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PreprintCited by 119RNA Research and SplicingGlycosylation and Glycoproteins ResearchRNA and protein synthesis mechanisms

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O-GlcNAc regulates gene expression by controlling detained intron splicing

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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·2020·Nucleic Acids Research
DOI 10.1101/2020.03.27.012781PMC PMC7261177

Preprint — published as 10.1093/nar/gkaa263 · Paper page

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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.

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Metadata

Authors
Tan, Z.-W., Fei, G., Paulo, J. A., Bellaousov, S., Martin, S. E. S., Duveau, D. Y., Thomas, C. J., Gygi, S. P., Boutz, P. L., & Walker, S.
Affiliations
  • Harvard University (US)
  • University of Rochester Medicine (US)
  • National Institutes of Health (US)
Corresponding author
  • Boutz, Paul L.
  • Walker, Suzanne
ORCID
Venue
Nucleic Acids Research
Publisher
openRxiv
Published
2020-03-28
Volume
48
Issue
10
Pages
5656-5669
ISSN
0305-1048 (ISSN-L)
DOI
10.1101/2020.03.27.012781
PMC
PMC7261177
OpenAlex
W3020244548
Cited by
119
References
1
Citations by year
2026: 12 · 2025: 28 · 2024: 22 · 2023: 16 · 2022: 12 · 2021: 21 · 2020: 8
FWCI
4.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • University of Rochester
  • Agency for Science, Technology and Research
  • National Institutes of Health (BB123456, GM034277)
  • National Institute of General Medical Sciences (R01GM034277, R01GM094263, R37GM034277, R01GM132129)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
O-GlcNAc, O-GlcNAc transferase, O-GlcNAcase, intron retention, alternative splicing, gene expression regulation, post-translational modification, nutrient signaling, mRNA levels
MeSH terms
RNA Splicing Factors, RNA-Seq, Acetylglucosamine, Cell Line, Glycoside Hydrolases, Humans, Introns, Phosphorylation, RNA Splicing, RNA, Messenger, N-Acetylglucosaminyltransferases, HEK293 Cells

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