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. PearceNina Cabezas-Wallscheid

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)131-148.e10
JournalCell Stem Cell
Volume29
Issue number1
DOIs
StatePublished - Jan 6 2022

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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