2. Academic Validation
  3. METTL3-dependent m6A modification programs T follicular helper cell differentiation

METTL3-dependent m6A modification programs T follicular helper cell differentiation

  • Nat Commun. 2021 Feb 26;12(1):1333. doi: 10.1038/s41467-021-21594-6.
Yingpeng Yao  # 1,  Ying Yang  # 2 3,  Wenhui Guo  # 1,  Lifan Xu  # 4,  Menghao You 1,  Yi-Chang Zhang 2 3,  Zhen Sun 1,  Xiao Cui 1,  Guotao Yu 1,  Zhihong Qi 1,  Jingjing Liu 1,  Fang Wang 1,  Juanjuan Liu 1,  Tianyan Zhao 1,  Lilin Ye 5,  Yun-Gui Yang 6 7,  Shuyang Yu 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  • 2 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.
  • 3 University of Chinese Academy of Sciences, Beijing, China.
  • 4 Institute of Immunology, Third Military Medical University, Chongqing, China.
  • 5 Institute of Immunology, Third Military Medical University, Chongqing, China. yelilinlcmv@tmmu.edu.cn.
  • 6 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. ygyang@big.ac.cn.
  • 7 University of Chinese Academy of Sciences, Beijing, China. ygyang@big.ac.cn.
  • 8 State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. ysy@cau.edu.cn.
  • # Contributed equally.
PMID: 33637761 DOI: 10.1038/s41467-021-21594-6
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.

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