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Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning

'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 and self-organized tissue architecture'
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Abstract

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, spatially organized fates remains poorly understood. Using in vivo mouse intestinal regeneration models and organoids, we identify a critical density regime that produces a permissive window for heterogeneity in the mechanosensor Yes-associated protein 1 (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 supracellular feedback and lineage commitment. This circuit generates fate bistability and preserves a memory of transient YAP1 activity, thereby 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 and self-organized tissue architecture.

Authors:

Affiliations

  • 1Friedrich Miescher Institute for Biomedical Research, 4056 Basel, Switzerland; ETH Zürich, Department for Biosystems Science and Engineering (D-BSSE), 4056 Basel, Switzerland.
  • 2Friedrich Miescher Institute for Biomedical Research, 4056 Basel, Switzerland; ETH Zürich, Department for Biosystems Science and Engineering (D-BSSE), 4056 Basel, Switzerland; University of Basel, 4001 Basel, Switzerland.
  • 3Institute of Science and Technology Austria, 3400 Klosterneuburg, Austria; Biozentrum, University of Basel, 4056 Basel, Switzerland; Department of Physics, University of Basel, 4056 Basel, Switzerland.
  • 4Friedrich Miescher Institute for Biomedical Research, 4056 Basel, Switzerland.
  • 5Friedrich Miescher Institute for Biomedical Research, 4056 Basel, Switzerland; University of Basel, 4001 Basel, Switzerland.
  • 6Department of Metabolic Biology and Nutrition, UC Berkeley, Berkeley, CA 94720, USA.
  • 7The Francis Crick Institute, London NW1 1AT, UK.
  • 8ETH Zürich, Department for Biosystems Science and Engineering (D-BSSE), 4056 Basel, Switzerland.
  • 9Biozentrum, University of Basel, 4056 Basel, Switzerland; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, 4070 Basel, Switzerland.
  • 10Friedrich Miescher Institute for Biomedical Research, 4056 Basel, Switzerland; University of Basel, 4001 Basel, Switzerland; Swiss Institute of Bioinformatics, 4056 Basel, Switzerland.
  • 11Institute of Science and Technology Austria, 3400 Klosterneuburg, Austria. Electronic address: edouard.hannezo@ist.ac.at.
  • 12Friedrich Miescher Institute for Biomedical Research, 4056 Basel, Switzerland; ETH Zürich, Department for Biosystems Science and Engineering (D-BSSE), 4056 Basel, Switzerland; University of Basel, 4001 Basel, Switzerland. Electronic address: prisca.liberali@fmi.ch.
 Cell. 2026 Jun 30:S0092-8674(26)00696-3. doi: 10.1016/j.cell.2026.06.009. Epub ahead of print. PMID: 42379166.
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WORC Update (He/Him)
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