Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Joint National Laboratory for Antibody Drug Engineering, Institute of Immunology, Henan University School of Medicine, Kaifeng 475004, China.
National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
J Autoimmun. 2017 Jun;80:85-94. doi: 10.1016/j.jaut.2017.02.007. Epub 2017 Mar 8.
Molecular regulation of innate signal-initiated proinflammatory cytokine production has been extensively investigated. However, the roles of epigenetic modifiers and their underlying mechanisms in regulating innate inflammatory response and development of autoimmune diseases need to be further understood. Demethylase Kdm6a promotes gene transcription in cell-lineage specification through demethylating histone H3 lysine di/tri-methylation (H3K27me2/3), and loss of Kdm6a results in developmental defects. However, the function of Kdm6a in innate immunity and inflammation remains largely unknown. Here we found that Kdm6a, significantly downregulated via JNK pathway upon innate stimuli, promotes cytokine IL-6 and IFN-β transcription in primary macrophages during innate response. Kdm6a promoted IL-6 expression through demethylating H3K27me3 at promoter in a demethylase enzymatic activity-dependent manner. Interestingly, Kdm6a promoted IFN-β expression independent of its demethylase enzymatic activity, but through increasing transcription of IFN-β-specific enhancer-derived RNA (eRNA) S-IRE1. For the underlying mechanism, Kdm6a interacted with MLL4 and promoted MLL4 recruitment and H3K4me2 level in S-IRE1 region of Ifnb1 gene for full activation of enhancer. Our results reveal a previously unknown role of kdm6a in promoting innate IFN-β gene transcription at enhancer, in addition to demethylation at promoter. The function of Kdm6a in promoting innate inflammatory response also adds insights to better understanding of epigenetic modifiers in inflammatory and autoimmune disease.
已广泛研究了先天信号引发的促炎性细胞因子产生的分子调控。然而，需要进一步了解表观遗传修饰剂及其潜在机制在调节先天炎症反应和自身免疫性疾病发展中的作用。去甲基酶 Kdm6a 通过去甲基化组蛋白 H3 赖氨酸二/三甲基化（H3K27me2/3）促进细胞谱系特化中的基因转录，而 Kdm6a 的缺失会导致发育缺陷。然而，Kdm6a 在先天免疫和炎症中的功能在很大程度上仍未知。在这里，我们发现先天刺激会通过 JNK 途径显著下调 Kdm6a，从而促进先天反应中原代巨噬细胞中细胞因子 IL-6 和 IFN-β 的转录。Kdm6a 通过依赖于去甲基酶酶活性的方式在启动子处去甲基化 H3K27me3 来促进 IL-6 的表达。有趣的是，Kdm6a 通过增加 IFN-β 特异性增强子衍生 RNA（eRNA）S-IRE1 的转录，从而促进 IFN-β 的表达，而不依赖于其去甲基酶酶活性。对于潜在机制，Kdm6a 与 MLL4 相互作用，并促进 MLL4 在 Ifnb1 基因的 S-IRE1 区域募集和 H3K4me2 水平，以完全激活增强子。我们的结果揭示了 Kdm6a 在促进先天 IFN-β 基因转录方面的一个先前未知的作用，除了在启动子处的去甲基化作用外，还在增强子处发挥作用。Kdm6a 促进先天炎症反应的功能也为更好地理解炎症和自身免疫性疾病中的表观遗传修饰剂提供了新的认识。
