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Abstract
Regulation of glucocorticoid receptor (GR) levels is an important stress adaptation mechanism. Transcription factor Nfgi-a and environmentally induced Gr promoter 17 methylation have been implicated in fine-tuning the expression of Gr 17 transcripts. Here, we investigated Gr promoter 17 methylation and Gr 17 expression in adult rats exposed to either acute or chronic stress paradigms. A strong negative correlation was observed between the sum of promoter-wide methylation levels and Gr 17 transcript levels, independent of the stressor. Methylation of individual sites did not, however, correlate with transcript levels. This suggested that promoter 17 was directly regulated by promoter-wide DNA methylation. Although acute stress increased Ngfi-a expression in the hypothalamic paraventricular nucleus (PVN), Gr 17 transcript levels remained unaffected despite low methylation levels. Acute stress had little effect on these low methylation levels, except at four hippocampal CpGs. Chronic stress altered the corticosterone response to an acute stressor. In the adrenal and pituitary glands, but not in the brain, this was accompanied by an increase in methylation levels in orchestrated clusters rather than individual CpGs. PVN methylation levels, unaffected by acute or chronic stress, were significantly more variable within- than between-groups, suggesting that they were instated probably during the perinatal period and represent a pre-established trait. Thus, in addition to the known perinatal programming, the Gr 17 promoter is epigenetically regulated by chronic stress in adulthood, and retains promoter-wide tissue-specific plasticity. Differences in methylation susceptibility between the PVN in the perinatal period and the peripheral HPA axis tissues in adulthood may represent an important “trait” vs. “state” regulation of the Gr gene.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
We would like to thank Kiki Gortzak for her technical assistance, and we are grateful to Hartmut Schächinger for his initiatives within the Trier-Leiden International Research Training Group (IRTG GRK 1389/1) and the Graduate School of Psychobiology. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (GRK 1389/1) and grants from the Fonds National de la Recherche, Luxembourg (AFR grants TR-PHD BFR07-043, EXT-BFR07-043 TR).
Supplemental Materials
Supplemental materials may be found here: www.landesbioscience.com/journals/epigenetics/article/22363
