ZFP42 maintains stemness and rhythmic transcription in human epidermal stem and progenitor cells via CRY1

The role of circadian rhythm in regulating stemness in adult stem cells remains unclear. We investigated this in human epidermal stem and progenitor cells (EPSCs), finding that ~10% of expressed genes exhibit rhythmicity, with shared genes between fetal and adult EPSCs enriched in critical biological processes including the cell cycle, senescence, and apoptosis. Promoter motif analysis revealed ZFP42, a pluripotent stem cell marker, enriched in fetal rhythmic genes. ZFP42 knockdown led to the loss of stemness in human EPSCs and reduced expression of Cryptochrome Circadian Regulator 1 (CRY1), a core component of the molecular circadian clock that functions as a transcriptional repressor within the CLOCK-BMAL1 feedback loop, resulting in decreased cell proliferation and increased differentiation gene expression. These results highlight the critical role of ZFP42 in the circadian regulation of epidermal homeostasis, linking stemness maintenance to circadian mechanisms. Our findings deepen the understanding of how circadian rhythms govern epidermal stem cell functions.