title: Histone lysine methyltransferase Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing Tollip.
abstract: Histone modifications play critical roles in the regulation of gene expression; however, their roles in the regulation of the innate response remain to be fully investigated. Using transcriptome analysis of mouse immature dendritic cells (DCs) and LPS-induced mature DCs, we identified that Ezh1 was the most upregulated histone methyltransferase during DC maturation. In this study, we investigated the role of Ezh1 in regulating the innate immune response. We found that silencing of Ezh1 significantly suppressed TLR-triggered production of cytokines, including IL-6, TNF-α, and IFN-β, in DCs and macrophages. Accordingly, TLR-activated signaling pathways were impaired in Ezh1-silenced macrophages. By transcriptome analysis of Ezh1-silenced macrophages, we found that Toll-interacting protein (Tollip), one well-known negative regulator of TLR signaling, was upregulated. Silencing of Tollip rescued TLR-triggered cytokine production in Ezh1-silenced macrophages. The SET domain of Ezh1 is essential for its enhancing effect on the TLR-triggered innate immune response and downstream signaling, indicating that Ezh1 promotes a TLR-triggered innate response through its lysine methyltransferase activity. Finally, Ezh1 was found to suppress the transcription of Tollip by directly targeting the proximal promoter of tollip and maintaining the high level of trimethylation of histone H3 lysine 27 there. Therefore, Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing the TLR negative regulator Tollip, contributing to full activation of the innate immune response against invading pathogens.
authors: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China; and.
authors: Yiqi
authors: Y
authors: Liu
authors: National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China; and.
authors: Qian
authors: Q
authors: Zhang
authors: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors: Yuanyuan
authors: Y
authors: Ding
authors: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors: Xia
authors: X
authors: Li
authors: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors: Dezhi
authors: D
authors: Zhao
authors: National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China; and.
authors: Kai
authors: K
authors: Zhao
authors: National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China; and.
authors: Zhenhong
authors: Z
authors: Guo
authors: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China; and National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China caoxt@immunol.org.
authors: Xuetao
authors: X
authors: Cao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006657:Histones / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008239:Lysine / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008745:Methylation; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome / Q000276:immunology
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; D006657:Histones; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors; C485837:Tollip protein, mouse; C498408:Ezh1 protein, mouse; D063151:Polycomb Repressive Complex 2; D008239:Lysine; D011070:Poly I-C