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

Saskia-Larissa Jauch-Speer, Marisol Herrera-Rivero, Nadine Ludwig, Bruna Caroline Véras De Carvalho, Leonie Martens, Jonas Wolf, Achmet Imam Chasan, Anika Witten, Birgit Markus, Bernhard Schieffer, Thomas Vogl, Jan Rossaint, Monika Stoll, Johannes Roth, Olesja Fehler

Research output: Contribution to journalArticleAcademicpeer-review

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 (KO)-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 characterized by S100a8 and S100a9 overexpression.

Original languageEnglish
Article number75594
Number of pages33
JournalElife
Volume11
DOIs
Publication statusPublished - 11 May 2022

Keywords

  • A9
  • ACTIVATION
  • ARTHRITIS
  • Alarmins
  • Animals
  • BINDING-PROTEIN-DELTA
  • C
  • C/EBP-DELTA
  • CCAAT-Enhancer-Binding Protein-delta/genetics
  • CELLS
  • CRISPR
  • Calgranulin A/genetics
  • Calgranulin B/genetics
  • Cas9 screen
  • EBP delta
  • EXPRESSION
  • Epigenesis, Genetic
  • INFLAMMATION
  • JMJD3
  • MRP14
  • Mice
  • Mouse
  • S100A8
  • SCALE CRISPR-CAS9 KNOCKOUT
  • Transcription, Genetic
  • calprotectin
  • human
  • monocytes
  • BETA

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