title: Histone methyltransferase Ash1l suppresses interleukin-6 production and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme A20.
abstract: Histone modifications play important roles in multiple physiological processes by regulating gene expression. However, the roles of histone modifications in immunity remain poorly understood. Here we report that Ash1l, a H3K4 methyltransferase, suppressed interleukin-6 (IL-6), and tumor necrosis factor (TNF) production in Toll-like receptor (TLR)-triggered macrophages, protecting mice from sepsis. Ash1l-silenced mice were more susceptible to autoimmune disease as a result of enhanced IL-6 production. Ash1l enhanced A20 expression through induction of H3K4 modification at the Tnfaip3 promoter via H3K4 methyltransferase activity of Ash1l SET (Su[var]3-9, E[z] and trithorax) domain. Ash1l suppressed NF-κB, mitogen-activated protein kinase (MAPK) pathways, and subsequent IL-6 production via facilitating A20-mediated NF-κB signal modulator NEMO and transducer TRAF6 deubiquitination. Therefore, Ash1l-mediated H3K4 methylation at the Tnfaip3 promoter is required for controlling innate IL-6 production and suppressing inflammatory autoimmune diseases, providing mechanistic insight into epigenetic modulation of immune responses and inflammation.
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310057, China; National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xia
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wu
authors.forename: Shuxun
authors.initials: S
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Han
authors.forename: Lijun
authors.initials: L
authors.lastname: Song
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Li
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.forename: Jianli
authors.initials: J
authors.lastname: Wang
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007249:Inflammation; D015850:Interleukin-6 / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism*; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D018805:Sepsis / Q000276:immunology / Q000517:prevention & control; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D048069:Tumor Necrosis Factors / Q000096:biosynthesis; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins; D006657:Histones; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D048069:Tumor Necrosis Factors; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C499317:Ascl1 protein, mouse; C514981:NEMO protein, mouse; C513261:Tnfaip3 protein, mouse