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Methylation of exons 1D, 1F, and 1H of the glucocorticoid receptor gene promoter and exposure to adversity in preschool-aged children

  • Audrey R. Tyrka (a1) (a2), Stephanie H. Parade (a2) (a3), Nicole M. Eslinger (a1), Carmen J. Marsit (a4), Corina Lesseur (a4), David A. Armstrong (a4), Noah S. Philip (a1) (a2), Brittney Josefson (a3) and Ronald Seifer (a2) (a3)...


Epigenetic modifications to the genome are a key mechanism involved in the biological encoding of experience. Animal studies and a growing body of literature in humans have shown that early adversity is linked to methylation of the gene for the glucocorticoid receptor (GR), which is a key regulator of the hypothalamic–pituitary–adrenal axis as well as a broad range of physiological systems including metabolic and immune function. One hundred eighty-four families participated, including n = 74 with child welfare documentation of moderate-severe maltreatment in the past 6 months. Children ranged in age from 3 to 5 years, and were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors, and a composite variable assessed the number exposures to these adversities. Methylation of regions 1D, 1F, and 1H of the GR gene was measured via sodium bisulfite pyrosequencing. The composite measure of adversity was positively correlated with methylation at exons 1D and 1F in the promoter of the GR gene. Individual stress measures were significantly associated with a several CpG sites in these regions. GR gene methylation may be a mechanism of the biobehavioral effects of adverse exposures in young children.


Corresponding author

Address correspondence and reprint requests to: Audrey R. Tyrka, Butler Hospital, 345 Blackstone Boulevard, Providence, RI 02906; E-mail:


