Methyltransferase Dot1l preferentially promotes innate IL-6 and IFN-β production by mediating H3K79me2/3 methylation in macrophages  

作　　者：Xiang Chen Xingguang Liu Yunkai Zhang Wanwan Huai Qingqing Zhou Sheng Xu Xi Chen Nan Li Xuetao Cao 

机构地区：[1]National Key Laboratory of Medical Immunology&Institute of Immunology,Second Military Medical University,Shanghai 200433,China [2]Institute of Immunology,Zhejiang University School of Medicine,Hangzhou 310058,China [3]Department of Immunology&Center for Immunotherapy,Institute of Basic Medical Sciences,Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing 100005,China

出　　处：《Cellular & Molecular Immunology》2020年第1期76-84,共9页中国免疫学杂志（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(81788101,31570871,31770970);CAMS Innovation Fund for Medical Sciences(2016-12M-1-003);the National Key Basic Research Program of China(2015CB964403).

摘　　要：Epigenetic modification,including histone modification,precisely controls target gene expression.The posttranscriptional regulation of the innate signaling-triggered production of inflammatory cytokines and type I interferons has been fully elucidated,whereas the roles of histone modification alteration and epigenetic modifiers in regulating inflammatory responses need to be further explored.Di/tri-methylation modifications of histone 3 lysine 79(H3K79me2/3)have been shown to be associated with gene transcriptional activation.Disruptor of telomeric silencing-1-like(Dot1l)is the only known exclusive H3K79 methyltransferase and regulates the proliferation and differentiation of tumor cells.However,the roles of Dot1l and Dot1l-mediated H3K79 methylation in innate immunity and inflammatory responses remain unclear.Here,we found that H3K79me2/3 modification levels at the Il6 and Ifnb1 promoters,as well as H3K79me2 modification at the Tnfαpromoter,were increased in macrophages activated by Toll-like receptor(TLR)ligands or virus infection.The innate signals upregulated Dot1l expression in macrophages and THP1 cells.Dot1l silencing or a Dot1l inhibitor preferentially suppressed the production of IL-6 and interferon(IFN)-βbut not of TNFαin macrophages and THP1 cells triggered by TLR ligands or virus infection.Dot1l was recruited to the proximal promoter of the Il6 and Ifnb1 but not Tnfαgene and then mediated H3K79me2/3 modification at the Il6 and Ifnb1 promoters,consequently facilitating the transcription and expression of Il6 and Ifnb1.Thus,Dot1l-mediated selective H3K79me2/3 modifications at the Il6 and Ifnb1 promoters are required for the full activation of innate immune responses.This finding adds new insights into the epigenetic regulation of inflammatory responses and pathogenesis of autoimmune diseases.

关 键 词：H3K79me2/3 Dot1l epigenetic regulation IL-6 IFN-Β MACROPHAGES inflammation 

分 类 号：R392[医药卫生—免疫学]