TY - JOUR
T1 - TET2 and TET3 loss disrupts small intestine differentiation and homeostasis
AU - Ansari, Ihab
AU - Solé-Boldo, Llorenç
AU - Ridnik, Meshi
AU - Gutekunst, Julian
AU - Gilliam, Oliver
AU - Korshko, Maria
AU - Liwinski, Timur
AU - Jickeli, Birgit
AU - Weinberg-Corem, Noa
AU - Shoshkes-Carmel, Michal
AU - Pikarsky, Eli
AU - Elinav, Eran
AU - Lyko, Frank
AU - Bergman, Yehudit
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/7/6
Y1 - 2023/7/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85164191077&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-39512-3
DO - 10.1038/s41467-023-39512-3
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C2 - 37414790
AN - SCOPUS:85164191077
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4005
ER -