UTX (KDM6A) promotes differentiation noncatalytically in somatic self-renewing epithelia

Area of Science:

• Epigenetics
• Dermatology
• Molecular Biology

Background:

• The X-linked histone demethylase UTX (KDM6A) is crucial for gene regulation but its function in self-renewing epithelia, like skin, remains unclear.
• Retinoic acid (RA) signaling is vital for skin homeostasis and treating various skin conditions, including cancer, acne, and aging.

Purpose of the Study:

• To investigate the role of UTX in skin differentiation and homeostasis.
• To explore the connection between UTX, retinoic acid signaling, and epidermal stem cell fate.

Main Methods:

• Utilized genetic deletion of Utx in mouse skin models.
• Performed spatial analyses and genome-wide epigenetic profiling (H3K27ac, H3K27me3).
• Examined regulation of retinoid metabolic and differentiation-related genes.

Main Results:

• UTX deletion dysregulates epidermal, sebaceous, and hair follicle differentiation programs in female mice.
• UTX directly regulates retinoid metabolic genes (e.g., Crabp2) and stem cell fate genes (e.g., Cdh1, Grhl3, Ctnnb1).
• UTX primarily functions noncatalytically, leading to H3K27ac loss, and its paralog UTY compensates in males.

Conclusions:

• UTX is a key regulator of skin differentiation through retinoic acid signaling.
• Epigenetic modulation of UTX offers potential therapeutic strategies for skin diseases.
• UTX's noncatalytic function and sex-specific regulation are critical for skin homeostasis.