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

• Published in: Nature communications 2022-07, Vol.13 (1), p.4148-4148, Article 4148
• Main Authors: Ma, Xiaojie, Cao, Jie, Zhou, Ziyu, Lu, Yunkun, Li, Qin, Jin, Yan, Chen, Guo, Wang, Weiyun, Ge, Wenyan, Chen, Xi, Hu, Zhensheng, Shu, Xiao, Deng, Qian, Pu, Jiaqi, Liang, Chengzhen, Fu, Junfen, Liu, Jianzhao, Zhu, Saiyong
• Format: Article
• Language: English
• Subjects: 13; 13/100; 49; 49/91; 631/136/2060; 631/337/1645/2570; 631/45/500; 631/532/1360; Cell differentiation; Differentiation; Humanities and Social Sciences; Ketoglutaric acid; Metabolism; mRNA stability; multidisciplinary; N6-methyladenosine; Organogenesis; Pancreas; Pluripotency; RNA modification; Science; Science (multidisciplinary); Specifications; Stem cells; Transcription factors; Transcriptomes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31698-2

Pancreatic differentiation from human pluripotent stem cells (hPSCs) provides promising avenues for investigating development and treating diseases. N 6 -methyladenosine (m 6 A) 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 m 6 A transcriptome-wide during pancreatic differentiation. Next, we generate knockout hPSC lines of the major m 6 A 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 m 6 A 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 m 6 A modification-mediated mRNA metabolism presents an important layer of regulation during cell-fate specification and holds great potentials for translational applications. Ma et al. profile the dynamic landscape of m 6 A during pancreatic differentiation, and identify ALKBH5 as an essential m 6 A regulator supporting pancreatic differentiation, indicating a role for m 6 A-mediated mRNA metabolism in cell-fate specification.