Epigenetic regulation of the glucocorticoid receptor promoter 17in adult rats

Witzmann, Simone R.; Turner, Jonathan D.; Mériaux, Sophie B.; Meijer, Onno C.; Muller, Claude P.

doi:10.4161/epi.22363

Cited by 90Epigenetics and DNA MethylationStress Responses and CortisolGenomics and Chromatin Dynamics

Epigenetic regulation of the glucocorticoid receptor promoter 17in adult rats

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Witzmann, Simone R., Turner, Jonathan D., Mériaux, Sophie B., Meijer, Onno C., Muller, Claude P.·2012·Epigenetics

DOI 10.4161/epi.22363PMC PMC3499330

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Abstract

Regulation of glucocorticoid receptor (GR) levels is an important stress adaptation mechanism. Transcription factor Nfgi-a and environmentally induced Gr promoter 1 7 methylation have been implicated in fine-tuning the expression of Gr 1 7 transcripts. Here, we investigated Gr promoter 1 7 methylation and Gr 1 7 expression in adult rats exposed to either acute or chronic stress paradigms. A strong negative correlation was observed between the sum of promoter-wide methylation levels and Gr 1 7 transcript levels, independent of the stressor. Methylation of individual sites did not, however, correlate with transcript levels. This suggested that promoter 1 7 was directly regulated by promoter-wide DNA methylation. Although acute stress increased Ngfi-a expression in the hypothalamic paraventricular nucleus (PVN), Gr 1 7 transcript levels remained unaffected despite low methylation levels. Acute stress had little effect on these low methylation levels, except at four hippocampal CpGs. Chronic stress altered the corticosterone response to an acute stressor. In the adrenal and pituitary glands, but not in the brain, this was accompanied by an increase in methylation levels in orchestrated clusters rather than individual CpGs. PVN methylation levels, unaffected by acute or chronic stress, were significantly more variable within- than between-groups, suggesting that they were instated probably during the perinatal period and represent a pre-established trait. Thus, in addition to the known perinatal programming, the Gr 1 7 promoter is epigenetically regulated by chronic stress in adulthood, and retains promoter-wide tissue-specific plasticity. Differences in methylation susceptibility between the PVN in the perinatal period and the peripheral HPA axis tissues in adulthood may represent an important "trait" vs. "state" regulation of the Gr gene.

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When the timing of the stressor was shifted to adulthood, there was little effect on GR promoter methylation levels in the brain, neither in the hippocampus nor hypothalamic paraventricular nucleus.
“However, when the timing of the stressor was shifted to adulthood, there was little effect on the GR promoter methylation levels in the brain (neither in the hippocampus or hypothalamic paraventricular nucleus).77”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [77]
An increase in methylation levels in peripheral hypothalamic-pituitary-adrenal (HPA) axis tissues was found to be accompanied by chronic stress.
“However, an increase in methylation levels in the peripheral hypothalamic-pituitary-adrenal (HPA) axis tissues was found to be accompanied by chronic stress.77”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [77]

