1397 LSD1 is critical for epidermal development and skin barrier formation

Histone lysine-specific demethylase 1 (LSD1) is a key epigenetic enzyme known to be involved in lineage-specific development and cell differentiation. Through its demethylase function, LSD1 represses crucial differentiation genes and preserves progenitor-like cell fates. As such, LSD1 is frequently overexpressed in human malignancies, portending poor prognosis in cancers including cutaneous squamous cell carcinoma (cSCC). LSD1 inhibitors show significant promise in the treatment of cSCC, underscoring the need to have a better understanding of LSD1’s role in skin homeostasis and development. Previously, our lab demonstrated that LSD1 inhibition in vitro unleashes an epidermal differentiation program to prevent cSCC (Egolf & Aubert, Cell Reports, 2019). However, it is virtually unknown how LSD1 functions in the skin in vivo. Here, we provide evidence for LSD1 as an essential epigenetic regulator of epidermal development. Mice with epidermal deletion of Lsd1 are embryonic lethal stemming from profound barrier dysfunction, lack of proper epidermal stratification, and impaired hair follicle development. Utilizing RNA-sequencing, we show that Lsd1 embryonic deficiency results in dramatic reduction of key epidermal barrier genes. Intriguingly, several of these barrier genes include those involved in lipid processing. In contrast, we find that Lsd1 deficiency upregulates Ovol2, a master transcription factor, suggesting a potential mechanism whereby Lsd1 orchestrates epidermal development through repression of Ovol2. Taken together, our data supports a pivotal role for LSD1 in establishing the embryonic skin barrier, providing insight into epigenetic regulation of skin development. This insight also opens avenues for LSD1 intervention in cutaneous diseases characterized by aberrant barrier formation.