PT  - JOURNAL ARTICLE
AU  - Saskia-L. Jauch-Speer
AU  - Jonas Wolf
AU  - Marisol Herrera-Rivero
AU  - Leonie Martens
AU  - Achmet Imam Chasan
AU  - Anika Witten
AU  - Birgit Markus
AU  - Bernhard Schieffer
AU  - Thomas Vogl
AU  - Monika Stoll
AU  - Johannes Roth
AU  - Olesja Fehler
TI  - C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100A8 and S100A9
AID  - 10.1101/2021.12.05.471309
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.05.471309
4099  - http://biorxiv.org/content/early/2021/12/09/2021.12.05.471309.short
4100  - http://biorxiv.org/content/early/2021/12/09/2021.12.05.471309.full
AB  - The proinflammatory alarmins S100A8 and S100A9 are among the most abundant proteins in neutrophils and monocytes but 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. 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.Competing Interest StatementThe authors have declared no competing interest.