TET activity safeguards pluripotency throughout embryonic dormancy

  • Nat Struct Mol Biol. 2024 May 23. doi: 10.1038/s41594-024-01313-7.
Maximilian Stötzel  1  2 ,  Chieh-Yu Cheng  1  2 ,  Ibrahim A IIik  3 ,  Abhishek Sampath Kumar  2  4 ,  Persia Akbari Omgba  1  5 ,  Vera A van der Weijden  1 ,  Yufei Zhang  6 ,  Martin Vingron  6 ,  Alexander Meissner  4 ,  Tuğçe Aktaş  3 ,  Helene Kretzmer  4 ,  Aydan Bulut-Karslioğlu  7
Affiliations
  • 1. Stem Cell Chromatin Lab, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 2. Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany.
  • 3. Otto Warburg Laboratories, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 4. Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 5. Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany.
  • 6. Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 7. Stem Cell Chromatin Lab, Max Planck Institute for Molecular Genetics, Berlin, Germany. [email protected].
PMID: 38783076 DOI: 10.1038/s41594-024-01313-7
Abstract

Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus in a dormant state called diapause, which can be induced in vitro through mTOR inhibition. Cellular strategies that safeguard original cell identity within the silent genomic landscape of dormancy are not known. Here we show that the protection of cis-regulatory elements from silencing is key to maintaining pluripotency in the dormant state. We reveal a TET-transcription factor axis, in which TET-mediated DNA demethylation and recruitment of methylation-sensitive transcription factor TFE3 drive transcriptionally inert chromatin adaptations during dormancy transition. Perturbation of TET activity compromises pluripotency and survival of mouse embryos under dormancy, whereas its enhancement improves survival rates. Our results reveal an essential mechanism for propagating the cellular identity of dormant cells, with implications for regeneration and disease.

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