LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth. It is unclear how neonatal intestinal epithelial development is regulated. We found that Lysine-specific demethylase 1A (Kdm1a/Lsd1) is required for the postnatal maturation of crypts, including Paneth cell differentiation. Lsd1-deficient epithelium retains a neonatal state into adulthood, which is beneficial for repair after irradiation injury. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form and maintain organoids. Mechanistically, we find a spatiotemporal expression of LSD1 during crypt formation, and LSD1 represses genes that are normally expressed in fetal and neonatal epithelium. Surprisingly, we could not link the transcriptional control by LSD1 functionally to fetal- or neonatal specific H3K4me1 sites. Nevertheless, enzymatic inhibition of LSD1 also leads to a loss of Paneth cells and increase in LGR5-expressing cells in human organoids. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium towards a reparative state.