title: The arginine methyltransferase PRMT5 regulates CIITA-dependent MHC II transcription.
abstract: Class II major histocompatibility complex (MHC II) dependent antigen presentation serves as a key step in mammalian adaptive immunity and host defense. In antigen presenting cells (e.g., macrophages), MHC II transcription can be activated by interferon gamma (IFN-γ) and mediated by class II transactivator (CIITA). The underlying epigenetic mechanism, however, is not completely understood. Here we report that following IFN-γ stimulation, symmetrically dimethylated histone H3 arginine 2 (H3R2Me2s) accumulated on the MHC II promoter along with CIITA. IFN-γ augmented expression, nuclear translocation, and promoter binding of the protein arginine methyltransferase PRMT5 in macrophages. Over-expression of PRMT5 potentiated IFN-γ induced activation of MHC II transcription in an enzyme activity-dependent manner. In contrast, PRMT5 silencing or inhibition of PRMT5 activity by methylthioadenosine (MTA) suppressed MHC II transactivation by IFN-γ. CIITA interacted with and recruited PRMT5 to the MHC II promoter and mediated the synergy between PRMT5 and ASH2/WDR5 to activate MHC II transcription. PRMT5 expression was down-regulated in senescent and H2O2-treated macrophages rendering ineffectual induction of MHC II transcription by IFN-γ. Taken together, our data reveal a pathophysiologically relevant role for PRMT5 in MHC II transactivation in macrophages.
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China; Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Xiaocen
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xia
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China. Electronic address: yxu2005@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics* / Q000276:immunology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007371:Interferon-gamma / Q000008:administration & dosage; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D011484:Protein-Arginine N-Methyltransferases; D013872:Thionucleosides / Q000008:administration & dosage; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D000949:Histocompatibility Antigens Class II; D006657:Histones; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D013872:Thionucleosides; D015534:Trans-Activators; C071306:methylthioadenosine sulfoxide; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D011496:Protein Methyltransferases; C498518:Prmt5 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; D000241:Adenosine
keywords: CIITA; Epigenetics; MHC II; Macrophage; PRMT5; Transcriptional regulation