2. Academic Validation
  3. N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis

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

  • Nat Commun. 2022 Jul 18;13(1):4148. doi: 10.1038/s41467-022-31698-2.
Xiaojie Ma  # 1,  Jie Cao  # 2 3,  Ziyu Zhou  # 1,  Yunkun Lu  # 1,  Qin Li 1,  Yan Jin 1,  Guo Chen 1,  Weiyun Wang 1,  Wenyan Ge 1,  Xi Chen 1,  Zhensheng Hu 1,  Xiao Shu 2,  Qian Deng 1,  Jiaqi Pu 1 4,  Chengzhen Liang 5,  Junfen Fu 4,  Jianzhao Liu 6 7,  Saiyong Zhu 8 9
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 2 MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310008, China.
  • 3 Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.
  • 4 The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 5 Department of Orthopedics Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
  • 6 MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310008, China. liujz@zju.edu.cn.
  • 7 Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China. liujz@zju.edu.cn.
  • 8 MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China. saiyong@zju.edu.cn.
  • 9 Department of Orthopedics Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. saiyong@zju.edu.cn.
  • # Contributed equally.
PMID: 35851388 DOI: 10.1038/s41467-022-31698-2
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.

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