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

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.

Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment

“…7E). Consistent with this notion, the transcription factor, CCAAT/enhancer-binding protein delta (CEBPδ) involved in macrophage differentiation 47 , was also suppressed by Minnelide (Fig. 7F).…”

The roles of toll-like receptor 4, CD33, CD68, CD69, or CD147/EMMPRIN for monocyte activation by the DAMP S100A8/S100A9

“…Thus, differentiation can be initiated via estrogen withdrawal in a controlled process and also be further modified by the type of growth factor used. Differentiation into macrophages via GM-CSF has been described as functional and efficient in several studies ( 30 , 37 , 38 , 48 ).…”

Pathogenic roles of neutrophil‐derived alarmins (S100A8/A9) in heart failure: From molecular mechanisms to therapeutic insights

“…The weighted gene co‐expression network analysis recognized S100A9 as one of the top hub genes expressed in peripheral blood mononuclear cells, correlating to the manifestation of acute myocardial infarction (Niu et al, 2019; Wang et al, 2021). Moreover, expression of S100A8 / A9 showed an even stronger association with classical, proinflammatory (CD14 ++ CD16 − ) monocytes compared to non‐classical (CD14 + CD16 ++ ) monocytes of acute myocardial infarction patients (Jauch‐Speer et al, 2022). A proteomic study further identified the S100A8 protein as one of 95 proteins that were differentially expressed in the plasma of acute myocardial infarction patients.…”

“…By contrast, when Hoxb8 cells were differentiated into the neutrophilic lineage, S100a8/a9 mRNA expression gradually increased and peaked after day 4 of the culture. This dynamic transcriptional regulation was controlled by the transcription factor CCAAT enhancer‐binding protein (C/EBP) δ‐dependent JMJD3‐mediated demethylation of histone H3 (Jauch‐Speer et al, 2022). CCAAT enhancer‐binding protein was also responsible for the up‐regulation of S100A8 gene expression in monocytic cells in response to the dexamethasone, noradrenaline, interleukins or lipopolysaccharide (LPS) stimuli (Hsu et al, 2005; Nacken et al, 2001; Suryono et al, 2006; Xu et al, 2001).…”