O-GlcNAc regulates gene expression by controlling detained intron splicing

Nucleic Acids Res. 2020 Jun 4;48(10):5656-5669. doi: 10.1093/nar/gkaa263.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism*
  • Cell Line
  • Glycoside Hydrolases / genetics*
  • Glycoside Hydrolases / metabolism
  • HEK293 Cells
  • Humans
  • Introns*
  • N-Acetylglucosaminyltransferases / antagonists & inhibitors
  • N-Acetylglucosaminyltransferases / genetics*
  • N-Acetylglucosaminyltransferases / metabolism
  • Phosphorylation
  • RNA Splicing Factors / metabolism
  • RNA Splicing*
  • RNA, Messenger / metabolism
  • RNA-Seq


  • RNA Splicing Factors
  • RNA, Messenger
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • Glycoside Hydrolases
  • Acetylglucosamine