Genome-wide methylation patterns associated with chronic stress
- 13 hours ago
- 2 min read
Feb. 2026
Nicholas O’Toole, Tie-Yuan Zhang, Eamon Fitzgerald, Xianglan Wen, Josie Diorio, Patricia P. Silveira, Benoit Labonté, Eric J. Nestler & Michael J Meaney
ABSTRACT
Background
Chronic social defeat stress (CSDS) is a validated animal model for depression that produces sustained behavioral and transcriptional changes in the brain, notably the nucleus accumbens (nAcc).
Research design and methods
We used genome-wide analysis of cytosine methylation patterns in mouse nAcc following CSDS to identify candidate epigenetic mechanisms.
Results
CSDS produced extensive differential methylation, increasing CG hypermethylation compared to control conditions; non-CG methylation showed the opposite trend. Highly differentially methylated (DM) regions included several genes implicated in behavioral effects of CSDS, including estrogen receptor alpha (Esr1).
Conclusions
Analysis of DM sites within gene bodies revealed ß-catenin as a hub gene of a network including the ß-catenin-related WNT/frizzled signaling pathway. Analysis of DM sites upstream of transcription start sites revealed a gene network with the Tcf4 transcription factor as a hub. Genes DM within the gene body were enriched for synaptic function and primarily expressed in D1+ and D2+ medium spiny neurons, which, like the WNT/ß-catenin pathway, are estrogen sensitive and implicated in the behavioral effects of CSDS. We found significant overlap between DM genes associated with CSDS and those associated with major depressive disorder in genome-wide association studies, suggesting that effects on DNA methylation are implicated in the molecular pathways that link chronic stress to depression.
Plain Language Summary
Depression is a serious health problem affecting millions of people worldwide. One of the major risk factors for depression is long-term stress. To better understand how stress affects the brain and its links to depression, we studied mice exposed to chronic social defeat stress – a model which mimics features of depression in humans. The research focused on an area of the brain called the nucleus accumbens, which is well known to regulate motivational and emotional responses. DNA methylation is a modification to DNA that can turn genes “on” or “off” without altering the genetic code itself. In this study, we obtained data on methylation across the entire mouse genome at the resolution of single bases of DNA. It was found that stress caused widespread methylation changes throughout the genome. Some of the genes that contained the highest levels of methylation changes are known to be involved in stress and depression. Importantly, many of these genes overlapped with ones associated with depression in human studies. We identified networks of genes affected by stress, one centered on the gene which produces a protein called β-catenin, another on the transcription factor Tcf4. These genes are involved in communication between brain cells. Our results suggest that stress-induced methylation changes in the brain could be one of the ways that chronic stress increases the risk for depression. Further understanding of the mechanisms involved may eventually lead to new approaches for the prevention or treatment of depression.
CITE
O’Toole, N., Zhang, T. Y., Fitzgerald, E., Wen, X., Diorio, J., Silveira, P. P., … Meaney, M. J. (2026). Genome-wide methylation patterns associated with chronic stress. Epigenomics, 18(1), 73–88. https://doi.org/10.1080/17501911.2026.2613012
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