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m6A modulates haematopoietic stem and progenitor cell specification
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Journal Article
m6A modulates haematopoietic stem and progenitor cell specification
2017
Overview
N
6
-methyladenosine modification of mRNA determines cell fate decisions during the specification of the first haematopoietic stem cells in zebrafish.
Stem cell specification by m
6
A
Adding modified
N
6
-methyladenosine (m
6
A) on messenger RNA (mRNA) has recently been reported to modulate mRNA translation and degradation. However, the effects of the modification on vertebrate development are so far unclear. Feng Liu and colleagues show that addition of m
6
A determines cell fate during the specification of the earliest haematopoietic stem cell in zebrafish. Blocking addition of this modification on genes that regulate Notch signalling maintains the endothelial fate of progenitors that should be specified as the earliest haematopoietic stem cell progenitors.
N
6
-methyladenosine (m
6
A) has been identified as the most abundant modification on eukaryote messenger RNA (mRNA)
1
. Although the rapid development of high-throughput sequencing technologies has enabled insight into the biological functions of m
6
A modification
2
,
3
,
4
,
5
,
6
,
7
,
8
,
9
,
10
,
11
,
12
,
13
, the function of m
6
A during vertebrate embryogenesis remains poorly understood. Here we show that m
6
A determines cell fate during the endothelial-to-haematopoietic transition (EHT) to specify the earliest haematopoietic stem/progenitor cells (HSPCs) during zebrafish embryogenesis. m
6
A-specific methylated RNA immunoprecipitation combined with high-throughput sequencing (MeRIP–seq) and m
6
A individual-nucleotide-resolution cross-linking and immunoprecipitation with sequencing (miCLIP–seq) analyses reveal conserved features on zebrafish m
6
A methylome and preferential distribution of m
6
A peaks near the stop codon with a consensus RRACH motif. In
mettl3
-deficient embryos, levels of m
6
A 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 m
6
A modification in the fate determination of HSPCs during vertebrate embryogenesis.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
