GCN5-mediated H3K27cr regulates hair follicle stem cell migration and hair follicle development through KRT80 activation

The biological functions and molecular mechanisms of histone crotonylation (Kcr) during hair follicle morphogenesis remain largely unexplored. Here, we sought to elucidate these aspects using skin samples from cashmere goat fetuses at key stages of hair follicle morphogenesis; dynamic changes in histone 3 lysine 27 crotonylation (H3K27cr) were profiled using CUT&Tag sequencing. H3K27cr was specifically enriched at the promoter region of the keratin family gene KRT80 and positively regulated its transcriptional activity. The histone acetyltransferase GCN5 functioned as a critical crotonylation writer that modulated H3K27cr levels in hair follicle stem cells. Alteration of GCN5 activity affected H3K27cr occupancy at the KRT80 promoter, thereby regulating KRT80 expression and subsequently influencing the migratory capacity of secondary hair follicle stem cells in cashmere goats. Overall, our findings identify a previously unrecognized GCN5–H3K27cr–KRT80 regulatory axis governing hair follicle development and provide mechanistic insights into the role of histone crotonylation in folliculogenesis. We map dynamic H3K27 crotonylation during cashmere goat hair follicle development using CUT&Tag and functional assays. GCN5-mediated H3K27cr targets KRT80 and promotes secondary hair follicle stem cell migration.