No abstract

Historically, N6-methyladenosine (m6A) has been identified as the most abundant internal modification of messenger RNA (mRNA) in eukaryotes 1. Its mammalian function remained unknown until recently, when it was reported that thousands of mammalian mRNAs and long noncoding RNAs (lncRNAs) show m6A modification 2,3 and that m6A demethylases are required for mammalian energy homeostasis and fertility 4,5. As yet, the identity of m6A methyltransferases (MTase) and the molecular mechanisms regulated by m6A remains unclear. Here, we show that two proteins, the putative m6A MTase, methyltransferase-like 3 (Mettl3) 6, and a related but uncharacterized protein Mettl14, function synergistically to control m6A formation in mammalian cells. Since m6A modification is involved in cell fate determination in yeast 7,8 and embryo development in plant 9,10, we knocked down Mettl3 and Mettl14, respectively, in mouse embryonic stem cells (mESCs). The resulting cells displayed equivalent phenotypes characterized by lack of m6A RNA methylation and lost self-renewal capability. We also observed that a large number of transcripts, including many encoding developmental regulators, showed m6A methylation inversely correlated with mRNA stability and gene expression. Further analysis suggested that some of these effects were mediated through Human antigen R (HuR) and microRNA pathways. Overall our work provides first experimental evidence of mammalian m6A MTases and reveals a previously unknown gene regulatory mechanism operating in mESCs through m6A methylation. This mechanism is required to keep mESCs at their ground state and may be relevant to thousands of mRNAs and lncRNAs in various cell types.

Elevated cardiac-specific miR-208a in plasma may be a novel biomarker for early detection of myocardial injury in humans.

No abstract

SUMMARY Mutations affecting spliceosomal proteins are the most common class of mutations in patients with myelodysplastic syndromes (MDS), yet their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2’s normal sequence-specific RNA binding activity, thereby altering recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2 that triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in splicing of key regulators, and impaired hematopoiesis.