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KDM2B promotes IL-6 production and inflammatory responses through Brg1-mediated chromatin remodeling

Cellular & Molecular Immunology volume 17, pages 834–842 (2020)Cite this article

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Abstract

IL-6 plays important and pleiotropic roles in infection and inflammatory diseases, and its production needs to be tightly regulated. However, the epigenetic mechanism underlying Il6 gene 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 the Il6 promoter 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 the Il6 promoter. Furthermore, KDM2B directly recruited RNA Polymerase II to further initiate and promote Il6 transcription. Thus, our finding identifies a novel nonclassical function of KDM2B in gene-specific transcription initiation and enhancement of Il6 independent of its demethylase activity and adds new insight into the specific epigenetic modification mechanism of inflammatory immune responses.

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Acknowledgements

We thank X. Sun and M. Jin for technical assistance. This work was supported by the National Natural Science Foundation of China (31570871, 81571541, 81771695, 31770970, and 81770094), Program of Shanghai Chief Scientist of Medical and Health Subject (2018BR16), and Shuguang Program sponsored by the Shanghai Education Development Foundation and Shanghai Municipal Education Commission (18SG33).

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  1. These authors contributed equally: Qingqing Zhou, Yunkai Zhang, Bo Wang

Authors and Affiliations

  1. Institute of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, 200120, Shanghai, China

    Qingqing Zhou, Bo Wang, Wenhui Zhou & Zhongmin Liu

  2. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, 200433, Shanghai, China

    Yunkai Zhang & Xingguang Liu

  3. Shanghai Fourth People’s Hospital, Tongji University School of Medicine, 200081, Shanghai, China

    Yong Bi & Zhenzhen Zhan

  4. Institute of Immunology, Zhejiang University School of Medicine, 310058, Hangzhou, China

    Wanwan Huai & Xi Chen

  5. Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, 200120, Shanghai, China

    Yihan Chen & Zhenzhen Zhan

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  1. Qingqing Zhou
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Correspondence to Xingguang Liu or Zhenzhen Zhan.

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Zhou, Q., Zhang, Y., Wang, B. et al. KDM2B promotes IL-6 production and inflammatory responses through Brg1-mediated chromatin remodeling. Cell Mol Immunol 17, 834–842 (2020). https://doi.org/10.1038/s41423-019-0251-z

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