TET2 and TET3 loss disrupts small intestine differentiation and homeostasis

Ihab Ansari, Llorenç Solé-Boldo, Meshi Ridnik, Julian Gutekunst, Oliver Gilliam, Maria Korshko, Timur Liwinski, Birgit Jickeli, Noa Weinberg-Corem, Michal Shoshkes-Carmel, Eli Pikarsky, Eran Elinav, Frank Lyko and Yehudit Bergman ()
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Ihab Ansari: Hebrew University Medical School
Llorenç Solé-Boldo: German Cancer Research Center
Meshi Ridnik: Hebrew University Medical School
Julian Gutekunst: German Cancer Research Center
Oliver Gilliam: German Cancer Research Center
Maria Korshko: Hebrew University Medical School
Timur Liwinski: The Weizmann Institute of Science
Birgit Jickeli: The Weizmann Institute of Science
Noa Weinberg-Corem: Hebrew University Medical School
Michal Shoshkes-Carmel: Hebrew University Medical School
Eli Pikarsky: Hebrew University Medical School
Eran Elinav: The Weizmann Institute of Science
Frank Lyko: German Cancer Research Center
Yehudit Bergman: Hebrew University Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39512-3

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