PT  - JOURNAL ARTICLE
AU  - Jan Mauer
AU  - Miriam Sindelar
AU  - Théo Guez
AU  - Jean-Jacques Vasseur
AU  - Andrea Rentmeister
AU  - Steven S. Gross
AU  - Livio Pellizzoni
AU  - Françoise Debart
AU  - Hani Goodarzi
AU  - Samie R. Jaffrey
TI  - The RNA demethylase FTO targets m<sup>6</sup>Am in snRNA to establish distinct methyl isoforms that influence splicing
AID  - 10.1101/327924
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 327924
4099  - http://biorxiv.org/content/early/2018/05/23/327924.short
4100  - http://biorxiv.org/content/early/2018/05/23/327924.full
AB  - Small nuclear RNAs (snRNAs) are core spliceosome components and mediate pre-mRNA splicing. During their biogenesis, snRNAs acquire several constitutive nucleotide modifications. Here we show that snRNAs also contain a regulated and reversible nucleotide modification causing them to exist as two different methyl isoforms, m1 and m2, reflecting the methylation state of the adenosine adjacent to the snRNA cap. We find that snRNA biogenesis involves the formation of an initial m1-isoform with a single-methylated adenosine (2’-O-methyladenosine, Am), which is then converted to a dimethylated m2-isoform (N6,2’-O-dimethyladenosine, m6Am). The relative m1- and m2-isoform levels are determined by the RNA demethylase FTO, which selectively demethylates the m2-isoform. We show FTO is inhibited by endogenous metabolites, resulting in increased m2-snRNA levels. Furthermore, cells that exhibit high m2-snRNA levels show altered patterns of alternative splicing. Together, these data reveal that FTO has a central role in snRNA biogenesis and controls a previously unknown step of snRNA processing involving reversible methylation, thereby providing a potential link between reversible RNA modifications and mRNA splicing.