m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells

N6-methyl-adenosine (m(6)A) 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 m(6)A by mapping the m(6)A methylome in mouse and human embr...

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Bibliographic Details
Published in:Cell stem cell 2014-12, Vol.15 (6), p.707-719
Main Authors: Batista, Pedro J, Molinie, Benoit, Wang, Jinkai, Qu, Kun, Zhang, Jiajing, Li, Lingjie, Bouley, Donna M, Lujan, Ernesto, Haddad, Bahareh, Daneshvar, Kaveh, Carter, Ava C, Flynn, Ryan A, Zhou, Chan, Lim, Kok-Seong, Dedon, Peter, Wernig, Marius, Mullen, Alan C, Xing, Yi, Giallourakis, Cosmas C, Chang, Howard Y
Format: Article
Language:English
Subjects:
Adenine - analogs & derivatives
Adenine - metabolism
Animals
Base Sequence
Cell Differentiation - genetics
Cell Line
Cell Lineage - genetics
Cell Proliferation - genetics
Conserved Sequence - genetics
Embryonic Stem Cells - physiology
Female
Gene Expression Regulation, Developmental
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Methyltransferases - genetics
Methyltransferases - metabolism
Mice
Mice, SCID
Molecular Sequence Data
Mutation - genetics
Nanog Homeobox Protein
RNA Processing, Post-Transcriptional - genetics
RNA, Small Interfering - genetics
Transcriptome
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Summary:N6-methyl-adenosine (m(6)A) 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 m(6)A by mapping the m(6)A methylome in mouse and human embryonic stem cells. Thousands of messenger and long noncoding RNAs show conserved m(6)A modification, including transcripts encoding core pluripotency transcription factors. m(6)A 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 m(6)A methylases, led to m(6)A 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, m(6)A is a mark of transcriptome flexibility required for stem cells to differentiate to specific lineages.
ISSN:1875-9777
DOI:10.1016/j.stem.2014.09.019