FTO controls reversible m6Am RNA methylation during snRNA biogenesis. Academic Article uri icon

Overview

abstract

  • 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, 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 the oncometabolite D-2-hydroxyglutarate, 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 controls a previously unknown central step of snRNA processing involving reversible methylation, and suggest that epitranscriptomic information in snRNA may influence mRNA splicing.

publication date

  • February 18, 2019

Research

keywords

  • Adenosine
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • RNA, Small Nuclear

Identity

PubMed Central ID

  • PMC6984009

Scopus Document Identifier

  • 85061700216

Digital Object Identifier (DOI)

  • 10.1038/nature12311

PubMed ID

  • 30778204

Additional Document Info

volume

  • 15

issue

  • 4