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Behav Brain Res. 2015 Jun 1;286:236-240. doi: 10.1016/j.bbr.2015.03.002. Epub 2015 Mar 6.

Hippocampal increase of 5-hmC in the glucocorticoid receptor gene following acute stress.

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Neuroscience training program, Departments of, University of Wisconsin, Madison, WI, USA.
Department of Psychiatry, University of Wisconsin, Madison, WI, USA.
Department of Pediatrics, University of Wisconsin, Madison, WI, USA.
The Waisman Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Biotechnology Center, University of Wisconsin, Madison, WI, USA.
Contributed equally


5-Hydroxymethylcytosine (5-hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Recently, 5-hmC was functionally linked to learning and cognition and these studies revealed an accumulation of 5-hmC in the prefrontal cortex of mice undergoing fear extinction. These studies led us to hypothesize a role for 5-hmC in response to stress. To test this hypothesis, we combined immunohistochemistry, tandem mass spectrometry, and tet-assisted sodium bisulfite sequencing (TAB-seq) analyses on tissue and DNA from the hippocampus of 7-week old male mice exposed to a single 30-min restraint stress. After first identifying that the broad neuronal distribution of 5-hmC is not disrupted by acute stress, we used TAB-seq to find a stress-induced increase of 5-hmC in the 3'UTR of the glucocorticoid receptor gene (Nr3c1). Nr3c1 has a well-defined role in the stress pathway and these data suggest that 5-hmC contributes to these processes. Together, these data indicate that a deeper investigation of stress-related 5-hmC levels may reveal an environmental impact on this newly discovered epigenetic mark in the brain.


5-hmC; Acute stress; DNA methylation; Epigenetics

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