Abstract: Epidermal stem/progenitor cells (EPSCs) are vital for skin homeostasis, protecting against infections and preventing water loss. Disruption of EPSC development can lead to severe skin disorders. We have shown previously that SPT6, a histone chaperone, promotes EPSC differentiation by facilitating transcriptional elongation. However, its role in skin homeostasis in vivo is unclear. Since systemic SPT6 deletion causes embryonic lethality, studies on SPT6 knockout (KO) mice are rare. We are the first to generate an EPSC-specific SPT6 knockout mouse model. These mice exhibited severe scaly crusting, neutrophilic microabscesses, delayed hair follicle development, and impaired wound healing. Transmission electron microscopy revealed increased keratohyalin granules in the granualar layer, decreased cell-cell junction, relaxed euchromatic nucleus, and disrupted basement membrane in the SPT6 KO epidermis. RNA-Seq data showed strong correlations with psoriasis and atopic dermatitis gene signatures. Using single-cell RNA sequencing and ChIP-seq, we uncovered the molecular mechanisms by which SPT6 regulates skin homeostasis. This study investigated the role of SPT6 in adult stem cells in vivo for the first time and demonstrated that SPT6 regulates skin inflammation, hair follicle development, and wound healing, offering new therapeutic targets for skin diseases like psoriasis.
Funding Source: This work was supported by the National Natural Science Foundation of China (82273561,82073469 and 82473557 to J.L), Natural Science Foundation of Guangdong Province (2023A1515010146 and 2024A1515013194).
