Abstract
TET2/3 play a well-known role in epigenetic regulation and mouse development. However, their function in cellular differentiation and tissue homeostasis remains poorly understood. Here we show that ablation of TET2/3 in intestinal epithelial cells results in a murine phenotype characterized by a severe homeostasis imbalance in the small intestine. Tet2/3-deleted mice show a pronounced loss of mature Paneth cells as well as fewer Tuft and more Enteroendocrine cells. Further results show major changes in DNA methylation at putative enhancers, which are associated with cell fate-determining transcription factors and functional effector genes. Notably, pharmacological inhibition of DNA methylation partially rescues the methylation and cellular defects. TET2/3 loss also alters the microbiome, predisposing the intestine to inflammation under homeostatic conditions and acute inflammation-induced death. Together, our results uncover previously unrecognized critical roles for DNA demethylation, possibly occurring subsequently to chromatin opening during intestinal development, culminating in the establishment of normal intestinal crypts.
| Original language | American English |
|---|---|
| Article number | 4005 |
| Journal | Nature Communications |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2023 |
Bibliographical note
Funding Information:We thank all members of our groups for helpful discussions. We thank Prof. R. Shivdasani (Dana-Farber Cancer Institute) for his generous help with providing the Paneth-specific scATAC peaks. We also thank A. Jamous and M. Canella for their assistance in performing smFISH staining and imaging, M. Jumaa for his aid with histological sample preparation, and T. Bidany-Mizrahi for her help with histological slide imaging and scanning. This work was supported by research grants from the Israel Academy of Sciences (grant #1228/18, Y.B.), the Israel Cancer Research Foundation (grant 211410, Y.B.), The Emanuel Rubin Chair in Medical Sciences (Y.B.), The Binational Science Foundation (grant # 2100289, Y.B.), the Helmholtz-Israel-Cooperation in Personalized Medicine (Y.B. and F.L.), the Helmholtz program “Aging and Metabolic Programming” (AMPro, to F.L.), the German-Israeli Foundation (grant 1424, Y.B. and F.L.) and the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel’s Ministry of Science, Technology and Space (MOST) (Y.B. and F.L.).
Funding Information:
We thank all members of our groups for helpful discussions. We thank Prof. R. Shivdasani (Dana-Farber Cancer Institute) for his generous help with providing the Paneth-specific scATAC peaks. We also thank A. Jamous and M. Canella for their assistance in performing smFISH staining and imaging, M. Jumaa for his aid with histological sample preparation, and T. Bidany-Mizrahi for her help with histological slide imaging and scanning. This work was supported by research grants from the Israel Academy of Sciences (grant #1228/18, Y.B.), the Israel Cancer Research Foundation (grant 211410, Y.B.), The Emanuel Rubin Chair in Medical Sciences (Y.B.), The Binational Science Foundation (grant # 2100289, Y.B.), the Helmholtz-Israel-Cooperation in Personalized Medicine (Y.B. and F.L.), the Helmholtz program “Aging and Metabolic Programming” (AMPro, to F.L.), the German-Israeli Foundation (grant 1424, Y.B. and F.L.) and the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel’s Ministry of Science, Technology and Space (MOST) (Y.B. and F.L.).
Publisher Copyright:
© 2023, The Author(s).