snRNAs Exist as Different Methyl Isoforms and Are Targets of FTO

Small nuclear RNAs (snRNA) are uridine-rich noncoding RNAs that are incorporated into small nuclear ribonucleoproteins as part of the spliceosome to regulate pre-mRNA splicing. snRNAs undergo a series of nucleotide modifications over the course of their biogenesis that are essential for their function, with mature snRNAs thought to harbor a single set of final modifications. Mauer and colleagues made the unexpected discovery that a subset of spliceosomal snRNAs exist in two distinct isoforms differing in the methylation state of the adenosine residue immediately adjacent to the snRNA cap: a single-methylated m₁ isoform with 2′-O-methyladenosine (Am) and a dimethylated m₂ isoform with N⁶,2′-O-dimethyladenosine (m⁶Am). The methylation is reversible, with demethylation of m₂ snRNAs mediated by fat mass and obesity-associated protein (FTO), an RNA demethylase thought to primarily target N⁶-methyladenosine on mRNA. However, mRNAs are predominantly cytoplasmic whereas FTO is nuclear, raising the possibility that snRNAs are the major cellular targets of FTO. Of note, FTO is an α-KG–dependent dioxygenase that is inhibited by the metabolite D-2-hydroxyglutarate, which is generated at abnormally high levels in the presence of cancer-associated isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations. m₂ snRNA levels were significantly increased upon FTO knockout or in the presence of mutant IDH1 or IDH2 and could be restored by mutant isoform-selective IDH inhibitors. FTO deficiency also led to increased exon inclusion, and preliminary data suggested that higher m⁶Am in the absence of FTO might affect total levels of some snRNAs and spliceosome composition. Although further work is needed to determine the exact roles of snRNA methyl isoforms, these findings expand our understanding of epitranscriptomic regulation by FTO, suggest that reversible methylation of snRNA may affect alternative splicing, and link cancer-associated mutations to altered snRNA methylation.

Mauer J, Sindelar M, Despic V, Guez T, Hawley BR, Vasseur JJ, et al. FTO controls reversible m⁶Am RNA methylation during snRNA biogenesis. Nat Chem Biol 2019 Feb 18 [Epub ahead of print].

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