Open AccessFTO controls reversible m6Am RNA methylation during snRNA biogenesis
Author(s) -
Jan Mauer,
Miriam Sindelar,
Vladimir Despic,
Théo Guez,
Ben R Hawley,
JeanJacques Vasseur,
Andrea Rentmeister,
Steven S. Gross,
Livio Pellizzoni,
Hani Goodarzi,
Samie R. Jaffrey
Publication year - 2019
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-019-0231-8
Subject(s) - small nuclear rna , rna splicing , spliceosome , n6 methyladenosine , snrnp , biogenesis , methylation , biology , gene isoform , rna methylation , alternative splicing , rna , prp24 , microbiology and biotechnology , messenger rna , precursor mrna , biochemistry , non coding rna , gene , methyltransferase
Small nuclear RNAs (snRNAs) are core spliceosome components and mediate pre-mRNA splicing. Here we show that snRNAs contain a regulated and reversible nucleotide modification causing them to exist as two different methyl isoforms, m 1 and m 2 , reflecting the methylation state of the adenosine adjacent to the snRNA cap. We find that snRNA biogenesis involves the formation of an initial m 1 isoform with a single-methylated adenosine (2'-O-methyladenosine, Am), which is then converted to a dimethylated m 2 isoform (N 6 ,2'-O-dimethyladenosine, m 6 Am). The relative m 1 and m 2 isoform levels are determined by the RNA demethylase FTO, which selectively demethylates the m 2 isoform. We show FTO is inhibited by the oncometabolite D-2-hydroxyglutarate, resulting in increased m 2 -snRNA levels. Furthermore, cells that exhibit high m 2 -snRNA levels show altered patterns of alternative splicing. Together, these data reveal that FTO controls a previously unknown central step of snRNA processing involving reversible methylation, and suggest that epitranscriptomic information in snRNA may influence mRNA splicing.