2. Academic Validation
  3. Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells

Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells

  • Nat Commun. 2022 Sep 29;13(1):5726. doi: 10.1038/s41467-022-33147-6.
Sarah Tessier # 1 2 3,  Omar Ferhi # 1 2,  Marie-Claude Geoffroy # 1 2,  Román González-Prieto 4 5,  Antoine Canat 2 6,  Samuel Quentin 2 7,  Marika Pla 8,  Michiko Niwa-Kawakita 2,  Pierre Bercier 1 2,  Domitille Rérolle 1 2,  Pierre Therizols 2,  Emmanuelle Fabre 2,  Alfred C O Vertegaal 4,  Hugues de Thé 9 10 11,  Valérie Lallemand-Breitenbach 12 13
Affiliations

Affiliations

  • 1 Center for Interdisciplinary Research in Biology (CIRB), Collège de France, PSL research university, Inserm, Cnrs, 11 place Marcelin Berthelot, 75005, Paris, France.
  • 2 Université Paris Cité, Inserm, CNRS, GenCellDis, Institut de Recherche Saint-Louis, F-75010, Paris, France.
  • 3 Honing Biosciences, Hôpital Saint Louis, 16, rue de la Grange aux Belles, 75010, Paris, France.
  • 4 Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Einthovenweg 20, 2333, ZC, Leiden, The Netherlands.
  • 5 Genome Proteomics laboratory, Department of Cell Biology, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Seville, Seville, Spain.
  • 6 Institute of Epigenetics and Stem Cells (IES), Helmholtz Zentrum München, Feodor-Lynen-Straße 21, 81377, München, Germany.
  • 7 Service de Hématologie, AP-HP, Hôpital St. Louis, F-75010, Paris, France.
  • 8 Normal and pathological hematopoiesis: Emergence, Environment and translational research, Université de Paris Cité, Inserm, IRSL, F-75010, Paris, France.
  • 9 Center for Interdisciplinary Research in Biology (CIRB), Collège de France, PSL research university, Inserm, Cnrs, 11 place Marcelin Berthelot, 75005, Paris, France. hugues.dethe@inserm.fr.
  • 10 Université Paris Cité, Inserm, CNRS, GenCellDis, Institut de Recherche Saint-Louis, F-75010, Paris, France. hugues.dethe@inserm.fr.
  • 11 Service de Hématologie, AP-HP, Hôpital St. Louis, F-75010, Paris, France. hugues.dethe@inserm.fr.
  • 12 Center for Interdisciplinary Research in Biology (CIRB), Collège de France, PSL research university, Inserm, Cnrs, 11 place Marcelin Berthelot, 75005, Paris, France. valerie.lallemand@inserm.fr.
  • 13 Université Paris Cité, Inserm, CNRS, GenCellDis, Institut de Recherche Saint-Louis, F-75010, Paris, France. valerie.lallemand@inserm.fr.
  • # Contributed equally.
PMID: 36175410 DOI: 10.1038/s41467-022-33147-6
Abstract

Membrane-less organelles are condensates formed by phase separation whose functions often remain enigmatic. Upon oxidative stress, PML scaffolds Nuclear Bodies (NBs) to regulate senescence or metabolic adaptation. PML NBs recruit many partner proteins, but the actual biochemical mechanism underlying their pleiotropic functions remains elusive. Similarly, PML role in embryonic stem cell (ESC) and retro-element biology is unsettled. Here we demonstrate that PML is essential for oxidative stress-driven partner SUMO2/3 conjugation in mouse ESCs (mESCs) or leukemia, a process often followed by their poly-ubiquitination and degradation. Functionally, PML is required for stress responses in mESCs. Differential proteomics unravel the KAP1 complex as a PML NB-dependent SUMO2-target in arsenic-treated APL mice or mESCs. PML-driven KAP1 sumoylation enables activation of this key epigenetic repressor implicated in retro-element silencing. Accordingly, Pml-/- mESCs re-express transposable elements and display 2-Cell-Like features, the latter enforced by PML-controlled SUMO2-conjugation of DPPA2. Thus, PML orchestrates mESC state by coordinating SUMO2-conjugation of different transcriptional regulators, raising new hypotheses about PML roles in Cancer.

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