O-GlcNAc regulates gene expression by controlling detained intron splicing. Issue 10 (24th April 2020)

• Record Type: Journal Article
• Authors: Tan, Zhi-Wei; Fei, George; Paulo, Joao A; Bellaousov, Stanislav; Martin, Sara E S; Duveau, Damien Y; Thomas, Craig J; Gygi, Steven P; Boutz, Paul L; Walker, Suzanne
• Is Part Of: Nucleic acids research. Volume 48:Issue 10(2020)
• Page Start: 5656
• Page End: 5669
• Publication Date: 2020-04-24
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkaa263
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Intron detention in precursor RNAs serves to regulate expression of a substantial fraction of genes in eukaryotic genomes. How detained intron (DI) splicing is controlled is poorly understood. Here, we show that a ubiquitous post-translational modification called O-GlcNAc, which is thought to integrate signaling pathways as nutrient conditions fluctuate, controls detained intron splicing. Using specific inhibitors of the enzyme that installs O-GlcNAc (O-GlcNAc transferase, or OGT) and the enzyme that removes O-GlcNAc (O-GlcNAcase, or OGA), we first show that O-GlcNAc regulates splicing of the highly conserved detained introns in OGT and OGA to control mRNA abundance in order to buffer O-GlcNAc changes. We show that OGT and OGA represent two distinct paradigms for how DI splicing can control gene expression. We also show that when DI splicing of the O-GlcNAc-cycling genes fails to restore O-GlcNAc homeostasis, there is a global change in detained intron levels. Strikingly, almost all detained introns are spliced more efficiently when O-GlcNAc levels are low, yet other alternative splicing pathways change minimally. Our results demonstrate that O-GlcNAc controls detained intron splicing to tune system-wide gene expression, providing a means to couple nutrient conditions to the cell's transcriptional regime.