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This study reveals that Wnt/β-catenin signaling can actively remodel chromatin to create new regulatory elements, rather than simply activating pre-existing ones. Using time-resolved genomic analyses in HEK293T cells, researchers identified a class of "latent enhancers" that are initially closed but become accessible upon Wnt pathway activation, with β-catenin acting as a pioneer-like factor alongside HDAC1 and CBP to enable this remodeling. This discovery expands the understanding of Wnt signaling from a simple molecular switch to a dynamic system capable of establishing gene regulatory elements de novo.
Why it matters
This finding has important implications for understanding development and disease, particularly cancer, where aberrant Wnt signaling plays a critical role. The identification of β-catenin's pioneer activity could inform new therapeutic strategies that target the chromatin remodeling function of Wnt signaling rather than just its transcriptional activation.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Wnt/{beta}-catenin signaling is widely understood as a molecular switch that activates preprogrammed regula-tory states. Whether it also actively reshapes chromatin to establish those states has remained unclear. To address this, we performed time-resolved ATAC-seq and CUT&RUN analyses in HEK293T cells and monitored {beta}-catenin-dependent changes in chromatin accessibility and complex assembly following pathway activation. In addition to conventional Wnt-responsive elements (WREs), which are constitutively accessible and pre-bound by TCF/LEF transcription factors (TFs), we identified a second class of WREs, that are initially inaccessible but become activated upon stimulus. At these latent enhancers, {beta}-catenin functions as a pioneer-like factor together with HDAC1 and CBP, mediating chromatin remodeling and TCF/LEF occupancy. Together, these results extend the current view of Wnt/{beta}-catenin signaling by show-ing that it can establish regulatory elements de novo. Here, {beta}-catenin emerges as the central regulator of transcriptional control and remodeling, providing a framework for the dynamic and context-dependent nature of Wnt-driven gene regulation in development and disease.
Source: Enhancer pioneering activity of Wnt/β-catenin signaling