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Cell stem cell
01 06, 2022;29 (1): 131-148.e10.

Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity.

Katharina Schönberger, Nadine Obier, Mari Carmen Romero-Mulero, Pierre Cauchy, Julian Mess, Polina V Pavlovich, Yu Wei Zhang, Michael Mitterer, Jasmin Rettkowski, Maria-Eleni Lalioti, Karin Jäcklein, Jonathan D Curtis, Betty Féret, Pia Sommerkamp, Claudia Morganti, Keisuke Ito, Norbert B Ghyselinck, Eirini Trompouki, Joerg M Buescher, Erika L Pearce, Nina Cabezas-Wallscheid
Author Information
  1. Katharina Schönberger: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany.
  2. Nadine Obier: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  3. Mari Carmen Romero-Mulero: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  4. Pierre Cauchy: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  5. Julian Mess: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Freiburg, Germany; Centre for Integrative Biological Signalling Studies (CIBSS), Freiburg, Germany.
  6. Polina V Pavlovich: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany.
  7. Yu Wei Zhang: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany.
  8. Michael Mitterer: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  9. Jasmin Rettkowski: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Freiburg, Germany.
  10. Maria-Eleni Lalioti: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  11. Karin Jäcklein: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  12. Jonathan D Curtis: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  13. Betty Féret: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 Centre National de la Recherche Scientifique (CNRS) et Université de Strasbourg (UNISTRA), U1258 Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch, France.
  14. Pia Sommerkamp: German Cancer Research Center (DKFZ), Heidelberg, Germany.
  15. Claudia Morganti: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Departments of Cell Biology and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
  16. Keisuke Ito: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Departments of Cell Biology and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
  17. Norbert B Ghyselinck: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 Centre National de la Recherche Scientifique (CNRS) et Université de Strasbourg (UNISTRA), U1258 Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch, France.
  18. Eirini Trompouki: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  19. Joerg M Buescher: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  20. Erika L Pearce: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Johns Hopkins University, Baltimore, MD, USA.
  21. Nina Cabezas-Wallscheid: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Centre for Integrative Biological Signalling Studies (CIBSS), Freiburg, Germany. Electronic address: cabezas@ie-freiburg.mpg.de.
PMID: 34706256 DOI: 10.1016/j.stem.2021.10.002

Abstract

Hematopoietic stem cells (HSCs) rely on complex regulatory networks to preserve stemness. Due to the scarcity of HSCs, technical challenges have limited our insights into the interplay between metabolites, transcription, and the epigenome. In this study, we generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data, revealing distinct metabolic hubs that are enriched in HSCs and their downstream multipotent progenitors. Mechanistically, we uncover a non-classical retinoic acid (RA) signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Our findings emphasize that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes.

Keywords

4-oxo-RA Cyp26b1 Rarb at-RA epigenetics hematopoietic stem cells metabolites self-renewal vitamin A

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Grants

  1. R01 DK098263/NIDDK NIH HHS
  2. R01 DK115577/NIDDK NIH HHS
  3. R01 HL148852/NHLBI NIH HHS

MeSH Term

Cell Differentiation
Hematopoietic Stem Cells
Retinoic Acid 4-Hydroxylase
Signal Transduction
Tretinoin

Chemicals

Tretinoin
Retinoic Acid 4-Hydroxylase
Journal Article Research Support, Non-U.S. Gov't

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