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TET2 and TET3 loss disrupts small intestine differentiation and homeostasis

Author

Listed:
  • 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
    University Psychiatric Clinics Basel, Clinic for Adults, University of Basel)

  • 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
    German Cancer Research Center (DKFZ))

  • Frank Lyko

    (German Cancer Research Center)

  • Yehudit Bergman

    (Hebrew University Medical School)

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.

Suggested Citation

  • 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 & Era, 2023. "TET2 and TET3 loss disrupts small intestine differentiation and homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39512-3
    DOI: 10.1038/s41467-023-39512-3
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