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
-
monocyte subpopulation profilingNCBI BioProject, PRJNA706411.
-
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.
Metrics
-
- 1,488
- views
-
- 280
- downloads
-
- 14
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9
eLife 11:e75594.
https://doi.org/10.7554/eLife.75594
Further reading
-
- Cell Biology
Existence of cilia in the last eukaryotic common ancestor raises a fundamental question in biology: how the transcriptional regulation of ciliogenesis has evolved? One conceptual answer to this question is by an ancient transcription factor regulating ciliary gene expression in both uni- and multicellular organisms, but examples of such transcription factors in eukaryotes are lacking. Previously, we showed that an ancient transcription factor X chromosome-associated protein 5 (Xap5) is required for flagellar assembly in Chlamydomonas. Here, we show that Xap5 and Xap5-like (Xap5l) are two conserved pairs of antagonistic transcription regulators that control ciliary transcriptional programs during spermatogenesis. Male mice lacking either Xap5 or Xap5l display infertility, as a result of meiotic prophase arrest and sperm flagella malformation, respectively. Mechanistically, Xap5 positively regulates the ciliary gene expression by activating the key regulators including Foxj1 and Rfx families during the early stage of spermatogenesis. In contrast, Xap5l negatively regulates the expression of ciliary genes via repressing these ciliary transcription factors during the spermiogenesis stage. Our results provide new insights into the mechanisms by which temporal and spatial transcription regulators are coordinated to control ciliary transcriptional programs during spermatogenesis.
-
- Cell Biology
Chemokine receptors are GPCRs that regulate the chemotactic migration of a wide variety of cells including immune and cancer cells. Most chemokine receptors contain features associated with the ability to stimulate G protein signaling during β-arrestin-mediated receptor internalization into endosomes. As endosomal signaling of certain non-GPCR receptors plays a major role in cell migration, we chose to investigate the potential role of endosomal chemokine receptor signaling on mechanisms governing this function. Applying a combination of pharmacological and cell biological approaches, we demonstrate that the model chemokine receptor CCR7 recruits G protein and β-arrestin simultaneously upon chemokine stimulation, which enables internalized receptors to activate G protein from endosomes. Furthermore, spatiotemporal-resolved APEX2 proteome profiling shows that endosomal CCR7 uniquely enriches specific Rho GTPase regulators as compared to plasma membrane CCR7, which is directly associated with enhanced activity of the Rho GTPase Rac1 and chemotaxis of immune T cells. As Rac1 drives the formation of membrane protrusions during chemotaxis, our findings suggest an important integrated function of endosomal chemokine receptor signaling in cell migration.
