Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Nat Commun. 2023 Jan 30;14(1):497. doi: 10.1038/s41467-023-36228-2.
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.
胃肠道中的上皮-间充质信号对于器官发生过程中的区域身份建立和成年干细胞稳态维持至关重要。尽管最近的研究表明，间充质细胞表达的 Wnt 配体在胃肠道发育和干细胞稳态中是必需的，但驱动串扰时空控制的表观遗传机制仍不清楚。在这里，我们证明胃肠道间充质细胞通过 Polycomb 抑制复合物 2 介导的染色质二价态来控制上皮命运和功能。我们发现，虽然关键的谱系决定基因具有组织特异性的染色质可及性，但 Polycomb 抑制复合物 2 在不改变可及性的情况下控制间充质细胞中的 Wnt 表达。我们表明，减少间充质 Wnt 分泌可以挽救由 Polycomb 抑制复合物 2 缺失引起的胃肠道命运和增殖缺陷。我们证明，间充质 Polycomb 抑制复合物 2 还调节龛信号以维持成年肠道中的干细胞功能。我们的结果突出了间充质细胞中区域化的广泛许可染色质结构，然后进一步证明了龛位染色质结构如何影响相邻细胞的命运和功能。
