Epigenetic control of cellular crosstalk defines gastrointestinal organ fate and function

Ryan J. Smith, Minggao Liang, Adrian Kwan Ho Loe, Theodora Yung, Ji-Eun Kim, Matthew Hudson, Michael D. Wilson and Tae-Hee Kim ()
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Ryan J. Smith: The Hospital for Sick Children
Minggao Liang: University of Toronto
Adrian Kwan Ho Loe: The Hospital for Sick Children
Theodora Yung: The Hospital for Sick Children
Ji-Eun Kim: The Hospital for Sick Children
Matthew Hudson: University of Toronto
Michael D. Wilson: University of Toronto
Tae-Hee Kim: The Hospital for Sick Children

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Epithelial-mesenchymal signaling in the gastrointestinal system is vital in establishing regional identity during organogenesis and maintaining adult stem cell homeostasis. Although recent work has demonstrated that Wnt ligands expressed by mesenchymal cells are required during gastrointestinal development and stem cell homeostasis, epigenetic mechanisms driving spatiotemporal control of crosstalk remain unknown. Here, we demonstrate that gastrointestinal mesenchymal cells control epithelial fate and function through Polycomb Repressive Complex 2-mediated chromatin bivalency. We find that while key lineage-determining genes possess tissue-specific chromatin accessibility, Polycomb Repressive Complex 2 controls Wnt expression in mesenchymal cells without altering accessibility. We show that reduction of mesenchymal Wnt secretion rescues gastrointestinal fate and proliferation defects caused by Polycomb Repressive Complex 2 loss. We demonstrate that mesenchymal Polycomb Repressive Complex 2 also regulates niche signals to maintain stem cell function in the adult intestine. Our results highlight a broadly permissive chromatin architecture underlying regionalization in mesenchymal cells, then demonstrate further how chromatin architecture in niches can influence the fate and function of neighboring cells.

Date: 2023
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DOI: 10.1038/s41467-023-36228-2

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