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Cell Stem Cell. 2020 Mar 10. pii: S1934-5909(20)30017-5. doi: 10.1016/j.stem.2020.01.017. [Epub ahead of print]

C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells.

Author information

1
Aix Marseille University, CNRS, INSERM, CIML, 13009 Marseille, France.
2
Aix Marseille University, CNRS, INSERM, CIML, 13009 Marseille, France; Inovarion, 75005 Paris, France.
3
Aix Marseille University, CNRS, INSERM, CIML, 13009 Marseille, France; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307 Dresden, Germany.
4
Aix Marseille University, CNRS, INSERM, CIML, 13009 Marseille, France; Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), 13125 Berlin, Germany.
5
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
6
Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307 Dresden, Germany.
7
Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), 13125 Berlin, Germany.
8
Institute of Biology, Humboldt University of Berlin, 10115 Berlin, Germany; Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), 13125 Berlin, Germany.
9
Institut de Microbiologie de la Méditerranée, CNRS, 13009 Marseille, France.
10
Aix Marseille University, CNRS, INSERM, CIML, 13009 Marseille, France. Electronic address: sarrazin@ciml.univ-mrs.fr.
11
Aix Marseille University, CNRS, INSERM, CIML, 13009 Marseille, France; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307 Dresden, Germany; Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), 13125 Berlin, Germany. Electronic address: michael.sieweke@tu-dresden.de.

Abstract

Hematopoietic stem cells (HSCs) maintain life-long production of immune cells and can directly respond to infection, but sustained effects on the immune response remain unclear. We show that acute immune stimulation with lipopolysaccharide (LPS) induced only transient changes in HSC abundance, composition, progeny, and gene expression, but persistent alterations in accessibility of specific myeloid lineage enhancers occurred, which increased responsiveness of associated immune genes to secondary stimulation. Functionally, this was associated with increased myelopoiesis of pre-exposed HSC and improved innate immunity against the gram-negative bacterium P. aeruginosa. The accessible myeloid enhancers were enriched for C/EBPβ (targets, and C/EBPβ deletion erased the long-term inscription of LPS-induced epigenetic marks and gene expression. Thus, short-term immune signaling can induce C/EBPβ-dependent chromatin accessibility, resulting in HSC-trained immunity, during secondary infection. This establishes a mechanism for how infection history can be epigenetically inscribed in HSC as an integral memory function of innate immunity.

KEYWORDS:

C/EBPβ; HSC; epigenetic memory; innate immune response; trained immunity

PMID:
32169166
DOI:
10.1016/j.stem.2020.01.017

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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