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Epigenetic programming by stress and glucocorticoids along the human lifespan

Molecular Psychiatry volume 22, pages 640646 (2017) | Download Citation

Abstract

Psychosocial stress triggers a set of behavioral, neural, hormonal, and molecular responses that can be a driving force for survival when adaptive and time-limited, but may also contribute to a host of disease states if dysregulated or chronic. The beneficial or detrimental effects of stress are largely mediated by the hypothalamic-pituitary axis, a highly conserved neurohormonal cascade that culminates in systemic secretion of glucocorticoids. Glucocorticoids activate the glucocorticoid receptor, a ubiquitous nuclear receptor that not only causes widespread changes in transcriptional programs, but also induces lasting epigenetic modifications in many target tissues. While the epigenome remains sensitive to stressors throughout life, we propose two key principles that may govern the epigenetics of stress and glucocorticoids along the lifespan: first, the presence of distinct life periods, during which the epigenome shows heightened plasticity to stress exposure, such as in early development and at advanced age; and, second, the potential of stress-induced epigenetic changes to accumulate throughout life both in select chromatin regions and at the genome-wide level. These principles have important clinical and translational implications, and they show striking parallels with the existence of sensitive developmental periods and the cumulative impact of stressful experiences on the development of stress-related phenotypes. We hope that this conceptual mechanistic framework will stimulate fruitful research that aims at unraveling the molecular pathways through which our life stories sculpt genomic function to contribute to complex behavioral and somatic phenotypes.

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References

  1. 1.

    , , , , . ‘Seq-ing’ insights into the epigenetics of neuronal gene regulation. Neuron 2013; 77: 606–623.

  2. 2.

    , . Epigenetics and the regulation of stress vulnerability and resilience. Neuroscience 2014; 264: 157–170.

  3. 3.

    , . Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 2014; 17: 89–96.

  4. 4.

    , , , . Life stress, glucocorticoid signaling, and the aging epigenome: Implications for aging-related diseases. Neurosci Biobehav Rev 2016 (in press).

  5. 5.

    , , , , , et al. Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB j 2010; 24: 3135–3144.

  6. 6.

    , , , , , et al. Direct GR Binding Sites Potentiate Clusters of TF Binding across the Human Genome. Cell 2016; 166: 1269–1281.e1219.

  7. 7.

    , , , , , et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci 2013; 16: 33–41.

  8. 8.

    , , , , , et al. DNA methylation status predicts cell type-specific enhancer activity. EMBO j 2011; 30: 3028–3039.

  9. 9.

    , , , . Glucocorticoid-induced DNA demethylation and gene memory during development. EMBO j 2001; 20: 1974–1983.

  10. 10.

    , , , , , et al. Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling. Genome Biol 2015; 16: 266.

  11. 11.

    , , , , , . Glucocorticoids induce long-lasting effects in neural stem cells resulting in senescence-related alterations. Cell Death Dis 2010; 1: e92.

  12. 12.

    , , , , , et al. Tet3 mediates stable glucocorticoid-induced alterations in DNA methylation and Dnmt3a/Dkk1 expression in neural progenitors. Cell Death Dis 2015; 6: e1793.

  13. 13.

    , , , , , et al. Reduced DNA methylation of FKBP5 in Cushing's syndrome. Endocrine 2016; 54: 768–777.

  14. 14.

    , , , , , et al. Adolescent stress-induced epigenetic control of dopaminergic neurons via glucocorticoids. Science 2013; 339: 335–339.

  15. 15.

    , , , , , et al. Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala. Neuropsychopharmacology 2015; 41: 832–846.

  16. 16.

    , , , , , et al. Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine. Sci Signal 2015; 8: ra119.

  17. 17.

    , , , , , et al. Glucocorticoid-induced loss of DNA methylation in non-neuronal cells and potential involvement of DNMT1 in epigenetic regulation of Fkbp5. Biochem Biophys Res Commun 2012; 420: 570–575.

  18. 18.

    , , . Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression. Behav Brain Res 2015; 281: 1–8.

  19. 19.

    , , , , , . Brain-derived neurotrophic factor epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice. Biol Psychiatry 2015; 77: 589–596.

  20. 20.

    , . Glucocorticoid signaling drives epigenetic and transcription factors to induce key regulators of human parturition. Sci Signal 2015; 8: fs19.

  21. 21.

