Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells
Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells
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DOI：
10.15252/embj.2019103949
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发表时间：
2020-03-03
期刊：
影响因子：
11.4
通讯作者：
Kanki, Yasuharu
中科院分区：
文献类型：
--
作者：
Higashijima, Yoshiki;Matsui, Yusuke;Kanki, Yasuharu
组蛋白H3赖氨酸-9二甲基化（H3 K9 me 2）和赖氨酸-27三甲基化（H3 K27 me 3）与基因表达的抑制有关，但在炎症反应期间抑制性组蛋白甲基化动力学的功能仍然是个谜。在这里，我们报告了赖氨酸脱甲基酶7A（KDM 7A）和6A（UTX）在内皮细胞（EC）中的肿瘤坏死因子（TNF）-α信号转导中起着至关重要的作用，在那里它们受到一种新型TNF-α响应性microRNA miR-3679- 5 p的调控。TNF-α快速诱导KDM 7A和UTX在人EC中核因子κ-B（NF-κ B）相关元件处的共占据。KDM 7A和UTX分别使H3 K9 me 2和H3 K27 me 3去甲基化，并且都是NF-κ B依赖性炎症基因激活所需的。基于染色体构象捕获的方法进一步揭示了TNF-α诱导的超级增强子在NF-κ B相关基因座上的相互作用增加，与KDM 7A和UTX募集一致。同时药理学抑制KDM 7A和UTX显著降低小鼠中的白细胞粘附，确立了该机制的生物学和潜在翻译相关性。总的来说，这些研究结果表明，KDM 7A和UTX快速擦除抑制性组蛋白标记对于控制EC炎症反应的基因的NF-κ B依赖性调节至关重要。
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)-alpha signaling in endothelial cells (ECs), where they are regulated by a novel TNF-alpha-responsive microRNA, miR-3679-5p. TNF-alpha rapidly induces co-occupancy of KDM7A and UTX at nuclear factor kappa-B (NF-kappa B)-associated elements in human ECs. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and are both required for activation of NF-kappa B-dependent inflammatory genes. Chromosome conformation capture-based methods furthermore uncover increased interactions between TNF-alpha-induced super enhancers at NF-kappa B-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-kappa B-dependent regulation of genes that control inflammatory responses of ECs.