Strong evidence of an epigenetic effect on mRNA that modulates hematopoietic stem cell fate and progenitor cell specification

In previous GEITP emails, we have emphasized the importance of genetics, epigenetic effects, AND environmental factors –– all contributing to a phenotype (trait) –– whether the trait is a complex disease, drug efficacy or toxicity, or some metric (quantitative measurement) such as height or body mass index. Classically, “epigenetic effects” include nucleic acid-methylatiion, RNA-interference, histone modifications, and chromatin remodeling. This article [attached] describes nucleic acid (RNA)-methylation, and the trait being measured is determination of cell fate during the endothelial-to-hematopoietic transition (EHT) to specify the earliest hematopoietic (blood cell-forming) stem/progenitor cells (HSPCs) during zebrafish embryogenesis.

In vertebrates, which include zebrafish, HSPCs are derived from hemogenic endothelium –– a subset of endothelial cells in the ventral wall of dorsal aorta, by means of endothelial-to-hematopoietic transition (EHT) during embryogenesis. Previous studies have suggested the role of N6-methyladenosine (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. Given the early embryolethality of mice having the complete knockout of the m6A methyltransferase catalytic subunit Mettl3, authors herein chose to investigate the m6A methylome during embryogenesis of zebrafish.

The m6A appears to be the most abundant modification of messenger RNA (mRNA) in animals having pairs of chromosomes (eukaryotes). Herein authors show that m6A determines cell fate during the EHT, to specify the earliest HSPCs during zebrafish embryogenesis. In Mettl3-deficient embryos, levels of m6A are significantly decreased, and emergence of HSPCs is blocked. Mechanistically, authors determined that the YTH N6-methyladenosine RNA-binding protein-2 (YTHDF2)-mediated mRNA decay of the arterial endothelial genes Notch1a and Rhoca contributes to this deleterious effect. The continuous activation of Notch-signaling in arterial endothelial cells of Mettl3-deficient embryos blocks the EHT, thereby repressing generation of the earliest HSPCs. Furthermore, knockdown of Mettl3 in mice confers a similar phenotype. Collectively, the exciting findings in the attached paper demonstrate the critical function of m6A modification in the fate determination of HSPCs during vertebrate embryogenesis.

Nature 14 Sept 2o17; 549: 273–276

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