C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9
- University of Münster, Germany
- University Hospital Münster, Germany
- University Hospital Marburg, Germany
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
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monocyte subpopulation profilingNCBI BioProject, PRJNA706411.
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ATAC-seq in precursor and differentiated ER-Hoxb8 cellsNCBI Gene Expression Omnibus, GSE200730.
Article and author information
Author details
Marisol Herrera-Rivero
Achmet Imam Chasan
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.
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.
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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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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