METTL3-dependent m6A modification programs T follicular helper cell differentiation

Yingpeng Yao, Ying Yang, Wenhui Guo, Lifan Xu, Menghao You, Yi-Chang Zhang, Zhen Sun, Xiao Cui, Guotao Yu, Zhihong Qi, Jingjing Liu, Fang Wang, Juanjuan Liu, Tianyan Zhao, Lilin Ye (), Yun-Gui Yang () and Shuyang Yu ()
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Yingpeng Yao: China Agricultural University
Ying Yang: Chinese Academy of Sciences
Wenhui Guo: China Agricultural University
Lifan Xu: Third Military Medical University
Menghao You: China Agricultural University
Yi-Chang Zhang: Chinese Academy of Sciences
Zhen Sun: China Agricultural University
Xiao Cui: China Agricultural University
Guotao Yu: China Agricultural University
Zhihong Qi: China Agricultural University
Jingjing Liu: China Agricultural University
Fang Wang: China Agricultural University
Juanjuan Liu: China Agricultural University
Tianyan Zhao: China Agricultural University
Lilin Ye: Third Military Medical University
Yun-Gui Yang: Chinese Academy of Sciences
Shuyang Yu: China Agricultural University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract T follicular helper (TFH) cells are specialized effector CD4+ T cells critical to humoral immunity. Whether post-transcriptional regulation has a function in TFH cells is unknown. Here, we show conditional deletion of METTL3 (a methyltransferase catalyzing mRNA N6-methyladenosine (m6A) modification) in CD4+ T cells impairs TFH differentiation and germinal center responses in a cell-intrinsic manner in mice. METTL3 is necessary for expression of important TFH signature genes, including Tcf7, Bcl6, Icos and Cxcr5 and these effects depend on intact methyltransferase activity. m6A-miCLIP-seq shows the 3′ UTR of Tcf7 mRNA is subjected to METTL3-dependent m6A modification. Loss of METTL3 or mutation of the Tcf7 3′ UTR m6A site results in accelerated decay of Tcf7 transcripts. Importantly, ectopic expression of TCF-1 (encoded by Tcf7) rectifies TFH defects owing to METTL3 deficiency. Our findings indicate that METTL3 stabilizes Tcf7 transcripts via m6A modification to ensure activation of a TFH transcriptional program, indicating a pivotal function of post-transcriptional regulation in promoting TFH cell differentiation.

Date: 2021
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DOI: 10.1038/s41467-021-21594-6

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