1. Cell Biology

C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9

  1. Saskia-Larissa Jauch-Speer
  2. Marisol Herrera-Rivero
  3. Nadine Ludwig
  4. Bruna Caroline Véras De Carvalho
  5. Leonie Martens
  6. Jonas Wolf
  7. Achmet Imam Chasan
  8. Anika Witten
  9. Birgit Markus
  10. Bernhard Schieffer
  11. Thomas Vogl
  12. Jan Rossaint
  13. Monika Stoll
  14. Johannes Roth  Is a corresponding author
  15. Olesja Fehler
  1. University of Münster, Germany
  2. University Hospital Münster, Germany
  3. University Hospital Marburg, Germany
https://doi.org/10.7554/eLife.75594
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Cite this article
  1. Saskia-Larissa Jauch-Speer
  2. Marisol Herrera-Rivero
  3. Nadine Ludwig
  4. Bruna Caroline Véras De Carvalho
  5. Leonie Martens
  6. Jonas Wolf
  7. Achmet Imam Chasan
  8. Anika Witten
  9. Birgit Markus
  10. Bernhard Schieffer
  11. Thomas Vogl
  12. Jan Rossaint
  13. Monika Stoll
  14. Johannes Roth
  15. Olesja Fehler
(2022)
C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9
eLife 11:e75594.
https://doi.org/10.7554/eLife.75594
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Abstract

The proinflammatory alarmins S100A8 and S100A9 are among the most abundant proteins in neutrophils and monocytes but are completely silenced after differentiation to macrophages. The molecular mechanisms of the extraordinarily dynamic transcriptional regulation of S100a8 and S100a9 genes, however, are only barely understood. Using an unbiased genome-wide CRISPR/Cas9 knockout based screening approach in immortalized murine monocytes we identified the transcription factor C/EBPδ as a central regulator of S100a8 and S100a9 expression. We showed that S100A8/A9 expression and thereby neutrophil recruitment and cytokine release were decreased in C/EBPδ KO mice in a mouse model of acute lung inflammation. S100a8 and S100a9 expression was further controlled by the C/EBPδ-antagonists ATF3 and FBXW7. We confirmed the clinical relevance of this regulatory network in subpopulations of human monocytes in a clinical cohort of cardiovascular patients. Moreover, we identified specific C/EBPδ-binding sites within S100a8 and S100a9 promoter regions, and demonstrated that C/EBPδ-dependent JMJD3-mediated demethylation of H3K27me3 is indispensable for their expression. Overall, our work uncovered C/EBPδ as a novel regulator of S100a8 and S100a9 expression. Therefore, C/EBPδ represents a promising target for modulation of inflammatory conditions that are characterised by S100a8 and S100a9 overexpression.

Data availability

data and code availabilityhttps://www.ncbi.nlm.nih.gov/bioproject/PRJNA754262https://www.ncbi.nlm.nih.gov/bioproject/PRJNA706411https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE200730

The following data sets were generated

Article and author information

Author details

  1. Saskia-Larissa Jauch-Speer

    Institute of Immunology, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.

  2. Marisol Herrera-Rivero

    Department of Genetic Epidemiology, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7064-9487

  3. Nadine Ludwig

    Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.

  4. Bruna Caroline Véras De Carvalho

    Institute of Immunology, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.

  5. Leonie Martens

    Institute of Immunology, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.

  6. Jonas Wolf

    Institute of Immunology, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.

  7. Achmet Imam Chasan

    Institute of Immunology, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5137-6890

  8. Anika Witten

    Department of Genetic Epidemiology, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.

  9. Birgit Markus

    Clinic for Cardiology, Angiology and Internal Intensive Medicine, University Hospital Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.

  10. Bernhard Schieffer

    Clinic for Cardiology, Angiology and Internal Intensive Medicine, University Hospital Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.

  11. Thomas Vogl

    Institute of Immunology, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.

  12. Jan Rossaint

    Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.

  13. Monika Stoll

    Department of Genetic Epidemiology, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.

  14. Johannes Roth

    Institute of Immunology, University of Münster, Münster, Germany
    For correspondence
    rothj@uni-muenster.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7035-8348

  15. Olesja Fehler

    Institute of Immunology, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6386-7080

Funding

Deutsche Forschungsgemeinschaft (CRC 1009 B9)

  • Johannes Roth

Deutsche Forschungsgemeinschaft (CRC 1009 Z2)

  • Johannes Roth

Deutsche Forschungsgemeinschaft (CRC 1009 B8)

  • Thomas Vogl

Deutsche Forschungsgemeinschaft (CRU 342 P3)

  • Johannes Roth

Deutsche Forschungsgemeinschaft (RO 1190/14-1)

  • Johannes Roth

Deutsche Forschungsgemeinschaft (CRU 342 P5)

  • Thomas Vogl

Interdisciplinary Center of Clinical Research at the University of Münster (Ro2/023/19)

  • Johannes Roth

Interdisciplinary Center of Clinical Research at the University of Münster (Vo2/011/19)

  • Thomas Vogl

EU EFRE Bio NRW programme (005-1007-0006)

  • Monika Stoll

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jalees Rehman, University of Illinois at Chicago, United States

Ethics

Animal experimentation: Mouse experiments were in accordance with German Animal Welfare Legislation and performed as approved by the North Rhine-Westphalia Office of Nature, Environment and Consumer Protection (LANUV) and the District Government and District Veterinary Office Muenster under the reference number 81-02.04.2019.A445.

Human subjects: The BioNRW Study is conducted in accordance with the guidelines of the Declaration of Helsinki. The research protocol, including the case report forms, was approved by the local ethics committee (#245-12). Written informed consent was obtained from all study participants.

Version history

  1. Received: November 16, 2021
  2. Preprint posted: December 9, 2021 (view preprint)
  3. Accepted: May 6, 2022
  4. Accepted Manuscript published: May 11, 2022 (version 1)
  5. Version of Record published: May 20, 2022 (version 2)

Copyright

© 2022, Jauch-Speer et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Saskia-Larissa Jauch-Speer
  2. Marisol Herrera-Rivero
  3. Nadine Ludwig
  4. Bruna Caroline Véras De Carvalho
  5. Leonie Martens
  6. Jonas Wolf
  7. Achmet Imam Chasan
  8. Anika Witten
  9. Birgit Markus
  10. Bernhard Schieffer
  11. Thomas Vogl
  12. Jan Rossaint
  13. Monika Stoll
  14. Johannes Roth
  15. Olesja Fehler
(2022)
C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9
eLife 11:e75594.
https://doi.org/10.7554/eLife.75594

Share this article

https://doi.org/10.7554/eLife.75594

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