Site-specific decreases in DNA methylation in replicating cells following exposure to oxidative stress.

Abstract

Oxidative stress is a common feature of inflammation-driven cancers, and it promotes genomic instability and aggressive tumour phenotypes. It is known that oxidative stress transiently modulates gene expression through the oxidation of transcription factors and associated regulatory proteins. Neutrophils are our most abundant white blood cells and accumulate at sites of infection and inflammation. Activated neutrophils produce hypochlorous acid and chloramines, which can disrupt DNA methylation by oxidizing methionine. The goal of the current study was to determine whether chloramine exposure results in sequence-specific modifications in DNA methylation that enable long-term alterations in transcriptional output. Proliferating Jurkat T-lymphoma cells were exposed to sublethal doses of glycine chloramine and differential methylation patterns were compared using Illumina EPIC 850 K bead chip arrays. There was a substantial genome-wide decrease in methylation 4 h after exposure that correlated with altered RNA expression for 24 and 48 h, indicating sustained impacts on exposed cells. A large proportion of the most significant differentially methylated CpG sites were situated towards chromosomal ends, suggesting that these regions are most susceptible to inhibition of maintenance DNA methylation. This may contribute to epigenetic instability of chromosomal ends in rapidly dividing cells, with potential implications for the regulation of telomere length and cellular longevity.

• Authors: Annika R Seddon, Andrew B Das, Mark B Hampton, Aaron J Stevens
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 32 Issue 4 Pg. 632-648 (01 27 2023) ISSN: 1460-2083 [Electronic] England
• PMID: 36106794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Transcription Factors

Topics

• DNA Methylation (genetics)
• Transcription Factors
• Oxidation-Reduction
• Oligonucleotide Array Sequence Analysis
• Oxidative Stress (genetics)
• CpG Islands (genetics)
• Epigenesis, Genetic