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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

Published online by Cambridge University Press:  06 May 2015

Audrey R. Tyrka ,
Stephanie H. Parade ,
Nicole M. Eslinger ,
Carmen J. Marsit ,
Corina Lesseur ,
David A. Armstrong ,
Noah S. Philip ,
Brittney Josefson  and
Ronald Seifer
Audrey R. Tyrka*
Affiliation:
Butler Hospital Brown University Alpert Medical School
Stephanie H. Parade
Affiliation:
Brown University Alpert Medical School E. P. Bradley Hospital
Nicole M. Eslinger
Affiliation:
Butler Hospital
Carmen J. Marsit
Affiliation:
Geisel School of Medicine at Dartmouth
Corina Lesseur
Affiliation:
Geisel School of Medicine at Dartmouth
David A. Armstrong
Affiliation:
Geisel School of Medicine at Dartmouth
Noah S. Philip
Affiliation:
Butler Hospital Brown University Alpert Medical School
Brittney Josefson
Affiliation:
E. P. Bradley Hospital
Ronald Seifer
Affiliation:
Brown University Alpert Medical School E. P. Bradley Hospital
*
Address correspondence and reprint requests to: Audrey R. Tyrka, Butler Hospital, 345 Blackstone Boulevard, Providence, RI 02906; E-mail: [email protected].
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Abstract

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.

Type
Regular Articles
Information
Development and Psychopathology , Volume 27 , Special Issue 2: Neural Plasticity, Sensitive Periods, and Psychopathology , May 2015 , pp. 577 - 585
Copyright
Copyright © Cambridge University Press 2015 

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References

Akiyama, Y. (1995). TFSEARCH: Searching transcription factor binding sites (ver 1.3). Retrieved from http://www.cbrc.jp/research/db/TFSEARCH.htmlGoogle Scholar
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, 2088–2097.CrossRefGoogle ScholarPubMed
Barden, N. (2004). Implication of the hypothalamic–pituitary–adrenal axis in the physiopathology of depression. Journal of Psychiatry and Neuroscience, 29, 185–193.Google ScholarPubMed
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. 7–73). Norwood, NJ: Ablex.Google Scholar
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, 673–683.CrossRefGoogle ScholarPubMed
Champagne, F. A., & Curley, J. P. (2009). Epigenetic mechanisms mediating the long-term effects of maternal care on development. Neuroscience & Biobehavioral Reviews, 33, 593–600.CrossRefGoogle ScholarPubMed
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, 1321–1329.CrossRefGoogle ScholarPubMed
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, 1454–1462.CrossRefGoogle ScholarPubMed
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, 615–627.CrossRefGoogle Scholar
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, 782–788.CrossRefGoogle Scholar
Dias, B. G., & Ressler, K. J. (2014). Parental olfactory experience influences behavior and neural structure in subsequent generations. Nature Neuroscience, 17, 89–96.CrossRefGoogle ScholarPubMed
Duman, R. S. (2009). Neuronal damage and protection in the pathophysiology and treatment of psychiatric illness: Stress and depression. Dialogues in Clinical Neuroscience, 11, 239–255.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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, 95–98.CrossRefGoogle ScholarPubMed
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, 58–75.CrossRefGoogle ScholarPubMed
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, 560–565.CrossRefGoogle ScholarPubMed
Gudsnuk, K., & Champagne, F. A. (2014). Epigenetic influence of stress and the social environment. Ilar Journal, 53, 279–288.CrossRefGoogle Scholar
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, 362–367.CrossRefGoogle ScholarPubMed
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, 880–891.CrossRefGoogle ScholarPubMed
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, 455–467.CrossRefGoogle Scholar
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, 33–41.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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, 41–48.CrossRefGoogle Scholar
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, 4332–4343.CrossRefGoogle ScholarPubMed
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, 434–445.CrossRefGoogle ScholarPubMed
Lutz, P. E., & Turecki, G. (2013). DNA methylation and childhood maltreatment: From animal models to human studies. Neuroscience. Advance online publication.Google Scholar
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, 342–348.CrossRefGoogle ScholarPubMed
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, 1513–1528.CrossRefGoogle ScholarPubMed
Moore, L. D., Le, T., & Fan, G. (2012). DNA methylation and its basic function. Neuropsychopharmacology, 38, 23–38.CrossRefGoogle ScholarPubMed
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, 853–857.CrossRefGoogle ScholarPubMed
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, 97–106.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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, 15626–15642.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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, 96–106.CrossRefGoogle ScholarPubMed
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, 80–97.CrossRefGoogle ScholarPubMed
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, 299–312.CrossRefGoogle ScholarPubMed
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, 700–708.Google ScholarPubMed
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, 246–255.CrossRefGoogle ScholarPubMed
Szyf, M. (2007). The dynamic epigenome and its implications in toxicology. Toxicological Sciences, 100, 7–23.CrossRefGoogle ScholarPubMed
Szyf, M. (2012). Mind–body interrelationship in DNA methylation. Chemical Immunology and Allergy, 98, 85–99.CrossRefGoogle ScholarPubMed
Szyf, M. (2013). How do environments talk to genes? Nature Neuroscience, 16, 2–4.CrossRefGoogle ScholarPubMed
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, 281–283.CrossRefGoogle ScholarPubMed
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, 3135–3144.CrossRefGoogle ScholarPubMed
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, 575–577.CrossRefGoogle Scholar
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.Google ScholarPubMed
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, 283–292.CrossRefGoogle ScholarPubMed
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, 434–447.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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, 89–96.CrossRefGoogle ScholarPubMed
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), 71–76.Google ScholarPubMed
Vyas, A., Jadhav, S., & Chattarji, S. (2006). Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala. Neuroscience, 143, 387–393.CrossRefGoogle ScholarPubMed
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, 847–854.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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, 405–417.CrossRefGoogle ScholarPubMed
Yehuda, R., & Seckl, J. (2011). Minireview: Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis. Endocrinology, 152, 4496–4503.CrossRefGoogle Scholar
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, 111–123.CrossRefGoogle ScholarPubMed