Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning [scATAC-Seq]

Tissue regeneration requires de novo patterning, which has been proposed to be facilitated by cellular heterogeneity. Yet, how such heterogeneities are integrated with the mechanochemical state of the tissue, and stabilized at the chromatin level into stable and spatially organised fates, remains poorly understood. Using in vivo mouse intestinal regeneration models and organoids, we identify a critical density regime which produces a permissive window of heterogeneity in the mechanosensor YAP1. We show that YAP1 heterogeneity is coupled to lineage-biased chromatin accessibility and is decoded through FOXA1, which integrates the permissive chromatin state to Delta-Notch supra-cellular feedback and lineage commitment. This circuit generates fate bistability and preserves a memory of transient YAP1 activity, maintaining spatial patterning as tissues return to homeostasis after injury. Together, our findings establish a multiscale framework in which tissue-scale mechanics tune single-cell competence and, through FOXA1-mediated bistability, convert transient heterogeneity into stable, reproducible, and self-organised tissue architecture.