N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells

Abstract

N6-methyladenosine (m6A) is an abundant internal modification of messenger RNA (mRNA) that has been reported recently in thousands of mammalian mRNAs and long non-coding RNAs (lncRNAs). Zhao and colleagues identify two methyltransferases responsible for this modification in mammalian cells, and demonstrate that they are required for embryonic stem cell self-renewal maintenance through an effect of the modification on the degradation of developmental regulator transcripts. N6-methyladenosine (m6A) has been identified as the most abundant internal modification of messenger RNA in eukaryotes1. m6A modification is involved in cell fate determination in yeast2,3 and embryo development in plants4,5. Its mammalian function remains unknown but thousands of mammalian mRNAs and long non-coding RNAs (lncRNAs) show m6A modification6,7 and m6A demethylases are required for mammalian energy homeostasis and fertility8,9. We identify two proteins, the putative m6A MTase, methyltransferase-like 3 (Mettl3; ref. 10), 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.