Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Meaney, M.J. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu. Rev. Neurosci. 24, 1161–1192 (2001).

    CAS  Article  Google Scholar 

  2. Higley, J.D., Hasert, M.F., Suomi, S.J. & Linnoila, M. Nonhuman primate model of alcohol abuse: effects of early experience, personality and stress on alcohol consumption. Proc. Natl. Acad. Sci. USA 88, 7261–7265 (1991).

    CAS  Article  Google Scholar 

  3. Liu, D. et al. Maternal care, hippocampal glucocorticoid receptors and hypothalamic-pituitary-adrenal responses to stress. Science 277, 1659–1662 (1997).

    CAS  Article  Google Scholar 

  4. Weaver, I.C. et al. Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847–854 (2004).

    CAS  Article  Google Scholar 

  5. de Kloet, E.R., Joels, M. & Holsboer, F. Stress and the brain: from adaptation to disease. Nat. Rev. Neurosci. 6, 463–475 (2005).

    CAS  Article  Google Scholar 

  6. Boyle, M.P. et al. Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior. Proc. Natl. Acad. Sci. USA 102, 473–478 (2005).

    CAS  Article  Google Scholar 

  7. Ridder, S. et al. Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions. J. Neurosci. 25, 6243–6250 (2005).

    CAS  Article  Google Scholar 

  8. Reichardt, H.M., Tronche, F., Bauer, A. & Schutz, G. Molecular genetic analysis of glucocorticoid signaling using the Cre/loxP system. Biol. Chem. 381, 961–964 (2000).

    CAS  Article  Google Scholar 

  9. De Bellis, M.D. et al. Hypothalamic-pituitary-adrenal axis dysregulation in sexually abused girls. J. Clin. Endocrinol. Metab. 78, 249–255 (1994).

    CAS  PubMed  Google Scholar 

  10. Pruessner, J.C., Champagne, F., Meaney, M.J. & Dagher, A. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. J. Neurosci. 24, 2825–2831 (2004).

    CAS  Article  Google Scholar 

  11. Heim, C. & Nemeroff, C.B. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol. Psychiatry 49, 1023–1039 (2001).

    CAS  Article  Google Scholar 

  12. Webster, M.J., Knable, M.B., O'Grady, J., Orthmann, J. & Weickert, C.S. Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders. Mol. Psychiatry 7, 985–994 (2002).

    CAS  Article  Google Scholar 

  13. Schatzberg, A.F., Rothschild, A.J., Langlais, P.J., Bird, E.D. & Cole, J.O. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J. Psychiatr. Res. 19, 57–64 (1985).

    CAS  Article  Google Scholar 

  14. Isometsa, E.T. et al. Suicide in major depression. Am. J. Psychiatry 151, 530–536 (1994).

    CAS  Article  Google Scholar 

  15. Widom, C.S., DuMont, K. & Czaja, S.J. A prospective investigation of major depressive disorder and comorbidity in abused and neglected children grown up. Arch. Gen. Psychiatry 64, 49–56 (2007).

    Article  Google Scholar 

  16. Fergusson, D.M., Horwood, L.J. & Lynskey, M.T. Childhood sexual abuse and psychiatric disorder in young adulthood. II. Psychiatric outcomes of childhood sexual abuse. J. Am. Acad. Child Adolesc. Psychiatry 35, 1365–1374 (1996).

    CAS  Article  Google Scholar 

  17. Weaver, I.C. et al. The transcription factor nerve growth factor–inducible protein a mediates epigenetic programming: altering epigenetic marks by immediate-early genes. J. Neurosci. 27, 1756–1768 (2007).

    CAS  Article  Google Scholar 

  18. McCormick, J.A. et al. 5′-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: differential regulation of variant transcripts by early-life events. Mol. Endocrinol. 14, 506–517 (2000).

    CAS  PubMed  Google Scholar 

  19. Turner, J.D. & Muller, C.P. Structure of the glucocorticoid receptor (NR3C1) gene 5′ untranslated region: identification and tissue distribution of multiple new human exon 1. J. Mol. Endocrinol. 35, 283–292 (2005).

    CAS  Article  Google Scholar 

  20. Breslin, M.B., Geng, C.D. & Vedeckis, W.V. Multiple promoters exist in the human GR gene, one of which is activated by glucocorticoids. Mol. Endocrinol. 15, 1381–1395 (2001).

    CAS  Article  Google Scholar 

  21. Encio, I.J. & Detera-Wadleigh, S.D. The genomic structure of the human glucocorticoid receptor. J. Biol. Chem. 266, 7182–7188 (1991).

    CAS  PubMed  Google Scholar 

  22. Weaver, I.C. et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J. Neurosci. 25, 11045–11054 (2005).

    CAS  Article  Google Scholar 

  23. Razin, A. CpG methylation, chromatin structure and gene silencing a three-way connection. EMBO J. 17, 4905–4908 (1998).

    CAS  Article  Google Scholar 

  24. Bird, A. Molecular biology. Methylation talk between histones and DNA. Science 294, 2113–2115 (2001).

    CAS  Article  Google Scholar 

  25. Clark, S.J., Harrison, J., Paul, C.L. & Frommer, M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res. 22, 2990–2997 (1994).

