In vertebrates, haematopoietic stem/progenitor cells (HSPCs) are derived from haemogenic endothelium, a subset of endothelial cells in the ventral wall of dorsal aorta, through endothelial-to-haematopoietic transition (EHT) during embryogenesis. Previous studies have suggested the role of m⁶A modification in cell fate determination and lineage transition in embryonic stem cells. However, the exact physiological function of m⁶A modification in vertebrate definitive hematopoiesis remains unknown.

Recently, a study led by Dr. YANG Yungui from Beijing Institute of Genomics, Chinese Academy of Sciences, in collaboration with Dr. LIU Feng from Institute of Zoology (IOZ), Chinese Academy of Sciences, revealed a critical function of m⁶A modification in the fate determination of HSPCs during vertebrate embryogenesis, which is published online in Nature on September 6th, 2017.

In this study, they investigated the biological relevance of m⁶A modification in embryogenesis. By using m⁶A-MeRIP-Seq, they found a significantly decreased m⁶A levels and blocked emergence of HSPCs in mettl3-deficient embryos. Combing with RNA-Seq data, they detected decreased m6A levels but increased mRNA levels of a series of arterial endothelial genes, especially notch1a, indicating a potential role of METTL3-medicated m6A in the balance regulation of endothelial and haematopoietic gene expression during EHT.

In addition, the YTHDF2-RIP-Seq and the single base resolution m⁶A-miCLIP-Seq analyses revealed that the delayed YTHDF2-mediated mRNA decay of the arterial endothelial genes notch1a contributes to this deleterious effect. The continuous activation of Notch signaling 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, indicating a conversed function and mechanism of m⁶A regulation in definitive haematopoiesis in vertebrates.

This collaborative group also identified the m⁶A methyltransferase complex in zebrafish (Ping et al. Cell Research 2014). The present findings demonstrating the critical function of m⁶A modification in HSPC specification in vertebrates provide valuable resource for deciphering the physiological biological significance of RNA methylation and theoretical guidance for the in vitro induction of hematopoietic stem cells.

This research is supported by CAS Strategic Priority Research Programs, Ministry of Science and Technology and Natural Science Foundation of China.

Article web linker: doi:10.1038/nature23883

Figure 1. Schematic representation of the role of m6A methylation in HSC fate determination during EHT via METTL3-notch1a. (Image by IOZ)

Figure 2. The artistic image shows hematopoietic stem cell (blue) budding from hemogenic endothelial cell (green) through the endothelial-to-hematopoietic transition (EHT), which is modulated by m6A modification (pink) of Notch1a mRNA (brown) to ensure hematopoietic stem cell specification. (Image by IOZ)