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.
| Original language | English |
|---|---|
| Article number | eabc0367 |
| Number of pages | 14 |
| Journal | Science advances |
| Volume | 6 |
| Issue number | 37 |
| DOIs | |
| Publication status | Published - 11 Sept 2020 |
Funding
We thank S. Orkin, S. Robine, and S. Piccolo for sharing mouse strains. We thank C. Zaph for the initial support of this study and critical reading of the manuscript. We thank U. Nonstad for assistance with cell sorting. We are indebted to A. Marthinsen for performing the irradiation after working hours and to the Department of Radiology and Nuclear Medicine (St. Olavs Hospital) for allowing the use of their instruments. We thank the imaging (CMIC) and animal care (CoMed) core facilities that assisted in this work (NTNU). The WT KO crypt RNA-seq was done by the Genomics Core Facility at NTNU, which receives funding from the Faculty of Medicine and Health Sciences and Central Norway Regional Health Authority. The ChIP sequencing was done at the Norwegian Sequencing Centre (www.sequencing.uio.no), a national technology platform hosted by the University of Oslo and supported by the “Functional Genomics” and “Infrastructure” programs of the Research Council of Norway and the Southeastern Regional Health Authorities. Funding of this work was provided by the Norwegian Research Council (Centre of Excellence grant 223255/ F50 and “Young Research Talent” 274760 to M.J.O.) and the Norwegian Cancer Society (182767 to M.J.O.). M.M.-A. is the recipient of a Marie Skłodowska-Curie IF (DLV-794391). This work was also supported by the South-Eastern Norway Regional Health Authority, Early Career Grant 2016058, and the Research Council of Norway “Young Research Talent” grant to J.A.D. M.F. is supported by the Norwegian Research Council (grant no. 275286). The SGC is a registered charity (number 1097737) that receives funds from AbbVie; Bayer Pharma AG; Boehringer Ingelheim; Canada Foundation for Innovation; Eshelman Institute for Innovation; Genome Canada through Ontario Genomics Institute (OGI-055); Innovative Medicines Initiative (EU/ EFPIA) (ULTRA-DD grant no. 115766); Janssen; Merck KGaA, Darmstadt, Germany; MSD; Novartis Pharma AG; Ontario Ministry of Research, Innovation and Science (MRIS); Pfizer; São Paulo Research Foundation-FAPESP; Takeda; and Wellcome. This project also received funding from the European Union’s Horizon 2020 research and innovation programme (grant agreement INTENS 668294 to M.T.P. and K.B.J.). The Novo Nordisk Foundation Center for Stem Cell Biology is supported by Novo Nordisk Foundation grant number NNF17CC0027852
| Funders | Funder number |
|---|---|
| CMIC | |
| Centre of Excellence | 223255/ F50, 274760 |
| Department of Radiology and Nuclear Medicine | |
| Faculty of Medicine and Health Sciences and Central Norway Regional Health Authority | |
| Marie Skłodowska-Curie IF | DLV-794391 |
| Southeastern Regional Health Authorities | |
| ULTRA-DD | 115766 |
| Pfizer | |
| Bayer | |
| Boehringer Ingelheim | |
| Takeda Pharmaceutical Company | |
| Kreftforeningen | 182767 |
| Genome Canada | |
| Novartis Pharma | |
| Janssen Pharmaceuticals | |
| Norges Teknisk-Naturvitenskapelige Universitet | |
| Eshelman Institute for Innovation, University of North Carolina at Chapel Hill | |
| Merck KGaA | |
| Wellcome Trust | |
| Horizon 2020 Framework Programme | 668294, 794391 |
| European Federation of Pharmaceutical Industries and Associations | |
| Ontario Genomics Institute | OGI-055 |
| Canada Foundation for Innovation | |
| European Commission | |
| Ontario Ministry of Research, Innovation and Science | |
| Norges forskningsråd | |
| Helse Sør-Øst RHF | 275286, 1097737, 2016058 |
| Novo Nordisk Fonden | NNF17CC0027852 |
| Innovative Medicines Initiative |
