Hairless Is a Nuclear Receptor Corepressor Essential for Skin Function

The 2009 review highlighted the significance of the Hairless (HR) protein as a nuclear receptor corepressor crucial for skin and hair function. HR was shown to interact with nuclear receptors like the thyroid hormone receptor and vitamin D receptor, mediating transcriptional repression essential for skin function. Mutations in the HR gene cause congenital hair loss in humans and mice, emphasizing its role in regulating epithelial stem cell differentiation and gene expression through chromatin remodeling. HR's interaction with the vitamin D receptor is particularly notable, as it represses VDR activity both in the absence and presence of vitamin D. The review also suggested that HR might have histone demethylase activity and is involved in the regulation of gene expression via multiple nuclear receptors. The study using a gain-of-function mutant mouse model demonstrated that HR is necessary for hair growth, influencing hair follicle cycling by promoting Wnt signaling, a pathway critical for hair regeneration. The findings indicated that HR's dysregulation could lead to hair loss disorders, providing insights into the molecular mechanisms of hair growth and potential treatments for alopecia.