m6A modulates haematopoietic stem and progenitor cell specification

Abstract

N-methyladenosine (mA) 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 mA modification, the function of mA during vertebrate embryogenesis remains poorly understood. Here we show that mA determines cell fate during the endothelial-to-haematopoietic transition (EHT) to specify the earliest haematopoietic stem/progenitor cells (HSPCs) during zebrafish embryogenesis. mA-specific methylated RNA immunoprecipitation combined with high-throughput sequencing (MeRIP-seq) and mA individual-nucleotide-resolution cross-linking and immunoprecipitation with sequencing (miCLIP-seq) analyses reveal conserved features on zebrafish mA methylome and preferential distribution of mA peaks near the stop codon with a consensus RRACH motif. In mettl3-deficient embryos, levels of mA 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 mA modification in the fate determination of HSPCs during vertebrate embryogenesis.

N6-Methyladenosine Role in Acute Myeloid Leukaemia

“…It was also shown that the embryonic METTL3 function in the haematopoietic system is mediated by the YTHDF2 dependent decay of Notch encoding mRNA [66]. Similar results were obtained upon conditional METTL3 KO in the mouse AGM region [67], therein, indicating an evolutionally conserved function of METTL3 in HSPCs (haematopoietic stem and progenitor cells) specification in vertebrates.…”

“…Downregulation of METTL3 in zebrafish embryos and in the mouse aorta-gonad-mesonephros (AGM), the region of the primary origins of the definitive HSC in vertebrates, strongly affect HSC production by repressing Notch signaling [66]. It was also shown that the embryonic METTL3 function in the haematopoietic system is mediated by the YTHDF2 dependent decay of Notch encoding mRNA [66].…”

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

“…Here, we establish a novel link between TARBP2 intronic binding, m 6 A methylation, and controlled intron retention leading to transcript degradation in the nucleus. Although RNA methylation marks impact a variety of developmental and disease processes (Zhang et al, 2017a(Zhang et al, , 2017b (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

Long Noncoding RNA Discovery in Cardiovascular Disease

“…112 The same RNA signature can exert powerful effects on progenitor cell specificity and function. 113 More recently, Werner et al 114 described a unique class of lncRNAs based on their chromatin-binding features known as cheRNAs. The CheRNA HIDALGO (hemin-induced cheRNA downstream of fetal hemoglobin) stimulates the fetal HBG1 gene during erythroid differentiation by promoting contacts to a downstream enhancer.…”