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Nature cell biology
09, 2022;24 (9): 1350-1363.

Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity.

A Huyghe, G Furlan, J Schroeder, E Cascales, A Trajkova, M Ruel, F Stüder, M Larcombe, Y Bo Yang Sun, F Mugnier, L De Matteo, A Baygin, J Wang, Y Yu, N Rama, B Gibert, J Kielbassa, L Tonon, P Wajda, N Gadot, M Brevet, M Siouda, P Mulligan, R Dante, P Liu, H Gronemeyer, M Mendoza-Parra, J M Polo, F Lavial
Author Information
  1. A Huyghe: Cellular Reprogramming, Stem Cells and Oncogenesis Laboratory, Equipe Labellisée la Ligue Contre le Cancer, LabEx Dev2Can, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France. aurelia.huyghe@lyon.unicancer.fr. ORCID
  2. G Furlan: Cellular Reprogramming, Stem Cells and Oncogenesis Laboratory, Equipe Labellisée la Ligue Contre le Cancer, LabEx Dev2Can, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
  3. J Schroeder: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Clayton, Australia.
  4. E Cascales: Cellular Reprogramming, Stem Cells and Oncogenesis Laboratory, Equipe Labellisée la Ligue Contre le Cancer, LabEx Dev2Can, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
  5. A Trajkova: Cellular Reprogramming, Stem Cells and Oncogenesis Laboratory, Equipe Labellisée la Ligue Contre le Cancer, LabEx Dev2Can, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
  6. M Ruel: Cellular Reprogramming, Stem Cells and Oncogenesis Laboratory, Equipe Labellisée la Ligue Contre le Cancer, LabEx Dev2Can, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
  7. F Stüder: Génomique Métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Université d'Évry, Université Paris-Saclay, Évry, France. ORCID
  8. M Larcombe: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Clayton, Australia.
  9. Y Bo Yang Sun: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Clayton, Australia.
  10. F Mugnier: Cellular Reprogramming, Stem Cells and Oncogenesis Laboratory, Equipe Labellisée la Ligue Contre le Cancer, LabEx Dev2Can, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
  11. L De Matteo: Cellular Reprogramming, Stem Cells and Oncogenesis Laboratory, Equipe Labellisée la Ligue Contre le Cancer, LabEx Dev2Can, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
  12. A Baygin: Cellular Reprogramming, Stem Cells and Oncogenesis Laboratory, Equipe Labellisée la Ligue Contre le Cancer, LabEx Dev2Can, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
  13. J Wang: Wellcome Trust Sanger Institute, Cambridge, UK.
  14. Y Yu: Wellcome Trust Sanger Institute, Cambridge, UK.
  15. N Rama: Apoptosis, Cancer and Development Laboratory, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France. ORCID
  16. B Gibert: Apoptosis, Cancer and Development Laboratory, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France. ORCID
  17. J Kielbassa: Gilles Thomas Bioinformatics Platform, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.
  18. L Tonon: Gilles Thomas Bioinformatics Platform, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.
  19. P Wajda: Cellular Reprogramming, Stem Cells and Oncogenesis Laboratory, Equipe Labellisée la Ligue Contre le Cancer, LabEx Dev2Can, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
  20. N Gadot: Research Pathology Platform, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France.
  21. M Brevet: Department of Pathology, HCL Cancer Institute and Université Claude Bernard Lyon 1, Lyon, France. ORCID
  22. M Siouda: Epigenetics and cancer Laboratory - Lyon University, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.
  23. P Mulligan: Epigenetics and cancer Laboratory - Lyon University, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.
  24. R Dante: Apoptosis, Cancer and Development Laboratory, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.
  25. P Liu: Wellcome Trust Sanger Institute, Cambridge, UK. ORCID
  26. H Gronemeyer: Institut de génétique et de biologie moléculaire et Cellulaire, CNRS UMR 7104 INSERM, Strasbourg, France. ORCID
  27. M Mendoza-Parra: Génomique Métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Université d'Évry, Université Paris-Saclay, Évry, France.
  28. J M Polo: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Clayton, Australia. ORCID
  29. F Lavial: Cellular Reprogramming, Stem Cells and Oncogenesis Laboratory, Equipe Labellisée la Ligue Contre le Cancer, LabEx Dev2Can, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France. fabrice.lavial@lyon.unicancer.fr. ORCID
PMID: 36075976 DOI: 10.1038/s41556-022-00986-w

Abstract

Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. However, the sequences of events that orchestrate these intermingled modifications have never been comparatively dissected. Here, we deconvolute the cellular trajectories of reprogramming (via Oct4/Sox2/Klf4/c-Myc) and transformation (via Ras/c-Myc) at the single-cell resolution and reveal how the two processes intersect before they bifurcate. This approach led us to identify the transcription factor Bcl11b as a broad-range regulator of cell fate changes, as well as a pertinent marker to capture early cellular intermediates that emerge simultaneously during reprogramming and transformation. Multiomics characterization of these intermediates unveiled a c-Myc/Atoh8/Sfrp1 regulatory axis that constrains reprogramming, transformation and transdifferentiation. Mechanistically, we found that Atoh8 restrains cellular plasticity, independent of cellular identity, by binding a specific enhancer network. This study provides insights into the partitioned control of cellular plasticity and identity for both regenerative and cancer biology.

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MeSH Term

Cell Plasticity
Cellular Reprogramming
Induced Pluripotent Stem Cells
Octamer Transcription Factor-3
SOXB1 Transcription Factors
Transcription Factors
Tumor Suppressor Proteins

Chemicals

Octamer Transcription Factor-3
SOXB1 Transcription Factors
Transcription Factors
Tumor Suppressor Proteins
Journal Article Research Support, Non-U.S. Gov't
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