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METTL3-dependent m6A modification programs T follicular helper cell differentiation

Author

Listed:
  • Yingpeng Yao

    (China Agricultural University)

  • Ying Yang

    (Chinese Academy of Sciences
    University of 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
    University of 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
    University of Chinese Academy of Sciences)

  • Shuyang Yu

    (China Agricultural University)

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.

Suggested Citation

  • 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, 2021. "METTL3-dependent m6A modification programs T follicular helper cell differentiation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21594-6
    DOI: 10.1038/s41467-021-21594-6
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    Cited by:

    1. Wen-Lan Yang & Weinan Qiu & Ting Zhang & Kai Xu & Zi-Juan Gu & Yu Zhou & Heng-Ji Xu & Zhong-Zhou Yang & Bin Shen & Yong-Liang Zhao & Qi Zhou & Ying Yang & Wei Li & Peng-Yuan Yang & Yun-Gui Yang, 2023. "Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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