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Transcription Elongation Factor SPT6 Maintains Epidermal Homeostasis and Suppresses Skin Inflammation in Mice

ABSTRACT: We employed single-cell RNA sequencing (scRNA-seq) using 10x Genomics technology to investigate the impact of Supt6 epidermis-specific knockout on epidermal homeostasis in mice. The histone chaperone SPT6 is a central regulator of genomic stability. Our previous studies have shown that SPT6 promotes epidermal differentiation by regulating transcriptional elongation in human epidermal stem/progenitor cells, but its in vivo role remains unclear. Our research has discovered for the first time that the transcriptional elongation factor SPT6 regulates skin inflammation, hair follicle development, and wound healing, providing a novel therapeutic target for clinical treatment of psoriasis and related skin disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE294435 | GEO | 2026/03/26

REPOSITORIES: GEO

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SPT6 maintains epidermal homeostasis by inhibiting an NF-κB- positive feedback loop to prevent excessive inflammation

Project description:Keratinocytes are increasingly recognized as central regulators of cutaneous immune responses and key contributors to maintaining immune homeostasis. However, whether and how epidermal stem and progenitor cells (EPSCs) actively suppress proinflammatory signaling pathways to prevent excessive inflammation and maintain epidermal immune quiescence remains unclear. Here, we generated a conditional knockout mouse model (K14-CreERT; Supt6fl/fl) to investigate the role of SPT6, a transcription elongation factor, in epidermal and immune homeostasis. Loss of SPT6 in basal keratinocytes led to spontaneous, psoriasis-like skin inflammation, characterized by epidermal hyperplasia, immune cell infiltration, parakeratosis, and hyperkeratosis. SPT6-deficient mice also exhibited significantly delayed wound healing accompanied by impaired Wnt signaling. Moreover, single- cell RNA sequencing revealed distinct keratinocyte subpopulations with inflammatory signatures, elevated NF-κB signaling, and suppressed Wnt signaling. Mechanistically, SPT6 suppresses NF-κB signaling by binding to an enhancer of the RELA gene and preventing its positive transcriptional feedback loop. These findings support a new paradigm in which the default state of the skin may be primed for inflammation, and active suppression by factors such as SPT6 is required to maintain epidermal homeostasis. Taken together, the results of our study reveal a previously unrecognized role for SPT6 as a key regulator of epidermal immune quiescence and tissue integrity.

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SPT6 Promotes Epidermal Differentiation and Blockade of an Intestinal Phenotype through Control of Transcriptional Elongation

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