AsianScientist (Sep. 15, 2017) – Researchers in China have revealed how the mRNA methylation machinery in zebrafish embryos affects fate determination of hematopoietic stem cells. They report their findings in the journal Nature.
Hematopoietic stem cells (HSCs) are the only cells which have the capability to self-renew and differentiate into all blood lineages. The limit of the donors to provide sufficient HSCs in the clinic makes it urgent to produce HSCs ex vivo or in vitro in regenerative medicine.
In vertebrate embryos, HSCs are derived from hemogenic endothelium, a subset of endothelial cells in the ventral wall of the dorsal aorta, through a process known as endothelial-to-hematopoietic transition (EHT).
After decades of studies in this field, scientists have achieved some basic understanding about developmental hematopoiesis in vivo and have tried to recapitulate it in vitro to some extent. However, the detailed regulatory mechanism underlying this cell fate change during EHT is still largely unclear, and the role of epigenetic modification in this process is especially obscure.
N6-methyl-adenosine (m6A) is one of the most prevalent mRNA modifications in eukaryotes. There are three classes of proteins that regulate these epigenetic marks: m6A ‘writers’ (methyltransferase complex proteins such as METTL3, WTAP and METTL14), ‘readers’ (RNA binding proteins such as the YTH family members) and ‘erasers’ (demethylases such as FTO and ALKBH5).
Recently, a series of seminal studies have begun to reveal the important functions of m6A, including the maternal-to-zygotic transition in zebrafish, sex determination in drosophila and T cell homeostasis in mouse. However, the physiological functions and regulatory mechanism of m6A modification, especially during embryogenesis in vertebrates still remain elusive.
In this study, the Hematopoietic and Cardiovascular Development Group led by Professor Liu Feng from the Institute of Zoology of the Chinese Academy of Sciences (CAS) made use of two model systems—the zebrafish and the mouse—to study the regulatory mechanism of HSC development. The work was performed in collaboration with Professor Yang Yungui from Beijing Institute of Genomics of CAS.
The research team carried out m6A-sequencing in zebrafish embryos and found that the m6A enrichment on embryonic development-related mRNAs was significantly decreased upon the loss of METTL3.
Moreover, METTL3 is specifically expressed in the hemato-vascular systems in zebrafish embryos, indicating a potential function of METTL3-mediated m6A modification in hematopoietic development.
Further experiments revealed that, upon METTL3 depletion, the endothelial cell fate was enhanced, but the EHT was blocked, thereby leading to the failure of HSC generation. Bioinformatics analysis of m6A-sequencing and RNA-sequencing data revealed that the m6A modification on a series of arterial endothelial cell related genes, especially NOTCH1a mRNA, was decreased, while their mRNA levels were increased.
They then demonstrated that YTHDF2, an RNA binding protein, mediates m6A-modified NOTCH1a mRNA stability, supporting their hypothesis that m6A functions as a rheostat to maintain the balance of gene expression between endothelial cells and HSC during EHT.
These findings were also confirmed in mouse experiments, suggesting the evolutionally conserved function of m6A in HSC development across vertebrates.
Therefore, this study uncovers the regulatory mechanism of m6A mRNA methylation in vertebrate hematopoietic stem cell fate determination and provides useful insights to the in vitro generation of HSCs for clinical application.
The article can be found at: Zhang et al. (2017) m6A Modulates Hematopoietic Stem and Progenitor Cell Specification.
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Source: Chinese Academy of Sciences.
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