Han, Yunqiao, Sun, Kui, Yu, Shanshan, Qin, Yayun, Zhang, Zuxiao, Luo, Jiong, Hu, Hualei, Dai, Liyan, Cui, Manman, Jiang, Chaolin, Liu, Fei, Huang, Yuwen, Gao, Pan, Chen, Xiang, Xin, Tianqing, Ren, Xiang, Wu, Xiaoyan, Song, Jieping, Wang, Qing, and Tang, Zhaohui
Prenatal lethality associated with mouse knockout of Mettl16, a recently identified RNA N6-methyladenosine (m6A) methyltransferase, has hampered characterization of the essential role of METTL16-mediated RNA m6A modification in early embryonic development. Here, using cross-species single-cell RNA sequencing analysis, we found that during early embryonic development, METTL16 is more highly expressed in vertebrate hematopoietic stem and progenitor cells (HSPCs) than other methyltransferases. In Mettl16-deficient zebrafish, proliferation capacity of embryonic HSPCs is compromised due to G1/S cell cycle arrest, an effect whose rescue requires Mettl16 with intact methyltransferase activity. We further identify the cell-cycle transcription factor mybl2b as a directly regulated by Mettl16-mediated m6A modification. Mettl16 deficiency resulted in the destabilization of mybl2b mRNA, likely due to lost binding by the m6A reader Igf2bp1 in vivo. Moreover, we found that the METTL16-m6A-MYBL2-IGF2BP1 axis controlling G1/S progression is conserved in humans. Collectively, our findings elucidate the critical function of METTL16-mediated m6A modification in HSPC cell cycle progression during early embryonic development. Synopsis: METTL16 plays a crucial role in N6-methyladenosine (m6A) modification of RNA. This study sheds light on the significance of this event in early embryonic development and cell cycle progression. METTL16 is highly expressed in hematopoietic stem and progenitor cells (HSPCs) across vertebrates Mettl16 maintains HSPC populations by ensuring G1/S progression in vivo Mettl16-mediated m6A modification of mRNA coding for transcription factor mybl2b enhances its stability The METTL16/m6A/MYBL2/IGF2BP1 axis contributes to G1/S progression in both zebrafish and humans The N6-methyladenosine methyltransferase METTL16 regulates cell cycle progression of HPSCs during embryonic development by stabilizing mybl2b mRNA. [ABSTRACT FROM AUTHOR]