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Akiyama, Y. (1995). TFSEARCH: Searching transcription factor binding sites (ver 1.3). Retrieved from
Armstrong, D. A., Lesseur, C., Conradt, E., Lester, B. M., & Marsit, C. J. (2014). Global and gene-specific DNA methylation across multiple tissues in early infancy: Implications for children's health research. FASEB Journal, 28, 20882097.
Barden, N. (2004). Implication of the hypothalamic–pituitary–adrenal axis in the physiopathology of depression. Journal of Psychiatry and Neuroscience, 29, 185193.
Barnett, D., Manly, J. T., & Cicchetti, D. (1993). Defining child maltreatment: The interface between policy and research. In Cicchetti, D. & Toth, S. L. (Eds.), Child abuse, child development, and social policy (pp. 773). Norwood, NJ: Ablex.
Bromer, C., Marsit, C. J., Armstrong, D. A., Padbury, J. F., & Lester, B. (2012). Genetic and epigenetic variation of the glucocorticoid receptor (NR3C1) in placenta and infant neurobehavior. Developmental Psychobiology, 55, 673683.
Champagne, F. A., & Curley, J. P. (2009). Epigenetic mechanisms mediating the long-term effects of maternal care on development. Neuroscience & Biobehavioral Reviews, 33, 593600.
Conradt, E., Lester, B. M., Appleton, A. A., Armstrong, D. A., & Marsit, C. J. (2013). The roles of DNA methylation of NR3C1 and 11beta-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics, 8, 13211329.
Dammann, G., Teschler, S., Haag, T., Altmuller, F., Tuczek, F., & Dammann, R. H. (2011). Increased DNA methylation of neuropsychiatric genes occurs in borderline personality disorder. Epigenetics, 6, 14541462.
Daniels, W. M., Fairbairn, L. R., van Tilburg, G., McEvoy, C. R., Zigmond, M. J., Russell, V. A., et al. (2009). Maternal separation alters nerve growth factor and corticosterone levels but not the DNA methylation status of the exon 1(7) glucocorticoid receptor promoter region. Metabolic Brain Disease, 24, 615627.
de Rooij, S. R., Costello, P. M., Veenendaal, M. V., Lillycrop, K. A., Gluckman, P. D., Hanson, M. A., et al. (2011). Associations between DNA methylation of a glucocorticoid receptor promoter and acute stress responses in a large healthy adult population are largely explained by lifestyle and educational differences. Psychoneuroendocrinology, 37, 782788.
Dias, B. G., & Ressler, K. J. (2014). Parental olfactory experience influences behavior and neural structure in subsequent generations. Nature Neuroscience, 17, 8996.
Duman, R. S. (2009). Neuronal damage and protection in the pathophysiology and treatment of psychiatric illness: Stress and depression. Dialogues in Clinical Neuroscience, 11, 239255.
Edelman, S., Shalev, I., Uzefovsky, F., Israel, S., Knafo, A., Kremer, I., et al. (2012). Epigenetic and genetic factors predict women's salivary cortisol following a threat to the social self. PLOS ONE, 7, e48597.
Endler, G., Greinix, H., Winkler, K., Mitterbauer, G., & Mannhalter, C. (1999). Genetic fingerprinting in mouthwashes of patients after allogeneic bone marrow transplantation. Bone Marrow Transplant, 24, 9598.
Essex, M. J., Boyce, W. T., Hertzman, C., Lam, L. L., Armstrong, J. M., Neumann, S. M., et al. (2013). Epigenetic vestiges of early developmental adversity: Childhood stress exposure and DNA methylation in adolescence. Child Development, 84, 5875.
Evans, G. W., Gonnella, C., Marcynyszyn, L. A., Gentile, L., & Salpekar, N. (2005). The role of chaos in poverty and children's socioemotional adjustment. Psychological Science, 16, 560565.
Gudsnuk, K., & Champagne, F. A. (2014). Epigenetic influence of stress and the social environment. Ilar Journal, 53, 279288.
Heinemeyer, T., Wingender, E., Reuter, I., Hermjakob, H., Kel, A. E., Kel, O. V., et al. (1998). Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Research, 26, 362367.
Hompes, T., Izzi, B., Gellens, E., Morreels, M., Fieuws, S., Pexsters, A., et al. (2013). Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood. Journal of Psychiatric Research, 47, 880891.
Kember, R. L., Dempster, E. L., Lee, T. H., Schalkwyk, L. C., Mill, J., & Fernandes, C. (2012). Maternal separation is associated with strain-specific responses to stress and epigenetic alterations to nr3c1, avp, and nr4a1 in mouse. Brain and behavior, 2, 455467.
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., et al. (2013). Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nature Neuroscience, 16, 3341.
Kundakovic, M., Lim, S., Gudsnuk, K., & Champagne, F. A. (2013). Sex-specific and strain-dependent effects of early life adversity on behavioral and epigenetic outcomes. Frontiers in Psychiatry, 4, 78.
Labonte, B., Yerko, V., Gross, J., Mechawar, N., Meaney, M. J., Szyf, M., et al. (2012). Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. Biological Psychiatry, 72, 4148.
Lee, R. S., Tamashiro, K. L., Yang, X., Purcell, R. H., Harvey, A., Willour, V. L., et al. (2010). Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of fkbp5 in mice. Endocrinology, 151, 43324343.
Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009). Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Reviews Neuroscience, 10, 434445.
Lutz, P. E., & Turecki, G. (2013). DNA methylation and childhood maltreatment: From animal models to human studies. Neuroscience. Advance online publication.
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonte, B., Szyf, M., et al. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342348.
Melas, P. A., Wei, Y., Wong, C. C., Sjoholm, L. K., Aberg, E., Mill, J., et al. (2013). Genetic and epigenetic associations of MAOA and NR3C1 with depression and childhood adversities. International Journal of Neuropsychopharmacology, 16, 15131528.
Moore, L. D., Le, T., & Fan, G. (2012). DNA methylation and its basic function. Neuropsychopharmacology, 38, 2338.
