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Nature. 2017 Sep 14;549(7671):273-276. doi: 10.1038/nature23883. Epub 2017 Sep 6.

m6A modulates haematopoietic stem and progenitor cell specification.

Zhang C1,2, Chen Y2,3, Sun B3, Wang L1, Yang Y3, Ma D1, Lv J1,2, Heng J1,2, Ding Y1,2, Xue Y1,2, Lu X1,2, Xiao W3, Yang YG2,3, Liu F1,2.

Author information

1
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
2
University of Chinese Academy of Sciences, Beijing 100049, China.
3
CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, CAS Center for Excellence in Molecular Cell Science, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.

Abstract

N6-methyladenosine (m6A) has been identified as the most abundant modification on eukaryote messenger RNA (mRNA). Although the rapid development of high-throughput sequencing technologies has enabled insight into the biological functions of m6A modification, 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 notch1a and 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.

PMID:
28869969
DOI:
10.1038/nature23883
[Indexed for MEDLINE]

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