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

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 Liu () and Saiyong Zhu ()
Additional contact information
Xiaojie Ma: Zhejiang University
Jie Cao: 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
Chengzhen Liang: Zhejiang University
Junfen Fu: Zhejiang University School of Medicine
Jianzhao Liu: Zhejiang University
Saiyong Zhu: Zhejiang University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-31698-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31698-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-31698-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().