Mulligan, C. J., D'Errico, N. C., Stees, J., & Hughes, D. A. (2012). Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics, 7, 853857.
Oberlander, T. F., Weinberg, J., Papsdorf, M., Grunau, R., Misri, S., & Devlin, A. M. (2008). Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics, 3, 97106.
Perroud, N., Paoloni-Giacobino, A., Prada, P., Olie, E., Salzmann, A., Nicastro, R., et al. (2011). Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: A link with the severity and type of trauma. Translational Psychiatry, 1, e59.
Provencal, N., Suderman, M. J., Guillemin, C., Massart, R., Ruggiero, A., Wang, D., et al. (2012). The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. Journal of Neuroscience, 32, 1562615642.
Radtke, K. M., Ruf, M., Gunter, H. M., Dohrmann, K., Schauer, M., Meyer, A., et al. (2011). Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Translational Psychiatry, 1, e21.
Reed, K., Poulin, M. L., Yan, L., & Parissenti, A. M. (2010). Comparison of bisulfite sequencing PCR with pyrosequencing for measuring differences in DNA methylation. Analytical Biochemistry, 397, 96106.
Sameroff, A. J., Seifer, R., Baldwin, A., & Baldwin, C. (1993). Stability of intelligence from preschool to adolescence: The influence of social and family risk factors. Child Development, 64, 8097.
Scheeringa, M. S., & Haslett, N. (2010). The reliability and criterion validity of the Diagnostic Infant and Preschool Assessment: A new diagnostic instrument for young children. Child Psychiatry & Human Development, 41, 299312.
Smith, A. K., Conneely, K. N., Kilaru, V., Mercer, K. B., Weiss, T. E., Bradley, B., et al. (2011). Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. American Journal of Medical Genetics, 156B, 700708.
Steiger, H., Labonte, B., Groleau, P., Turecki, G., & Israel, M. (2013). Methylation of the glucocorticoid receptor gene promoter in bulimic women: Associations with borderline personality disorder, suicidality, and exposure to childhood abuse. International Journal of Eating Disorders, 46, 246255.
Szyf, M. (2007). The dynamic epigenome and its implications in toxicology. Toxicological Sciences, 100, 723.
Szyf, M. (2012). Mind–body interrelationship in DNA methylation. Chemical Immunology and Allergy, 98, 8599.
Szyf, M. (2013). How do environments talk to genes? Nature Neuroscience, 16, 24.
Tadic, A., Müller-Engling, L., Schlicht, K. F., Kotsiari, A., Dreimüller, N., Kleimann, A., et al. (2014). Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression. Molecular Psychiatry, 19, 281283.
Talens, R. P., Boomsma, D. I., Tobi, E. W., Kremer, D., Jukema, J. W., Willemsen, G., et al. (2010). Variation, patterns, and temporal stability of DNA methylation: Considerations for epigenetic epidemiology. FASEB Journal, 24, 31353144.
Thiede, C., Prange-Krex, G., Freiberg-Richter, J., Bornhauser, M., & Ehninger, G. (2000). Buccal swabs but not mouthwash samples can be used to obtain pretransplant DNA fingerprints from recipients of allogeneic bone marrow transplants. Bone Marrow Transplant, 25, 575577.
Tottenham, N., & Sheridan, M. A. (2009). A review of adversity, the amygdala and the hippocampus: A consideration of developmental timing. Frontiers in Human Neuroscience, 3, 68.
Turner, J. D., & Muller, C. P. (2005). Structure of the glucocorticoid receptor (NR3C1) gene 5' untranslated region: Identification, and tissue distribution of multiple new human exon 1. Journal of Molecular Endocrinology, 35, 283292.
Tyrka, A. R., Burgers, D. E., Philip, N. S., Price, L. H., & Carpenter, L. L. (2013). The neurobiological correlates of childhood adversity and implications for treatment. Acta Psychiatrica Scandinavica, 128, 434447.
Tyrka, A. R., Price, L. H., Marsit, C., Walters, O. C., & Carpenter, L. L. (2012). Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: Preliminary findings in healthy adults. PLOS ONE, 7, e30148.
van Zuiden, M., Geuze, E., Willemen, H. L., Vermetten, E., Maas, M., Heijnen, C. J., et al. (2011). Pre-existing high glucocorticoid receptor number predicting development of posttraumatic stress symptoms after military deployment. American Journal of Psychiatry, 168, 8996.
Ventura, S. J., Hamilton, B. E., & Mathews, T. J. (2013). Pregnancy and childbirth among females aged 10–19 years—United States, 2007–2010. MMWR Surveillance Summaries, 62(Suppl. 3), 7176.
Vyas, A., Jadhav, S., & Chattarji, S. (2006). Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala. Neuroscience, 143, 387393.
Weaver, I. C., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., et al. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7, 847854.
Yehuda, R., Daskalakis, N. P., Desarnaud, F., Makotkine, I., Lehrner, A. L., Koch, E., et al. (2013). Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Frontiers in Psychiatry, 4, 118.
Yehuda, R., Flory, J. D., Pratchett, L. C., Buxbaum, J., Ising, M., & Holsboer, F. (2010). Putative biological mechanisms for the association between early life adversity and the subsequent development of PTSD. Psychopharmacology (Berlin), 212, 405417.
Yehuda, R., & Seckl, J. (2011). Minireview: Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis. Endocrinology, 152, 44964503.
Zhang, T. Y., Labonte, B., Wen, X. L., Turecki, G., & Meaney, M. J. (2013). Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacology, 38, 111123.

Methylation of exons 1D, 1F, and 1H of the glucocorticoid receptor gene promoter and exposure to adversity in preschool-aged children

  • Audrey R. Tyrka (a1) (a2), Stephanie H. Parade (a2) (a3), Nicole M. Eslinger (a1), Carmen J. Marsit (a4), Corina Lesseur (a4), David A. Armstrong (a4), Noah S. Philip (a1) (a2), Brittney Josefson (a3) and Ronald Seifer (a2) (a3)...


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