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Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse

Abstract

Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A–inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.

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Figure 1: Hippocampal glucocorticoid receptor expression.
Figure 2: Methylation of the NR3C1 promoter in the hippocampus.
Figure 3: In vitro analysis of NR3C1 promoter methylation.
Figure 4: NGFI-A association with exon 1F NR3C1 promoter constructs.

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Acknowledgements

This research was supported by grants from the US National Institutes of Health (National Institute of Child Health and Human Development; M.J.M. and M.S.), the Canadian Institutes for Health Research (M.J.M., M.S. and G.T.), a Team Grant from the Human Frontiers Science Program (M.J.M. and M.S.) and a Maternal Adversity, Vulnerability and Neurodevelopment Project grant from the Canadian Institutes for Health Research (M.J.M. and M.S.).

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Correspondence to Moshe Szyf, Gustavo Turecki or Michael J Meaney.

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McGowan, P., Sasaki, A., D'Alessio, A. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12, 342–348 (2009). https://doi.org/10.1038/nn.2270

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