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  • O-GlcNAc regulates gene expression by controlling detained intron splicing.

O-GlcNAc regulates gene expression by controlling detained intron splicing.

Nucleic acids research (2020-04-25)
Zhi-Wei Tan, George Fei, Joao A Paulo, Stanislav Bellaousov, Sara E S Martin, Damien Y Duveau, Craig J Thomas, Steven P Gygi, Paul L Boutz, Suzanne Walker
초록

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.

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Sigma-Aldrich
Trimethylgallium, packaged for use in deposition systems
Sigma-Aldrich
OSMI-2, ≥98% (HPLC)
Sigma-Aldrich
Thiamet G, ≥98% (HPLC)