m⁶A drives structural changes in RNA

N⁶-methyladenosine (m⁶A) is the most abundant RNA modification in eukaryotes, present in a large subset of the transcriptome. m⁶A is thought to act as a dynamic switch that affects processes such as RNA degradation, localization and splicing. Although 'writers', 'erasers' and 'readers' of this mark have been identified, the mode by which m⁶A exerts its functions is still poorly understood. Parisien, Pan and colleagues now demonstrate that m⁶A controls RNA-protein interactions by altering local RNA structure. The authors initially identify heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNP C) as a protein that preferentially interacts with an m⁶A-modified hairpin originating from the long noncoding RNA MALAT1. hnRNP C affects pre-mRNA processing and binds nascent RNA transcripts via single-stranded U tracts. Curiously, the hnRNP C–binding site in the MALAT1 hairpin is located opposite the m⁶A-modification site. Adenosine methylation is known to destabilize RNA duplexes, and indeed m⁶A modification of the MALAT1 hairpin increased the accessibility of its opposing U tract. Transcriptome-wide analyses indicated that these 'm⁶A switches' are common: 7% of all hnRNP C–binding sites corresponded to an m⁶A-modified consensus motif located in the vicinity of a poly(U) tract. hnRNP C PAR-CLIP experiments in cells expressing siRNAs targeting METTL3 and METTL14, two enzymes involved in m⁶A deposition, demonstrated that a substantial number of the identified m⁶A switches showed decreased hnRNP C binding upon m⁶A depletion. Subsequent analysis of these 'high-confidence' m⁶A switches supported the finding that m⁶A influences hnRNP C binding by altering RNA structure, with striking effects on RNA abundance and splicing. The identification of m⁶A as a structural remodeler opens a new perspective on its mechanism of action, and it will be interesting to learn how many other RNA-binding proteins are affected by this mechanism. (Nature doi:10.1038/nature14234, 26 February 2015).