    , , , , . RelB/p52-mediated NF-kappaB signaling alters histone acetylation to increase the abundance of corticotropin-releasing hormone in human placenta. Sci Signal 2015; 8: ra85.

  22. 22.

    , , , , , . Chronic corticosterone-mediated dysregulation of microRNA network in prefrontal cortex of rats: relevance to depression pathophysiology. Transl Psychiatry 2015; 5: e682.

  23. 23.

    , , , , , . MicroRNA-29a mitigates glucocorticoid induction of bone loss and fatty marrow by rescuing Runx2 acetylation. Bone 2015; 81: 80–88.

  24. 24.

    , , , , , et al. Alterations in DNA methylation of Fkbp5 as a determinant of blood-brain correlation of glucocorticoid exposure. Psychoneuroendocrinology 2014; 44: 112–122.

  25. 25.

    , , , , , et al. Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of Fkbp5 in mice. Endocrinology 2010; 151: 4332–4343.

  26. 26.

    , , , , , et al. Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation. Biol Psychiatry 2015; 80: 372–380.

  27. 27.

    , , , , , et al. ‘Up-regulation of histone acetylation induced by social defeat mediates the conditioned rewarding effects of cocaine. Prog Neuropsychopharmacol Biol Psychiatry 2016; 70: 39–48.

  28. 28.

    , , , , . Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci 2013; 33: 9003–9012.

  29. 29.

    , , , . Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc Natl Acad Sci USA 2015; 112: 13699–13704.

  30. 30.

    , , , , , . Prenatal bystander stress alters brain, behavior, and the epigenome of developing rat offspring. Dev Neurosci 2011; 33: 159–169.

  31. 31.

    , , , , . Prenatal restraint stress is associated with demethylation of corticotrophin releasing hormone (CRH) promoter and enhances CRH transcriptional responses to stress in adolescent rats. Neurochem Res 2014; 39: 1193–1198.

  32. 32.

    , , , , . Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis. Epigenetics 2015; 10: 893–902.

  33. 33.

    , , , , , et al. Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats. Epigenetics 2014; 9: 437–447.

  34. 34.

    , , , , , et al. Prenatal stress down-regulates Reelin expression by methylation of its promoter and induces adult behavioral impairments in rats. PLoS ONE 2015; 10: e0117680.

  35. 35.

    , , , . Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics 2012; 7: 853–857.

  36. 36.

    , , , , , et al. DNA methylation signatures triggered by prenatal maternal stress exposure to a natural disaster: Project Ice Storm. PLoS ONE 2014; 9: e107653.

  37. 37.

    , , , , , et al. Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice. Transl Psychiatry 2014; 4: e473.

  38. 38.

    , , . Chronic prenatal stress epigenetically modifies spinal cord BDNF expression to induce sex-specific visceral hypersensitivity in offspring. Neurogastroenterol Motil 2014; 26: 715–730.

  39. 39.

    , , , , , . Prenatal stress changes the glycoprotein GPM6A gene expression and induces epigenetic changes in rat offspring brain. Epigenetics 2014; 9: 152–160.

  40. 40.

    , , , , , et al. Maternal stress induces epigenetic signatures of psychiatric and neurological diseases in the offspring. PLoS ONE 2013; 8: e56967.

  41. 41.

    , , , , , . Maternal separation is associated with DNA methylation and behavioural changes in adult rats. Eur Neuropsychopharmacol 2014; 24: 459–468.

  42. 42.

    , , . Global and gene-specific DNA methylation alterations in the adolescent amygdala and hippocampus in an animal model of caregiver maltreatment. Behav Brain Res 2016; 298(Pt A): 55–61.

  43. 43.

    , , , . Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry 2009; 65: 760–769.

  44. 44.

    , , , , , et al. Epigenetic programming by maternal behavior. Nat Neurosci 2004; 7: 847–854.

  45. 45.

    , , , , . Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults. PLoS ONE 2012; 7: e30148.

  46. 46.

    , , , , , et al. Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. Nat Commun 2016; 7: 10967.

  47. 47.

    , , , , , et al. Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins. Psychol Med 2013; 43: 1813–1823.

  48. 48.

    , , , , , et al. Dynamic changes in DNA methylation of stress-associated genes (OXTR, BDNF ) after acute psychosocial stress. Transl Psychiatry 2012; 2: e150.

  49. 49.

    , , , , , et al. Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study. Transl Psychiatry 2014; 4: e381.

  50. 50.

    , , , , , et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 2009; 12: 1559–1566.

  51. 51.

