FTO controls reversible m⁶Am RNA methylation during snRNA biogenesis

Area of Science:

• Molecular Biology
• RNA Biology
• Epigenetics

Background:

• Small nuclear RNAs (snRNAs) are essential for pre-mRNA splicing within the spliceosome.
• The methylation status of snRNAs is crucial for their function.
• Previous research has not fully elucidated the dynamic regulation of snRNA methylation.

Purpose of the Study:

• To investigate the existence and regulation of distinct methyl isoforms of snRNAs.
• To identify the enzymes involved in snRNA methylation and demethylation.
• To explore the functional consequences of snRNA methylation on alternative splicing.

Main Methods:

• Analysis of snRNA methylation states (m1 and m2 isoforms).
• Investigating the role of RNA demethylase FTO in regulating snRNA methylation.
• Assessing the impact of D-2-hydroxyglutarate on FTO activity and snRNA levels.
• Studying alternative splicing patterns in cells with varying m2-snRNA levels.

Main Results:

• snRNAs exist in two methyl isoforms: m1 (2'-O-methyladenosine, Am) and m2 (N6,2'-O-dimethyladenosine, m6Am).
• snRNA biogenesis involves conversion from m1 to m2, regulated by FTO which demethylates m2.
• FTO activity is inhibited by D-2-hydroxyglutarate, leading to increased m2-snRNA.
• High m2-snRNA levels correlate with altered alternative splicing patterns.

Conclusions:

• FTO controls a novel, reversible methylation step in snRNA processing.
• Epitranscriptomic modifications on snRNAs can influence mRNA splicing.
• This discovery opens new avenues for understanding gene regulation and potential therapeutic targets.