Long-lasting immunity depends on the generation of protective antibodies through the germinal center (GC) reaction. N6-methyladenosine (m6A) modification of mRNAs by METTL3 activity modulates transcript lifetime primarily through the function of m6A readers; however, the physiological role of this molecular machinery in the GC remains unknown. Here, we show that m6A modifications by METTL3 are required for GC maintenance through the differential functions of m6A readers. Mettl3-deficient GC B cells exhibited reduced cell-cycle progression and decreased expression of proliferation- and oxidative phosphorylation–related genes. The m6A binder, IGF2BP3, was required for stabilization of Myc mRNA and expression of its target genes, whereas the m6A reader, YTHDF2, indirectly regulated the expression of the oxidative phosphorylation gene program. Our findings demonstrate how two independent gene networks that support critical GC functions are modulated by m6A through distinct mRNA binders.

中文翻译：

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生发中心反应取决于 RNA 甲基化和特定甲基读取器的不同功能


持久的免疫力取决于通过生发中心 (GC) 反应产生保护性抗体。 METTL3 活性对 mRNA 的 N6-甲基腺苷 (m6A) 修饰主要通过 m6A 阅读器的功能调节转录物寿命；然而，GC 中这种分子机制的生理作用仍然未知。在这里，我们通过 m6A 阅读器的差异功能表明，GC 维护需要 METTL3 进行 m6A 修改。 Mettl3 缺陷的 GC B 细胞表现出细胞周期进程减少以及增殖和氧化磷酸化相关基因表达减少。 m6A 结合剂 IGF2BP3 是 Myc mRNA 稳定及其靶基因表达所必需的，而 m6A 阅读器 YTHDF2 则间接调节氧化磷酸化基因程序的表达。我们的研究结果证明了 m6A 如何通过不同的 mRNA 结合物来调节支持关键 GC 功能的两个独立基因网络。