title: Demethylase Kdm6a epigenetically promotes IL-6 and IFN-β production in macrophages.
abstract: Molecular regulation of innate signal-initiated proinflammatory cytokine production has been extensively investigated. However, the roles of epigenetic modifiers and their underlying mechanisms in regulating innate inflammatory response and development of autoimmune diseases need to be further understood. Demethylase Kdm6a promotes gene transcription in cell-lineage specification through demethylating histone H3 lysine di/tri-methylation (H3K27me2/3), and loss of Kdm6a results in developmental defects. However, the function of Kdm6a in innate immunity and inflammation remains largely unknown. Here we found that Kdm6a, significantly downregulated via JNK pathway upon innate stimuli, promotes cytokine IL-6 and IFN-β transcription in primary macrophages during innate response. Kdm6a promoted IL-6 expression through demethylating H3K27me3 at promoter in a demethylase enzymatic activity-dependent manner. Interestingly, Kdm6a promoted IFN-β expression independent of its demethylase enzymatic activity, but through increasing transcription of IFN-β-specific enhancer-derived RNA (eRNA) S-IRE1. For the underlying mechanism, Kdm6a interacted with MLL4 and promoted MLL4 recruitment and H3K4me2 level in S-IRE1 region of Ifnb1 gene for full activation of enhancer. Our results reveal a previously unknown role of kdm6a in promoting innate IFN-β gene transcription at enhancer, in addition to demethylation at promoter. The function of Kdm6a in promoting innate inflammatory response also adds insights to better understanding of epigenetic modifiers in inflammatory and autoimmune disease.
authors.affiliation: Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Joint National Laboratory for Antibody Drug Engineering, Institute of Immunology, Henan University School of Medicine, Kaifeng 475004, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qicong
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xingguang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Joint National Laboratory for Antibody Drug Engineering, Institute of Immunology, Henan University School of Medicine, Kaifeng 475004, China.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: caoxt@immunol.org.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate; D016899:Interferon-beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D006657:Histones; D015850:Interleukin-6; D016899:Interferon-beta; D056466:Histone Demethylases; C111778:Utx protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C516439:MLL4 protein, mouse
keywords: H3K27me3; IFN-β; IL-6; Inflammation; Kdm6a; Macrophages