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Methionine Commits Cells to Differentiate Into Plasmablasts Through Epigenetic Regulation of BTB and CNC Homolog 2 by the Methyltransferase EZH 2
Author(s) -
Zhang Mingzeng,
Iwata Shigeru,
Hajime Maiko,
Ohkubo Naoaki,
Todoroki Yasuyuki,
Miyata Hiroko,
Ueno Masanobu,
Hao He,
Zhang Tong,
Fan Jie,
Nakayamada Shingo,
Yamagata Kaoru,
Tanaka Yoshiya
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41208
Subject(s) - methionine , biology , receptor , cellular differentiation , b cell , amino acid , antibody , biochemistry , immunology , gene
Objective Plasmablasts play important roles in autoimmune diseases, including systemic lupus erythematosus ( SLE ). Activation of mechanistic target of rapamycin complex 1 ( mTORC 1) is regulated by amino acid levels. In patients with SLE , mTORC 1 is activated in B cells and modulates plasmablast differentiation. However, the detailed mechanisms of amino acid metabolism in plasmablast differentiation remain elusive. We undertook this study to evaluate the effects of methionine in human B cells. Methods Purified CD 19+ cells from healthy donors (n = 21) or patients with SLE (n = 35) were cultured with Toll‐like receptor 7/9 ligand, interferon‐α ( IFN α), and B cell receptor crosslinking, and we determined the types of amino acids that were important for plasmablast differentiation and amino acid metabolism. We also identified the transcriptional regulatory mechanisms induced by amino acid metabolism, and we assessed B cell metabolism and its relevance to SLE . Results The essential amino acid methionine strongly committed cells to plasmablast differentiation. In the presence of methionine, Syk and mTORC 1 activation synergistically induced methyltransferase EZH 2 expression. EZH 2 induced H3K27me3 at BTB and CNC homolog 2 (Bach2) loci and suppressed Bach2 expression, leading to induction of B lymphocyte–induced maturation protein 1 and X‐box binding protein 1 expression and plasmablast differentiation. CD 19+ cells from patients with SLE overexpressed EZH 2, which was correlated with disease activity and autoantibody production. Conclusion Our findings show that methionine activated signaling by controlling immunologic metabolism in B cells and played an important role in the differentiation of B cells into plasmablasts through epigenome modification of Bach2 by the methyltransferase EZH 2.