Cell Stem Cell
Volume 15, Issue 6, 4 December 2014, Pages 707-719
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Article
m6A RNA Modification Controls Cell Fate Transition in Mammalian Embryonic Stem Cells

https://doi.org/10.1016/j.stem.2014.09.019Get rights and content
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Highlights

  • m6A methylomes in ESCs mark the pluripotency network

  • m6A methylomes in human and mouse ESCs are highly conserved

  • m6A is guided by primary sequence and associated with mRNA turnover

  • m6A loss promotes ESC self-renewal and hinders differentiation

Summary

N6-methyl-adenosine (m6A) is the most abundant modification on messenger RNAs and is linked to human diseases, but its functions in mammalian development are poorly understood. Here we reveal the evolutionary conservation and function of m6A by mapping the m6A methylome in mouse and human embryonic stem cells. Thousands of messenger and long noncoding RNAs show conserved m6A modification, including transcripts encoding core pluripotency transcription factors. m6A is enriched over 3′ untranslated regions at defined sequence motifs and marks unstable transcripts, including transcripts turned over upon differentiation. Genetic inactivation or depletion of mouse and human Mettl3, one of the m6A methylases, led to m6A erasure on select target genes, prolonged Nanog expression upon differentiation, and impaired ESC exit from self-renewal toward differentiation into several lineages in vitro and in vivo. Thus, m6A is a mark of transcriptome flexibility required for stem cells to differentiate to specific lineages.

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