Transcription elongation factor SPT6 maintains epidermal homeostasis and suppresses skin inflammation in mice

Summary: Abstract Body: The development of epidermal stem and progenitor cells (EPSCs) is vital for maintaining skin homeostasis, including protection against bacterial and viral infections and prevention of water loss. Abnormal epidermal development can disrupt skin homeostasis, potentially leading to various severe skin diseases. Our previous work identified the histone chaperone SPT6, a key regulator of genomic stability, playing a crucial role in promoting epidermal differentiation and stratification by facilitating transcriptional elongation of key differentiation-inducing genes in human EPSCs. Notably, SPT6 deficiency leads to spontaneous transdifferentiation of EPSCs into intestinal-like cells due to stalled transcription of the epidermal fate master regulator P63. However, the specific role of SPT6 in epidermis in vivo remains poorly understood. To investigate this, we developed an inducible, epidermis specific SPT6 knockout mouse model. Five days after the final tamoxifen injection, SPT6 knockout mice exhibited severe skin abnormalities, including extensive scaly crusting, prominent neutrophilic microabscesses, delayed hair follicle development, and impaired wound healing. Transmission electron microscopy revealed partial disruption of the basement membrane, further indicating compromised skin integrity. RNA sequencing of lesional skin highlighted significant correlations between SPT6 knockout profiles and gene expression signatures associated with psoriasis and atopic dermatitis. By integrating single-cell RNA sequencing and ChIP-seq, we delineated the molecular mechanisms by which SPT6 sustains skin homeostasis. In conclusion, this study is the first to reveal that the transcription elongation factor SPT6 plays a critical role in regulating inflammation, hair follicle development, and wound healing in vivo. These findings provide valuable insights into the biological functions of SPT6 in skin homeostasis and open new avenues for developing therapeutic strategies to treat skin disorders, including psoriasis. Yushuang Sun¹, Jingting Li¹ 1. Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Stem Cell Biology, Tissue Regeneration and Wound Healing