Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome
- City of Hope, United States
- Translational Genomics Research Institute, United States
Abstract
The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by O-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O-GlcNAcylated on human DNMT1. Functional studies in human and mouse cells further revealed that O-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that preferentially occurs at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish O-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.
Data availability
PromethION sequencing data have been deposited in the NCBI Gene Expression Omnibus (GEO) and Sequence Read Archive (SRA) under accession no. GSE201470. Mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD043031.
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Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenomeNCBI Gene Expression Omnibus, GSE201470.
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Whole-genome analysis of the methylome and hydroxymethylome in normal and malignant lung and liverNCBI Gene Expression Omnibus, GSE70091.
Article and author information
Author details
Funding
National Institutes of Health (R01DK112041)
- Dustin E Schones
National Institutes of Health (R01CA220693)
- Dustin E Schones
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments conducted have been approved by the Institutional Animal Care and Use Committees at City of Hope. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#17010).
Reviewing Editor
- Carlos Isales, Augusta University, United States
Version history
- Preprint posted: May 11, 2022 (view preprint)
- Received: December 15, 2022
- Accepted: July 19, 2023
- Accepted Manuscript published: July 20, 2023 (version 1)
- Version of Record published: July 31, 2023 (version 2)
Copyright
© 2023, Shin et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome
eLife 12:e85595.
https://doi.org/10.7554/eLife.85595
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