The time-resolved genomic impact of Wnt/β-catenin signaling

• Published in: Cell systems Vol. 14; no. 7; pp. 563 - 581.e7
• Main Authors: Pagella, Pierfrancesco, Söderholm, Simon, Nordin, Anna, Zambanini, Gianluca, Ghezzi, Valeria, Jauregi-Miguel, Amaia, Cantù, Claudio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.07.2023
• Subjects: ATAC-seq; beta Catenin - genetics; cancer; chromatin; Chromatin - genetics; CUT&RUN; embryonic development; genome; Genomics; HEK293 Cells; Humans; transcription; transcription factor; Wnt signaling; Wnt Signaling Pathway - genetics; β-catenin; β-catenin; genome; transcription factor; Wnt signaling; transcription; embryonic development; CUT&RUN; cancer; chromatin; ATAC-seq
• ISSN: 2405-4712; 2405-4720
• DOI: 10.1016/j.cels.2023.06.004

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. [Display omitted] •Time-resolved CUT&RUN, ATAC-seq, and RNA-seq in Wnt-responding HEK293T and hESCs•β-Catenin targets are time and cell specific•β-Catenin binding is associated with both activation and repression of target genes•Wnt/β-catenin activation induces elastic or plastic chromatin responses Via time-resolved CUT&RUN, ATAC-seq, and RNA-seq on Wnt-responding HEK293Ts and hESCs, Pagella et al. show that β-catenin binds in time- and cell-specific manners to target genes leading to activation or repression of their expression. Furthermore, β-catenin can be recruited to non-accessible chromatin regions and induce elastic or plastic chromatin behaviors.