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Title: m6A Modulates Haematopoietic Stem and Progenitor Cell Specification
Author: Chunxia Zhang, Yusheng Chen, Baofa Sun, Lu Wang, Ying Yang, Dongyuan Ma, Junhua Lv, Jian Heng, Yanyan Ding, Yuanyuan Xue, Xinyan Lu, Wen Xiao, Yun-Gui Yang, Feng Liu
Abstract: N6-methyladenosine (m6A) has been identified as the most abundant modification on eukaryote messenger RNA (mRNA)1. Although the rapid development of high-throughput sequencing technologies has enabled insight into the biological functions of m6A modification2345678910111213, the function of m6A during vertebrate embryogenesis remains poorly understood. Here we show that m6A determines cell fate during the endothelial-to-haematopoietic transition (EHT) to specify the earliest haematopoietic stem/progenitor cells (HSPCs) during zebrafish embryogenesis. m6A-specific methylated RNA immunoprecipitation combined with high-throughput sequencing (MeRIP–seq) and m6A individual-nucleotide-resolution cross-linking and immunoprecipitation with sequencing (miCLIP–seq) analyses reveal conserved features on zebrafish m6A methylome and preferential distribution of m6A peaks near the stop codon with a consensus RRACH motif. In mettl3-deficient embryos, levels of m6A are significantly decreased and emergence of HSPCs is blocked. Mechanistically, we identify that the delayed YTHDF2-mediated mRNA decay of the arterial endothelial genes notch1aand rhoca contributes to this deleterious effect. The continuous activation of Notch signalling in arterial endothelial cells of mettl3-deficient embryos blocks EHT, thereby repressing the generation of the earliest HSPCs. Furthermore, knockdown of Mettl3 in mice confers a similar phenotype. Collectively, our findings demonstrate the critical function of m6A modification in the fate determination of HSPCs during vertebrate embryogenesis.
Corresponding author: Yun-Gui Yang, Feng Liu
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PubYear: 2017
Issue: DOI: 10.1038/nature23883
Journal: Nature
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URL: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature23883.html