Epigenetic controls of Sonic hedgehog guarantee fidelity of epithelial adult stem cells trajectory in regeneration

Given that adult stem cells (ASCs) fuel homeostasis and healing by providing tissue-specific descendants, the fidelity of ASC fate determination is crucial for regeneration. Here, we established that an epigenetic control of epithelial ASC fate fidelity via Ezh2/H3K27me3 was indispensable for incisor homeostasis and regeneration. Mechanistically, in homeostasis, H3K27me3 upstream occupies the Sonic hedgehog (Shh) promoter to directly restrain Shh expression, thereby precisely confining Shh expression. When injury occurred, Ezh2/H3K27me3 was substantially induced within inner enamel epithelium and preameloblast zones, and such epigenetic response guaranteed the fidelity of ASC commitment via pulling injury-increased Shh back to homeostatic levels, utterly underlying regeneration progression. Once losing H3K27me3-dependent restriction of Shh expression through the Cre-Loxp system totally disrupted lineage commitment and stemness exhaustion, and abolished hard tissue regeneration emerged in vivo. We next uncovered the molecular mechanisms by which injury-induced Ezh2 mediated the spatiotemporal dynamics of H3K27me3 to repress Shh expression, thus epigenetically deciding ASC fate.