Journal Article

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

Chen, Xi, Liu, Xingguang, Wang, Bo, Bi, Yong, Huai, Wanwan, Liu, Zhongmin, Chen, Yihan, Zhang, Yunkai, Zhou, Qingqing, Zhan, Zhenzhen, Zhou, Wenhui

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/127/1213 / 631/250/2502/2170 / 631/250/256/2515 / Adenosine triphosphatase / Animals / Antibodies / Biomedical and Life Sciences / Biomedicine / Brahma-related gene / BRG1 protein / Chromatin - metabolism / Chromatin Assembly and Disassembly - genetics / Chromatin remodeling / Colitis / Demethylation / Dendritic cells / DNA Helicases - metabolism / DNA Methylation - genetics / DNA-directed RNA polymerase / Endotoxin shock / Epigenetics / F-Box Proteins - metabolism / HEK293 Cells / Humans / Immunity, Innate / Immunology / Inflammation - genetics / Inflammation - immunology / Inflammatory diseases / Interleukin 1 / Interleukin 6 / Interleukin-6 - biosynthesis / Jumonji Domain-Containing Histone Demethylases - deficiency / Jumonji Domain-Containing Histone Demethylases - metabolism / Lysine / Macrophages / Medical Microbiology / Mice / Microbiology / Nuclear Proteins - metabolism / Phenotypes / Promoter Regions, Genetic / Protein Binding - genetics / RNA polymerase / RNA Polymerase II - metabolism / Transcription Factors - metabolism / Transcription initiation / Transcriptional Activation - genetics / Tumor necrosis factor-α / Vaccine / β-Interferon