    , , , , , et al. Adverse life events and allele-specific methylation of the serotonin transporter gene (SLC6A4) in adolescents: the TRAILS study. Psychosom Med 2015; 77: 246–255.

  52. 52.

    , , , , , et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009; 12: 342–348.

  53. 53.

    , , , , , et al. Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. Transl Psychiatry 2011; 1: e59.

  54. 54.

    , , , , , . Childhood maltreatment and methylation of FK506 binding protein 5 gene (FKBP5). Dev Psychopathol 2015; 27(4 Pt 2): 1637–1645.

  55. 55.

    , , , , , et al. Neonatal isolation decreases cued fear conditioning and frontal cortical histone 3 lysine 9 methylation in adult female rats. Eur J Pharmacol 2012; 697: 65–72.

  56. 56.

    , , , , , . Dopamine receptor D2 and associated microRNAs are involved in stress susceptibility and resistance to escitalopram treatment. Int J Neuropsychopharmacol 2015; 18: pii: pyv025.

  57. 57.

    , , , , , et al. Epigenetic status of Gdnf in the ventral striatum determines susceptibility and adaptation to daily stressful events. Neuron 2011; 69: 359–372.

  58. 58.

    , , , . Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. J Psychiatr Res 2011; 45: 919–926.

  59. 59.

    , , , , . Epigenetic regulation of the glucocorticoid receptor promoter 1 in adult rats. Epigenetics 2012; 7: 1290–1301.

  60. 60.

    , , , . Importance of epigenetic mechanisms in visceral pain induced by chronic water avoidance stress. Psychoneuroendocrinology 2013; 38: 898–906.

  61. 61.

    , , , , , et al. Chronic mild stress and antidepressant treatment alter 5-HT1A receptor expression by modifying DNA methylation of a conserved Sp4 site. Neurobiol Dis 2015; 82: 332–341.

  62. 62.

    , , , , , et al. Factors underlying variable DNA methylation in a human community cohort. Proc Natl Acad Sci USA 2012; 109(Suppl 2): 17253–17260.

  63. 63.

    , , , , , et al. Environmental stress affects DNA methylation of a CpG rich promoter region of serotonin transporter gene in a nurse cohort. PLoS ONE 2012; 7: e45813.

  64. 64.

    , , , , . Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice. Nat Neurosci 2010; 13: 1351–1353.

  65. 65.

    , , , , , et al. Stress-related methylation of the catechol-O-methyltransferase Val 158 allele predicts human prefrontal cognition and activity. J Neurosci 2011; 31: 6692–6698.

  66. 66.

    , , , , , et al. Chronic stress and antidepressant induced changes in Hdac5 and Sirt2 affect synaptic plasticity. Eur Neuropsychopharmacol 2015; 25: 2036–2048.

  67. 67.

    , , , , , et al. Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron 2007; 56: 517–529.

  68. 68.

    , , , , , et al. Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity. Proc Natl Acad Sci USA 2015; 112: 14960–14965.

  69. 69.

    , , , , , et al. MicroRNA-19b associates with Ago2 in the amygdala following chronic stress and regulates the adrenergic receptor beta 1. J Neurosci 2014; 34: 15070–15082.

  70. 70.

    , , , , , et al. Amygdalar MicroRNA-15a Is Essential for Coping with Chronic Stress. Cell Rep 2016; 17: 1882–1891.

  71. 71.

    , , , , , et al. ACF chromatin-remodeling complex mediates stress-induced depressive-like behavior. Nat Med 2015; 21: 1146–1153.

  72. 72.

    . DNA methylation age of human tissues and cell types. Genome Biol 2013; 14: R115.

  73. 73.

    , , , , , et al. Late-life environmental enrichment induces acetylation events and nuclear factor kappaB-dependent regulations in the hippocampus of aged rats showing improved plasticity and learning. J Neurosci 2016; 36: 4351–4361.

  74. 74.

    , . Timing is everything: the when and how of environmentally induced changes in the epigenome of animals. Epigenetics 2011; 6: 791–797.

  75. 75.

    , , , , , et al. Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome. Int J Epidemiol 2015; 44: 1211–1223.

  76. 76.

    , , , , , et al. Life course socioeconomic status and DNA methylation in genes related to stress reactivity and inflammation: The multi-ethnic study of atherosclerosis. Epigenetics 2015; 10: 958–969.

  77. 77.