    CAS  Article  Google Scholar 

  26. Yamada, K. et al. Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. Proc. Natl. Acad. Sci. USA 104, 2815–2820 (2007).

    CAS  Article  Google Scholar 

  27. Cervoni, N. & Szyf, M. Demethylase activity is directed by histone acetylation. J. Biol. Chem. 276, 40778–40787 (2001).

    CAS  Article  Google Scholar 

  28. Crosby, S.D., Puetz, J.J., Simburger, K.S., Fahrner, T.J. & Milbrandt, J. The early response gene NGFI-C encodes a zinc finger transcriptional activator and is a member of the GCGGGGGCG (GSG) element–binding protein family. Mol. Cell. Biol. 11, 3835–3841 (1991).

    CAS  Article  Google Scholar 

  29. Plotsky, P.M. et al. Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring. Neuropsychopharmacology 30, 2192–2204 (2005).

    CAS  Article  Google Scholar 

  30. Oberlander, T.F. et al. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3, 97–106 (2008).

    Article  Google Scholar 

  31. Fleming, A.S., O'Day, D.H. & Kraemer, G.W. Neurobiology of mother-infant interactions: experience and central nervous system plasticity across development and generations. Neurosci. Biobehav. Rev. 23, 673–685 (1999).

    CAS  Article  Google Scholar 

  32. Pilowsky, D.J. et al. Children of depressed mothers 1 year after the initiation of maternal treatment: findings from the STAR*D child study. Am. J. Psychiatry 165, 1136–1147 (2008).

    Article  Google Scholar 

  33. Holsboer, F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 477–501 (2000).

    CAS  Article  Google Scholar 

  34. Neigh, G.N. & Nemeroff, C.B. Reduced glucocorticoid receptors: consequence or cause of depression? Trends Endocrinol. Metab. 17, 124–125 (2006).

    CAS  Article  Google Scholar 

  35. Abdolmaleky, H.M. et al. Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum. Mol. Genet. 15, 3132–3145 (2006).

    CAS  Article  Google Scholar 

  36. Grayson, D.R. et al. Reelin promoter hypermethylation in schizophrenia. Proc. Natl. Acad. Sci. USA 102, 9341–9346 (2005).

    CAS  Article  Google Scholar 

  37. Siegmund, K.D. et al. DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS ONE 2, e895 (2007).

    Article  Google Scholar 

  38. Ernst, C. et al. The effects of pH on DNA methylation state: in vitro and postmortem brain studies. J. Neurosci. Methods 174, 123–125 (2008).

    CAS  Article  Google Scholar 

  39. Vythilingam, M. et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am. J. Psychiatry 159, 2072–2080 (2002).

    Article  Google Scholar 

  40. Seguin, M. et al. Life trajectories and burden of adversity: mapping the developmental profiles of suicide mortality. Psychol. Med. 37, 1575–1583 (2007).

    Article  Google Scholar 

  41. Brezo, J. et al. Natural history of suicidal behaviors in a population-based sample of young adults. Psychol. Med. 37, 1563–1574 (2007).

    PubMed  Google Scholar 

  42. Kaufman, J., Plotsky, P.M., Nemeroff, C.B. & Charney, D.S. Effects of early adverse experiences on brain structure and function: clinical implications. Biol. Psychiatry 48, 778–790 (2000).

    CAS  Article  Google Scholar 

  43. Teicher, M.H., Andersen, S.L., Polcari, A., Anderson, C.M. & Navalta, C.P. Developmental neurobiology of childhood stress and trauma. Psychiatr. Clin. North Am. 25, 397–426 (2002).

    Article  Google Scholar 

  44. Fisher, P.A., Gunnar, M.R., Chamberlain, P. & Reid, J.B. Preventive intervention for maltreated preschool children: impact on children's behavior, neuroendocrine activity and foster parent functioning. J. Am. Acad. Child Adolesc. Psychiatry 39, 1356–1364 (2000).

    CAS  Article  Google Scholar 

  45. Brezo, J. et al. Predicting suicide attempts in young adults with histories of childhood abuse. Br. J. Psychiatry 193, 134–139 (2008).

    Article  Google Scholar 

  46. Sequeira, A. & Turecki, G. Genome wide gene expression studies in mood disorders. OMICS 10, 444–454 (2006).

    CAS  Article  Google Scholar 

  47. Spitzer, R.L., Williams, J.B., Gibbon, M. & First, M.B. The Structured Clinical Interview for DSM-III-R (SCID). I: history, rationale and description. Arch. Gen. Psychiatry 49, 624–629 (1992).

    CAS  Article  Google Scholar 

  48. Dumais, A. et al. Risk factors for suicide completion in major depression: a case-control study of impulsive and aggressive behaviors in men. Am. J. Psychiatry 162, 2116–2124 (2005).

    CAS  Article  Google Scholar 

  49. Bifulco, A., Brown, G.W. & Harris, T.O. Childhood Experience of Care and Abuse (CECA): a retrospective interview measure. J. Child Psychol. Psychiatry 35, 1419–1435 (1994).

    CAS  Article  Google Scholar 

  50. Frommer, M. et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc. Natl. Acad. Sci. USA 89, 1827–1831 (1992).

    CAS  Article  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

Authors

Corresponding authors

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

Supplementary information

Supplementary Text and Figures

Supplementary Methods (PDF 138 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing