimental evidence indicates that the TCF/CDX/CAG mode of regulation is prevalent in multiple WREs. Put together, our results demonstrate the complex nature of cis- and trans- interactions required for signal-dependent enhancer activity.