Institute of Immunology, University of Münster, Münster, Germany.
Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.
Elife. 2022 May 11;11:e75594. doi: 10.7554/eLife.75594.
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 and 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 and 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. and 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 and promoter regions, and demonstrated that C/EBPδ-dependent JMJD3-mediated demethylation of H3K27me is indispensable for their expression. Overall, our work uncovered C/EBPδ as a novel regulator of and expression. Therefore, C/EBPδ represents a promising target for modulation of inflammatory conditions that are characterized by and overexpression.
促炎警报素 S100A8 和 S100A9 是中性粒细胞和单核细胞中最丰富的蛋白质之一，但在分化为巨噬细胞后完全沉默。然而， 和 基因转录调控的分子机制仅略知一二。我们使用一种无偏基因组范围的 CRISPR/Cas9 敲除 (KO) 基于筛选的方法在永生化的鼠单核细胞中鉴定了转录因子 C/EBPδ 是 和 表达的中央调节剂。我们表明，在急性肺炎症的小鼠模型中，C/EBPδ KO 小鼠中 S100A8/A9 的表达以及中性粒细胞募集和细胞因子释放减少。C/EBPδ 拮抗剂 ATF3 和 FBXW7 进一步控制 和 的表达。我们在心血管疾病患者的临床队列中，在人类单核细胞的亚群中证实了该调控网络的临床相关性。此外，我们在 和 启动子区域内鉴定了特定的 C/EBPδ 结合位点，并证明了 C/EBPδ 依赖性 JMJD3 介导的 H3K27me 去甲基化对于它们的表达是必不可少的。总的来说，我们的工作揭示了 C/EBPδ 是 和 表达的新型调节剂。因此，C/EBPδ 代表了调节以 和 过表达为特征的炎症状态的有前途的靶标。
