Division of Molecular Biology, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Noda, Chiba 278-0022, Japan.
Division of Molecular Biology, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Noda, Chiba 278-0022, Japan.
Cell Rep. 2020 Nov 3;33(5):108333. doi: 10.1016/j.celrep.2020.108333.
The germinal center (GC) reaction is essential for long-lived humoral immunity. However, molecular requirements for the induction of Bcl6, the master regulator for GC B cell differentiation, remain unclear. Through screening for cytokines and other stimuli that regulate Bcl6 expression, we identify IL-4 as the strongest inducer. IL-4 signaling alters the metabolomic profile in activated B cells and induces accumulation of the TCA cycle intermediate α-ketoglutarate (αKG), which is required for activation of the Bcl6 gene locus. Mechanistically, after IL-4 treatment, STAT6 bound to the known enhancers in the Bcl6 locus recruits UTX, a demethylase for the repressive histone mark H3K27me3 that requires αKG as a cofactor. In turn, the H3K27me3 demethylation activates the enhancers and transcription of the Bcl6 gene. We propose that IL-4-mediated metabolic reprogramming in B cells is pivotal for epigenomic activation of Bcl6 expression to promote GC B cell differentiation.
生发中心（GC）反应对于长期的体液免疫至关重要。然而，Bcl6 的诱导的分子要求，Bcl6 是 GC B 细胞分化的主要调节因子，仍然不清楚。通过筛选调节 Bcl6 表达的细胞因子和其他刺激物，我们确定了 IL-4 是最强的诱导物。IL-4 信号改变了活化 B 细胞的代谢组特征，并诱导 TCA 循环中间产物 α-酮戊二酸（αKG）的积累，这对于激活 Bcl6 基因座是必需的。从机制上讲，在 IL-4 处理后，STAT6 结合到 Bcl6 基因座的已知增强子上，募集 UTX，这是一种组蛋白 H3K27me3 的去甲基酶，需要 αKG 作为辅助因子。反过来，H3K27me3 的去甲基化激活了增强子和 Bcl6 基因的转录。我们提出，IL-4 介导的 B 细胞代谢重编程对于 Bcl6 表达的表观遗传激活以促进 GC B 细胞分化至关重要。
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