LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium
Open Access
- 11 September 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 6 (37), eabc0367
- https://doi.org/10.1126/sciadv.abc0367
Abstract
Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell–skewed organoid cultures. We found that lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 enzymatically represses genes that are normally expressed only in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium toward a reparative state.Funding Information
- Kreftforeningen (182767)
- H2020 Marie Skłodowska-Curie Actions (DLV-794391)
- Norges Forskningsråd (274760)
- Norges Forskningsråd (275286)
- Norges Forskningsråd (223255/F50)
- Horizon 2020 (668294)
- Novo Nordisk Fonden (NNF17CC0027852)
- Norway Regional Health Authority (2016058)
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