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N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis

Author

Listed:
  • Xiaojie Ma

    (Zhejiang University)

  • Jie Cao

    (Zhejiang University
    Zhejiang University)

  • Ziyu Zhou

    (Zhejiang University)

  • Yunkun Lu

    (Zhejiang University)

  • Qin Li

    (Zhejiang University)

  • Yan Jin

    (Zhejiang University)

  • Guo Chen

    (Zhejiang University)

  • Weiyun Wang

    (Zhejiang University)

  • Wenyan Ge

    (Zhejiang University)

  • Xi Chen

    (Zhejiang University)

  • Zhensheng Hu

    (Zhejiang University)

  • Xiao Shu

    (Zhejiang University)

  • Qian Deng

    (Zhejiang University)

  • Jiaqi Pu

    (Zhejiang University
    Zhejiang University School of Medicine)

  • Chengzhen Liang

    (Zhejiang University)

  • Junfen Fu

    (Zhejiang University School of Medicine)

  • Jianzhao Liu

    (Zhejiang University
    Zhejiang University)

  • Saiyong Zhu

    (Zhejiang University
    Zhejiang University)

Abstract

Pancreatic differentiation from human pluripotent stem cells (hPSCs) provides promising avenues for investigating development and treating diseases. N6-methyladenosine (m6A) is the most prevalent internal messenger RNA (mRNA) modification and plays pivotal roles in regulation of mRNA metabolism, while its functions remain elusive. Here, we profile the dynamic landscapes of m6A transcriptome-wide during pancreatic differentiation. Next, we generate knockout hPSC lines of the major m6A demethylase ALKBH5, and find that ALKBH5 plays significant regulatory roles in pancreatic organogenesis. Mechanistic studies reveal that ALKBH5 deficiency reduces the mRNA stability of key pancreatic transcription factors in an m6A and YTHDF2-dependent manner. We further identify that ALKBH5 cofactor α-ketoglutarate can be applied to enhance differentiation. Collectively, our findings identify ALKBH5 as an essential regulator of pancreatic differentiation and highlight that m6A modification-mediated mRNA metabolism presents an important layer of regulation during cell-fate specification and holds great potentials for translational applications.

Suggested Citation

  • Xiaojie Ma & Jie Cao & Ziyu Zhou & Yunkun Lu & Qin Li & Yan Jin & Guo Chen & Weiyun Wang & Wenyan Ge & Xi Chen & Zhensheng Hu & Xiao Shu & Qian Deng & Jiaqi Pu & Chengzhen Liang & Junfen Fu & Jianzhao, 2022. "N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31698-2
    DOI: 10.1038/s41467-022-31698-2
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    References listed on IDEAS

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