    , , , , , et al. Interaction of the glucocorticoid receptor with the chromatin landscape. Mol Cell 2008; 29: 611–624.

  78. 78.

    . The neuroendocrinology of stress: a never ending story. J Neuroendocrinol 2008; 20: 880–884.

  79. 79.

    , , , . Fetal exposure to maternal cortisol. Lancet 1998; 352: 707–708.

  80. 80.

    , , . Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 2015; 16: 593–610.

  81. 81.

    , , , , , et al. Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study. Mol Psychiatry 2013; 18: 576–581.

  82. 82.

    , , , , , et al. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci USA 2004; 101: 17312–17315.

  83. 83.

    , , , . Age-dependent DNA methylation changes in the ITGAL (CD11a) promoter. Mech Ageing Dev 2002; 123: 1257–1268.

  84. 84.

    , , , . Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. Exp Gerontol 2010; 45: 312–322.

  85. 85.

    , , , , , et al. A measure of glucocorticoid load provided by DNA methylation of Fkbp5 in mice. Psychopharmacology (Berl) 2011; 218: 303–312.

  86. 86.

    , , , , . Regulation of hippocampal H3 histone methylation by acute and chronic stress. Proc Natl Acad Sci USA 2009; 106: 20912–20917.

  87. 87.

    , , , . Facilitation of the HPA axis to a novel acute stress following chronic stress exposure modulates histone acetylation and the ERK/MAPK pathway in the dentate gyrus of male rats. Endocrinology 2014; 155: 2942–2952.

  88. 88.

    , , , , , . Previous history of chronic stress changes the transcriptional response to glucocorticoid challenge in the dentate gyrus region of the male rat hippocampus. Endocrinology 2013; 154: 3261–3272.

  89. 89.

    , , . DNA methylation: superior or subordinate in the epigenetic hierarchy? Genes Cancer 2011; 2: 607–617.

  90. 90.

    , , , , . Evolution, stress, and sensitive periods: the influence of unpredictability in early versus late childhood on sex and risky behavior. Dev Psychol 2012; 48: 674–686.

  91. 91.

    , . Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Exp Neurol 2012; 233: 102–111.

  92. 92.

    , , , . Cumulative traumas and psychosis: an analysis of the national comorbidity survey and the British Psychiatric Morbidity Survey. Schizophr Bull 2008; 34: 193–199.

  93. 93.

    , , , , , et al. Cumulative burden of lifetime adversities: Trauma and mental health in low-SES African Americans and Latino/as. Psychol Trauma 2015; 7: 243–251.

  94. 94.

    , , , , , . Stress exposure across the life span cumulatively increases depression risk and is moderated by neuroticism. Depress Anxiety 2014; 31: 737–745.

  95. 95.

    , , Hypothalamic-pituitary-adrenal axis and cardiovascular disease. In: Hjemdahl P, Rosengren A, Steptoe A (ed.). Stress and Cardiovascular Disease. Springer: London, UK, 2012.

  96. 96.

    , , . Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 1999; 156: 837–841.

  97. 97.

    , , , , . Stressful life events, perceived stress, and 12-month course of geriatric depression: direct effects and moderation by the 5-HTTLPR and COMT Val158Met polymorphisms. Stress 2012; 15: 425–434.

  98. 98.

    , , , , , et al. Effects of chronic stress on memory decline in cognitively normal and mildly impaired older adults. Am J Psychiatry 2009; 166: 1384–1391.

  99. 99.

    , . Life stress and losses and deficit in adulthood as breast cancer risk factor: a prospective case-control study in Kuopio, Finland. In Vivo 2010; 24: 899–904.

  100. 100.

    , , . Chronic stress at work and the metabolic syndrome: prospective study. BMJ 2006; 332: 521–525.

  101. 101.

    , , , , , et al. Effects of cigarette smoking and restraint stress on human colon tumor growth in mice. Digestion 2009; 80: 209–214.

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Acknowledgements

We apologize to those whose work could not be cited due to space constraints. ASZ is currently supported by a Marie-Sklodowska Curie Individual Fellowship (H2020 grant number 653240).

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Affiliations

  1. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

    • A S Zannas
  2. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA

    • A S Zannas
  3. First Department of Pediatrics and Division of Endocrinology, Metabolism and Diabetes, National and Kapodistrian University of Athens Medical School, Athens, Greece

    • G P Chrousos

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The authors declare no conflict of interest.

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Correspondence to A S Zannas.

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https://doi.org/10.1038/mp.2017.35

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