N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells

By Yang Wang, Yue Li, Julia I. Toth, M. Petroski, Zhaolei Zhang, Jing Crystal Zhao. Nature Cell Biology, 2014

1,138 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/436512064ca09bf29196de910347024453eea047

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Citations in the corpus

Tools for Sequence-Based miRNA Target Prediction: What to Choose? (2016, background): “Among these factors some regulatory processes, such as the binding of proteins to RNA [76] and the methylation of several RNA sites [77].”
Rethinking m6A Readers, Writers, and Erasers (2017, methodology): “…and stability, as well as the epigenetic effects of certain noncoding RNAs (Dominissini et al. 2012; Meyer et al. 2012, 2015; Patil et al. 2016; X. Wang et al. 2014, 2015; Xiao et al. 2016). m6A was first detected in poly(A) RNA fractions in 1974 (Desrosiers et al. 1974, Perry & Kelley 1974), but…”
Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d (2018, background): “…3 (METTL3; also calledMT-A70) (Bokar et al. 1997), which physically interacts with METTL14 (Liu et al. 2014; Ping et al. 2014; Schwartz et al. 2014; Wang et al. 2014), Wilms tumor 1-associated protein (WTAP) (Zhong et al. 2008; Agarwala et al. 2012), Virlike m6A methyltransferase-associated…”
YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs (2017, methodology): “Firefly luciferase was fused to five copies of the BoxB sequence and placed under control of a Tet-off promoter (Wang et al., 2014a).”
METTL3 promotes translation in human cancer cells (2016, methodology): “Consistent with published studies, a ‘‘GGAC’’ sequence motif was enriched in the immunopurified RNA, and a metagene analysis revealed that m(6)A peaks were predominantly localized near stop codons, with a subset of m(6)A peaks located in the 50 UTR and internal exons (Figures 1A and 1B) (Dominissini”
Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “Depletion of METTL14 causes a block in embryonic stem cell self-renewal and differentiation, embryonic developmental defects, and impaired gametogenesis in various organisms.(55,69,75) METTL14 and METTL3 participate in neurogenesis by modulating cell-cycle progression of cortical neural progenitor c”
Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation (2017, positive): “Cg-Tg(Nes-cre)1Kln/J Jackson Laboratory 003771 RRID: IMSR_JAX:003771 Mouse: Mettl14floxed;floxed From Dr. Chuan He N/A Mouse: Crl:CD1(ICR) Charles River Laboratory RRID: IMSR_CRL:22 Mouse: Crl:CF188 Charles River Laboratory RRID:IMSR_CRL:23 Oligonucleotides shRNA control sequence for mouse and human”
METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification (2017, background): “MYB and MYC It has been shown that m6A marks on mRNA transcripts affect mRNA stability and translation (Wang et al., 2014a; Li et al., 2017; Wang et al., 2015).”
Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases (2016, neutral): “In vitro studies showed that Mettl3 and Mettl14 help each other’s protein stability, and that they synergize to produce m(6)A marks on cognate RNA oligonucleotides (Liu et al., 2014; Wang et al., 2014b).”