Histone H3 lysine-9 di-methylation (H3K9me2) and lysine-27 tri-methylation (H3K27me3) are linked to repression of gene expression, but the functions of repressive histone methylation dynamics during inflammatory responses remain enigmatic. Here, we report that lysine demethylases 7A (KDM7A) and 6A (UTX) play crucial roles in tumor necrosis factor (TNF)-α signaling in endothelial cells (ECs), where they are regulated by a novel TNF-α-responsive microRNA, miR-3679-5p. TNF-α rapidly induces co-occupancy of KDM7A and UTX at nuclear factor kappa-B (NF-κB)-associated elements in human ECs. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and are both required for activation of NF-κB-dependent inflammatory genes. Chromosome conformation capture-based methods furthermore uncover increased interactions between TNF-α-induced super enhancers at NF-κB-relevant loci, coinciding with KDM7A and UTX recruitments. Simultaneous pharmacological inhibition of KDM7A and UTX significantly reduces leukocyte adhesion in mice, establishing the biological and potential translational relevance of this mechanism. Collectively, these findings suggest that rapid erasure of repressive histone marks by KDM7A and UTX is essential for NF-κB-dependent regulation of genes that control inflammatory responses of ECs.

中文翻译：

---

H3K9和H3K27的协同去甲基化是内皮细胞快速炎症反应所必需的。

组蛋白H3赖氨酸9二甲基化（H3K9me2）和赖氨酸27三甲基化（H3K27me3）与基因表达的抑制有关，但在炎症反应过程中，抑制性组蛋白甲基化动力学的功能仍然难以捉摸。在这里，我们报道赖氨酸脱甲基酶7A（KDM7A）和6A（UTX）在内皮细胞（ECs）中的肿瘤坏死因子（TNF）-α信号传导中起着关键作用，其中它们由新型TNF-α反应性microRNA调节， miR-3679-5p。TNF-α在人EC中迅速诱导KDM7A和UTX在核因子kappa-B（NF-κB）相关元件上共存。KDM7A和UTX分别使H3K9me2和H3K27me3去甲基化，并且都是激活NF-κB依赖性炎症基因所必需的。此外，基于染色体构象捕获的方法还揭示了TNF-α诱导的超增强子在NF-κB相关基因座之间增加的相互作用，与KDM7A和UTX募集相吻合。对KDM7A和UTX的同时药理抑制作用显着降低了小鼠中的白细胞粘附，建立了该机制的生物学和潜在翻译相关性。总而言之，这些发现表明，KDM7A和UTX快速清除抑制性组蛋白标记对于依赖NF-κB的调控EC炎症反应基因的调节至关重要。