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

Nature Neuroscience volume 12, pages 342348 (2009) | Download Citation

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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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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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Affiliations

  1. Douglas Mental Health University Institute, 6875 LaSalle Boulevard, Montreal, Quebec, H4H 1R3, Canada.

    • Patrick O McGowan
    • , Aya Sasaki
    • , Benoit Labonté
    • , Gustavo Turecki
    •  & Michael J Meaney
  2. Sackler Program for Epigenetics & Developmental Psychobiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada.

    • Patrick O McGowan
    • , Aya Sasaki
    • , Moshe Szyf
    •  & Michael J Meaney
  3. Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada.

    • Ana C D'Alessio
    • , Sergiy Dymov
    •  & Moshe Szyf
  4. McGill Group for Suicide Studies, 6875 LaSalle Boulevard, Douglas Mental Health University Institute, Montreal, Quebec, H4H 1R3, Canada.

    • Benoit Labonté
    •  & Gustavo Turecki
  5. Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore 117609.

    • Michael J Meaney

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Corresponding authors

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

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https://doi.org/10.1038/nn.2270

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