BMAL1 and YAP jointly activate inflammatory genes in the aging mouse epidermis

BMAL1 and YAP jointly activate inflammatory genes in the aging mouse epidermis

On August 19, Nature Aging published a study of the outer layer of mouse skin. The authors traced how BMAL1, a biological clock protein, and YAP, a protein that responds to the mechanical properties of tissue, alter inflammatory gene expression.

Epidermal cells in old mice receive two signals that change with age: one from the underlying tissue and another from immune cells. The basement membrane, a thin layer between the epidermis and the deeper dermis, becomes more resistant to deformation. Meanwhile, cells that release IL-17, an inflammatory signaling molecule, accumulate in the dermis.

In a 2023 study, the same group linked IL-17 to age-related changes in mouse skin. In the new study, the authors compared adult and old epidermis at six points in the daily cycle. Among 118 inflammatory genes that were more active in old skin, only four showed rhythmic changes. BMAL1 therefore contributes to a stable age-related shift in gene expression, rather than acting only through daily fluctuations.

To separate the effects of tissue mechanics and inflammation, the researchers studied mice in which the collagen XIV gene had been disabled. Their basement membrane was more resistant to deformation, and YAP was activated, but the cells mainly induced skin barrier genes. In old mice, blocking IL-17A/F reduced the proportion of cells containing phosphorylated YAP. The mechanical properties of the tissue affect YAP, while IL-17 provides an additional inflammatory signal.

Mapping the DNA regions bound by these proteins showed where the two pathways converge. In old epidermis, BMAL1 and YAP were found together more often at enhancers, which are regulatory DNA regions that increase inflammatory gene expression. The p65 protein from the inflammatory NF-κB pathway bound more often to promoters near the beginning of genes. In this way, age-related changes in tissue mechanics and immune signaling direct different regulators toward the same inflammatory program in mouse skin.