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N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells
Open accessAbstract
N6-methyladenosine (m6A) has been identified as the most abundant internal modification of messenger RNA in eukaryotes. m6A modification is involved in cell fate determination in yeast and embryo development in plants. Its mammalian function remains unknown but thousands of mammalian mRNAs and long non-coding RNAs (lncRNAs) show m6A modification and m6A demethylases are required for mammalian energy homeostasis and fertility. We identify two proteins, the putative m6A MTase, methyltransferase-like 3 (Mettl3; ref. ), and a related but uncharacterized protein Mettl14, that function synergistically to control m6A formation in mammalian cells. Knockdown of Mettl3 and Mettl14 in mouse embryonic stem cells (mESCs) led to similar phenotypes, characterized by lack of m6A RNA methylation and lost self-renewal capability. A large number of transcripts, including many encoding developmental regulators, exhibit m6A methylation inversely correlated with mRNA stability and gene expression. The human antigen R (HuR) and microRNA pathways were linked to these effects. This gene regulatory mechanism operating in mESCs through m6A methylation is required to keep mESCs at their ground state and may be relevant to thousands of mRNAs and lncRNAs in various cell types.
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Metadata
- Authors
- Wang, Y., Li, Y., Toth, J. I., Petroski, M. D., Zhang, Z., & Zhao, J. C.
- Venue
- Nature Cell Biology
- Published
- 2014-01-07
- Volume
- 16
- Issue
- 2
- Pages
- 191-198
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2009308529
- Cited by
- 1,290
- References
- 13
- FWCI
- 28.84
- Type
- journal article
- Language
- en
- Open access
- green
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