State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, CAS Center for Excellence in Molecular Cell Science, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
Nat Commun. 2021 Feb 26;12(1):1333. doi: 10.1038/s41467-021-21594-6.
T follicular helper (T) cells are specialized effector CD4 T cells critical to humoral immunity. Whether post-transcriptional regulation has a function in T cells is unknown. Here, we show conditional deletion of METTL3 (a methyltransferase catalyzing mRNA N-methyladenosine (mA) modification) in CD4 T cells impairs T differentiation and germinal center responses in a cell-intrinsic manner in mice. METTL3 is necessary for expression of important T signature genes, including Tcf7, Bcl6, Icos and Cxcr5 and these effects depend on intact methyltransferase activity. mA-miCLIP-seq shows the 3' UTR of Tcf7 mRNA is subjected to METTL3-dependent mA modification. Loss of METTL3 or mutation of the Tcf7 3' UTR mA site results in accelerated decay of Tcf7 transcripts. Importantly, ectopic expression of TCF-1 (encoded by Tcf7) rectifies T defects owing to METTL3 deficiency. Our findings indicate that METTL3 stabilizes Tcf7 transcripts via mA modification to ensure activation of a T transcriptional program, indicating a pivotal function of post-transcriptional regulation in promoting T cell differentiation.
滤泡辅助 T 细胞（Tfh 细胞）是一种专门的效应 CD4 T 细胞，对体液免疫至关重要。目前尚不清楚转录后调控是否在 T 细胞中发挥作用。在这里，我们发现在 CD4 T 细胞中条件性敲除 METTL3（一种催化 mRNA N6-甲基腺苷（m6A）修饰的甲基转移酶）会以细胞内固有方式损害 T 细胞分化和生发中心反应。METTL3 对于表达重要的 T 细胞特征基因（包括 Tcf7、Bcl6、Icos 和 Cxcr5）是必需的，这些效应依赖于完整的甲基转移酶活性。mA-miCLIP-seq 显示 Tcf7 mRNA 的 3'UTR 受到 METTL3 依赖性 mA 修饰。METTL3 的缺失或 Tcf7 3'UTR mA 位点的突变导致 Tcf7 转录物的降解加速。重要的是，TCF-1（由 Tcf7 编码）的异位表达纠正了由于 METTL3 缺乏引起的 T 缺陷。我们的研究结果表明，METTL3 通过 mA 修饰稳定 Tcf7 转录本，以确保 T 转录程序的激活，表明转录后调控在促进 T 细胞分化方面具有关键作用。
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