The Time-Resolved Genomic Impact of WNT/ β-Catenin Signaling

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.