KDM2B promotes IL-6 production and inflammatory responses through Brg1-mediated chromatin remodeling
KDM2B promotes IL-6 production and inflammatory responses through Brg1-mediated chromatin remodeling
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KDM2B 通过 Brg1 介导的染色质重塑促进 IL-6 的产生和炎症反应。
DOI：
10.1038/s41423-019-0251-z
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发表时间：
2020-08-01
影响因子：
24.1
通讯作者：
Zhan, Zhenzhen
中科院分区：
文献类型：
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作者：
Zhou, Qingqing;Zhang, Yunkai;Zhan, Zhenzhen
IL-6在感染和炎性疾病中起着重要的多效性作用，其产生需要严格调控。然而，I16基因转录的表观遗传机制仍有待充分阐明。在这里，我们报告了赖氨酸特异性脱甲基酶2b（KDM 2B），其脱甲基化H3 K4 me 3和H3 K36 me 2，在巨噬细胞和树突状细胞中诱导IL-6而不是TNF-α，IL-1和IFN-β是必需的。与野生型小鼠相比，KDM 2B缺陷型小鼠对内毒素休克和结肠炎的抵抗力更强，炎症发病机制表型不太严重，血清中IL-6的产生减少。KDM 2B选择性地结合IL 6启动子，但不改变组蛋白去甲基化;相反，KDM 2B与Brahma相关基因1（Brg 1）相互作用，SWI/SNF染色质重塑复合物的核心ATP酶亚基，以促进IL 6启动子的染色质可及性。此外，KDM 2B直接募集RNA聚合酶II以进一步启动和促进II 6转录。因此，我们的发现确定了一种新的非经典功能的KDM 2B在基因特异性转录启动和增强的IL 6独立的脱甲基酶活性，并增加了新的见解特定的表观遗传修饰机制的炎症免疫反应。
IL-6 plays important and pleiotropic roles in infection and inflammatory diseases, and its production needs to be tightly regulated. However, the epigenetic mechanism underlyingIl6gene transcription remains to be fully elucidated. Here, we report that lysine-specific demethylase 2b (KDM2B), which demethylates H3K4me3 and H3K36me2, is required in macrophages and dendritic cells for the induction of IL-6 but not TNF-α, IL-1, and IFN-β. Compared to wild-type mice, KDM2B-deficient mice were more resistant to endotoxin shock and colitis, with a less severe inflammatory pathogenesis phenotype and decreased IL-6 production in sera. KDM2B selectively bound theIl6promoter but did not alter histone demethylation; instead, KDM2B interacted with Brahma-related gene 1 (Brg1), the core ATPase subunit of SWI/SNF chromatin remodeling complexes, to facilitate chromatin accessibility of theIl6promoter. Furthermore, KDM2B directly recruited RNA Polymerase II to further initiate and promoteIl6transcription. Thus, our finding identifies a novel nonclassical function of KDM2B in gene-specific transcription initiation and enhancement ofIl6independent of its demethylase activity and adds new insight into the specific epigenetic modification mechanism of inflammatory immune responses.