EZH2 Represses the B Cell Transcriptional Program and Regulates Antibody-Secreting Cell Metabolism and Antibody Production

被引:98
作者
Guo, Muyao [1 ,2 ]
Price, Madeline J. [1 ]
Patterson, Dillon G. [1 ]
Barwick, Benjamin G. [3 ]
Haines, Robert R. [1 ]
Kania, Anna K. [1 ]
Bradley, John E. [4 ]
Randall, Troy D. [4 ]
Boss, Jeremy M. [1 ]
Scharer, Christopher D. [1 ]
机构
[1] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA
[2] Cent South Univ, Xiangya Sch Med, Changsha 410008, Hunan, Peoples R China
[3] Emory Univ, Dept Radiat Oncol, Atlanta, GA 30322 USA
[4] Univ Alabama Birmingham, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA
基金
美国国家卫生研究院;
关键词
GERMINAL CENTER FORMATION; HISTONE METHYLTRANSFERASE ACTIVITY; LONG-TERM SURVIVAL; GENE-EXPRESSION; MULTIPLE-MYELOMA; LYSINE; 27; DIFFERENTIATION; METHYLATION; H3; CHROMATIN;
D O I
10.4049/jimmunol.1701470
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Epigenetic remodeling is required during B cell differentiation. However, little is known about the direct functions of epigenetic enzymes in Ab-secreting cells (ASC) in vivo. In this study, we examined ASC differentiation independent of T cell help and germinal center reactions using mice with inducible or B cell-specific deletions of Ezh2. Following stimulation with influenza virus or LPS, Ezh2-deficient ASC poorly proliferated and inappropriately maintained expression of inflammatory pathways, B cell-lineage transcription factors, and Blimp-1-repressed genes, leading to fewer and less functional ASC. In the absence of EZH2, genes that normally gained histone H3 lysine 27 trimethylation were dysregulated and exhibited increased chromatin accessibility. Furthermore, EZH2 was also required for maximal Ab secretion by ASC, in part due to reduced mitochondrial respiration, impaired glucose metabolism, and poor expression of the unfolded-protein response pathway. Together, these data demonstrate that EZH2 is essential in facilitating epigenetic changes that regulate ASC fate, function, and metabolism.
引用
收藏
页码:1039 / 1052
页数:14
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