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

MPG-Autoren
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Schönberger,  Katharina
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Obier,  Nadine
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Romero-Mulero,  Mari Carmen
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Cauchy,  Pierre
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Mess,  Julian
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Pavlovich,  Polina V.
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Zhang,  Yu Wei
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Mitterer,  Michael
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Rettkowski,  Jasmin
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lalioti,  Maria-Eleni
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Jäcklein,  Karin
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Curtis,  Jonathan D.
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Trompouki,  Eirini
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons241896

Büscher,  Jörg Martin
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Pearce,  Erika Laine
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons204274

Cabezas-Wallscheid,  Nina
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Externe Ressourcen

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00414-8
(Verlagsversion)

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Zitation

Schönberger, K., Obier, N., Romero-Mulero, M. C., Cauchy, P., Mess, J., Pavlovich, P. V., et al. (2022). Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity. Cell Stem Cell, 29, 131-148. doi:10.1016/j.stem.2021.10.002.


Zitierlink: https://hdl.handle.net/21.11116/0000-000A-1100-2
Zusammenfassung
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 distinctmetabolic 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.