title: The histone methyltransferase Smyd2 is a negative regulator of macrophage activation by suppressing interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) production.
abstract: SET and MYND domain-containing 2 (Smyd2), a histone 3 lysine 4- and histone 3 lysine 36 (H3K36)-specific methyltransferase, plays critical roles in cardiac development and tumorigenesis. However, the role of Smyd2 in immunity and inflammation remains poorly understood. In this study, we report that Smyd2 is a novel negative regulator for macrophage activation and M1 polarization. Elevated Smyd2 expression suppresses the production of proinflammatory cytokines, including IL-6 and TNF, and inhibits the expression of important cell surface molecules, including major MHC-II and costimulatory molecules. Furthermore, macrophages with high Smyd2 expression inhibit Th-17 cell differentiation but promote regulatory T cell differentiation as a result of increased TGF-β production and decreased IL-6 secretion. In macrophages, Smyd2 specifically facilitates H3K36 dimethylation at Tnf and Il6 promoters to suppress their transcription and inhibits NF-κB and ERK signaling. Therefore, our data demonstrate that epigenetic modification by Smyd2-mediated H3K36 dimethylation at Tnf and Il6 promoters plays an important role in the regulation of macrophage activation during inflammation.
authors.affiliation: From the Jiangsu Key Laboratory of Infection and Immunity, Institute of Biological and Medical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Guiliang
authors.initials: G
authors.lastname: Xu
authors.affiliation: From the Jiangsu Key Laboratory of Infection and Immunity, Institute of Biological and Medical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Guilin
authors.initials: G
authors.lastname: Liu
authors.affiliation: From the Jiangsu Key Laboratory of Infection and Immunity, Institute of Biological and Medical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
authors.affiliation: From the Jiangsu Key Laboratory of Infection and Immunity, Institute of Biological and Medical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: the Shanghai Key Laboratory of Regulatory Biology, School of Biological Sciences, East China Normal University, Shanghai 200241, China, and the Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030 xichen0919@gmail.com.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: the Shanghai Key Laboratory of Regulatory Biology, School of Biological Sciences, East China Normal University, Shanghai 200241, China, and the Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030 bzheng@bcm.edu.
authors.forename: Biao
authors.initials: B
authors.lastname: Zheng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008262:Macrophage Activation / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008745:Methylation; D008810:Mice, Inbred C57BL; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D006657:Histones; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D011495:Histone-Lysine N-Methyltransferase; C512570:Smyd2 protein, mouse; D008239:Lysine
keywords: Autoimmunity; ChiP; Immunology; Macrophage; Signaling