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Published on: June 17, 2014
The time-resolved genomic impact of Wnt/β-catenin signaling
Pierfrancesco Pagella1, Simon Söderholm1, Anna Nordin1
1Wallenberg Centre for Molecular Medicine, Linköping University, 58185 Linköping, Sweden; Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology, Faculty of Medicine and Health Sciences, Linköping University, 58185 Linköping, Sweden.
Abstract:
Wnt signaling orchestrates gene expression via its effector, β-catenin. However, it is unknown whether β-catenin binds its target genomic regions simultaneously and how this impacts chromatin dynamics to modulate cell behavior. Using a combination of time-resolved CUT&RUN against β-catenin, ATAC-seq, and perturbation assays in different cell types, we show that Wnt/β-catenin physical targets are tissue-specific, β-catenin "moves" on different loci over time, and its association to DNA accompanies changing chromatin accessibility landscapes that determine cell behavior. In particular, Wnt/β-catenin progressively shapes the chromatin of human embryonic stem cells (hESCs) as they undergo mesodermal differentiation, a behavior that we define as "plastic." In HEK293T cells, on the other hand, Wnt/β-catenin drives a transient chromatin opening, followed by re-establishment of the pre-stimulation state, a response that we define as "elastic." Future experiments shall assess whether other cell communication mechanisms, in addition to Wnt signaling, are ruled by time, cellular idiosyncrasies, and chromatin constraints. A record of this paper's transparent peer review process is included in the supplemental information.
Insights
Wnt/β-catenin binding dynamics at genomic targets are tissue-specific and time-dependent, influencing chromatin accessibility and cell behavior. This study reveals plastic and elastic responses in human embryonic stem cells and HEK293T cells, respectively.
Area of Science:
- Molecular Biology
- Genomics
- Cell Biology
Background:
- Wnt signaling regulates gene expression through β-catenin.
- The dynamic binding of β-catenin to genomic targets and its impact on chromatin are not well understood.
Purpose of the Study:
- To investigate the temporal dynamics of β-catenin binding to genomic regions.
- To understand how β-catenin-mediated chromatin changes influence cell behavior.
- To characterize tissue-specific responses to Wnt signaling.
Main Methods:
- Time-resolved CUT&RUN assay for β-catenin.
- Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq).
- Perturbation assays in various cell types.
Main Results:
- Wnt/β-catenin physical targets are tissue-specific.
- β-catenin exhibits dynamic binding to loci over time.
- Chromatin accessibility landscapes change with β-catenin association, modulating cell behavior.
- Human embryonic stem cells show a 'plastic' chromatin response during mesodermal differentiation.
- HEK293T cells display an 'elastic' response with transient chromatin opening.
Conclusions:
- Wnt/β-catenin binding dynamics are crucial for tissue-specific gene regulation and cell plasticity.
- Cellular responses to Wnt signaling are influenced by time, cell type, and chromatin constraints.
- Future research should explore these principles in other cell communication pathways.
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