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

Area of Science:

• Cellular and Molecular Biology
• Developmental Biology
• Tissue Engineering

Background:

• Tissue regeneration relies on de novo patterning, potentially driven by cellular heterogeneity.
• The integration of cellular heterogeneity with tissue mechanochemistry and chromatin states for stable patterning is not well understood.

Purpose of the Study:

• To investigate how cellular heterogeneity is integrated with mechanical cues and chromatin states during tissue regeneration.
• To elucidate the molecular mechanisms underlying spatial patterning and lineage commitment in regenerating tissues.

Main Methods:

• Utilized in vivo mouse intestinal regeneration models and organoids.
• Analyzed the role of the mechanosensor Yes-associated protein 1 (YAP1) and the transcription factor FOXA1.
• Investigated chromatin accessibility and Delta-Notch signaling pathways.

Main Results:

• Identified a critical density regime that creates a permissive window for YAP1 heterogeneity.
• Demonstrated that YAP1 heterogeneity is linked to lineage-biased chromatin accessibility.
• Showed that FOXA1 integrates chromatin state with Delta-Notch feedback for lineage commitment and fate bistability.
• Established that this circuit preserves memory of transient YAP1 activity, maintaining spatial patterns during homeostasis recovery.

Conclusions:

• Tissue-scale mechanics modulate single-cell competence through YAP1.
• FOXA1-mediated bistability converts transient cellular heterogeneity into stable, self-organized tissue architecture.
• This provides a multiscale framework for understanding tissue regeneration and patterning.