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Alterations in DNA methylation of Fkbp5 as a determinant of blood–brain correlation of glucocorticoid exposure
Ewald, E. R., Wand, G. S., Seifuddin, F., Yang, X., Tamashiro, K. L., Potash, J. B., Zandi, P., & Lee, R. S. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.03.003 · Cited by 105 · see citing works
“One such study examined the 17 promoter of the glucocorticoid receptor (GR) and reported that the sum of methylation values between whole blood cells and the prefrontal cortex of stressed and unstressed animals show moderate association on a Pearson correlation heat map (Witzmann et al., 2012).”
Background
How Stress Gets Under the Skin: Early Life Adversity and Glucocorticoid Receptor Epigenetic Regulation
Liu, P. Z., & Nusslock, R. (2017) · Current Genomics · doi:10.2174/1389202919666171228164350 · Cited by 102 · see citing works
“However, in pups whose mothers did not express these affectionate behaviors, the 17 region in the hippocampus became significantly more methylated, which was associated with decreased NGFI-A binding [39].”
Background
Epigenetic Risk Factors in PTSD and Depression
Raabe, F. J., & Spengler, D. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2013.00080 · Cited by 94 · see citing works
“Chronic and acute stress during adulthood induces changes in the methylation level of the GR promoter at exon 17 in the pituitary and adrenal gland whereas brain tissues remained unaffected (123).”
Background
Socioeconomic Deprivation, Adverse Childhood Experiences and Medical Disorders in Adulthood: Mechanisms and Associations
Morris, G., Berk, M., Maes, M. H. J., Carvalho, A. F., & Puri, B. K. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1498-1 · Cited by 87 · see citing works
Sex, stress, and epigenetics: regulation of behavior in animal models of mood disorders
Hodes, G. E. (2013) · Biology of Sex Differences · doi:10.1186/2042-6410-4-1 · Cited by 82 · see citing works
“Methylation was decreased in the adrenal glands and increased in the pituitary, although there was no effect of either stressor on methylation of the same promoter in the hippocampus, PVN or cortex [75].”
Background
Understanding the epigenetic basis of sex differences in depression
Hodes, G. E., Walker, D. M., Labonté, B., Nestler, E. J., & Russo, S. J. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23876 · Cited by 82 · see citing works
Dynamic stress-related epigenetic regulation of the glucocorticoid receptor gene promoter during early development: The role of child maltreatment
Parent, J., Parade, S. H., Laumann, L. E., Ridout, K. K., Yang, B.-Z., Marsit, C. J., Seifer, R., & Tyrka, A. R. (2017) · Development and Psychopathology · doi:10.1017/s0954579417001298 · Cited by 72 · see citing works
Epigenetic pathways through which experiences become linked with biology
McGowan, P. O., & Roth, T. L. (2015) · Development and Psychopathology · doi:10.1017/s0954579415000206 · Cited by 72 · see citing works
Corticosteroid Receptors in the Brain: Transcriptional Mechanisms for Specificity and Context-Dependent Effects
Meijer, O. C., Buurstede, J. C., & Schaaf, M. J. M. (2018) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-018-0625-2 · Cited by 67 · see citing works
“It is of note that this intron is responsible for only a fraction of the total amount of GR mRNA, and its methylation should be seen as a marker for broader methylation of the gene (Weaver et al. 2006; Alt et al. 2010; Witzmann et al. 2012).”
Self-citation
Interindividual Variability in Stress Susceptibility: A Role for Epigenetic Mechanisms in PTSD
Zovkic, I. B., Meadows, J. P., Kaas, G. A., & Sweatt, J. D. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2013.00060 · Cited by 62 · see citing works
“…GC exposure are amplified during sensitive periods of development , although the GR promoter is also subject to epigenetic regulation in adulthood (Witzmann et al., 2012 the surface, some parallels can be drawn between high LG mothers and the children of Holocaust survivors who had lower levels…”
Background
Disease- and treatment-associated acquired glucocorticoid resistance
Wilkinson, L., Verhoog, N. J. D., & Louw, A. (2018) · Endocrine Connections · doi:10.1530/ec-18-0421 · Cited by 54 · see citing works
The Yin and Yang of the oxytocin and stress systems: opposites, yet interdependent and intertwined determinants of lifelong health trajectories
Uvnäs‐Moberg, K., Groß, M. M., Calleja‐Agius, J., & Turner, J. D. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1272270 · Cited by 53 · see citing works
Self-citation
Early-life stress interactions with the epigenome
Lewis, C. R., & Olive, M. F. (2014) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000057 · Cited by 51 · see citing works
“Although epigenetic influences on neuronal plasticity are highest early in development, stress during adulthood also influences the epigenome and subsequent gene expression (Witzmann et al., 2012).”
BackgroundInfluential
Rapid Down-Regulation of Glucocorticoid Receptor Gene Expression in the Dentate Gyrus after Acute Stress in vivo: Role of DNA Methylation and MicroRNA Activity
Mifsud, K. R., Saunderson, E. A., Spiers, H., Carter, S. D., Trollope, A. F., Mill, J. S., & Reul, J. M. H. M. (2016) · Neuroendocrinology · doi:10.1159/000445875 · Cited by 49 · see citing works
“DNA methylation analysis of this hippocampal sub‐region revealed a stress‐induced increase in methylation in an area of the gene previously shown to be a target of stress‐induced DNA methylation changes with long‐term consequences for HPA axis and behavioural function (14, 34, 37).”
Molecular mechanisms of repeated social defeat-induced glucocorticoid resistance: Role of microRNA
Jung, S. H., Wang, Y., Kim, T., Tarr, A., Reader, B., Powell, N., & Sheridan, J. F. (2015) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2014.09.015 · Cited by 47 · see citing works
“Although the decreased expression of mineralocorticoid receptor in splenic macrophages was not expected, for which future studies must be conducted to elucidate underlying mechanisms, the RSD-induced reduction of the GC receptor expression was consistent with other studies reporting similar expression pattern of GC re…”
The cardiovascular and hypothalamus-pituitary-adrenal axis response to stress is controlled by glucocorticoid receptor sequence variants and promoter methylation
Li-Tempel, T., Larra, M. F., Sandt, E., Mériaux, S. B., Schote, A. B., Schächinger, H., Muller, C. P., & Turner, J. D. (2016) · Clinical Epigenetics · doi:10.1186/s13148-016-0180-y · Cited by 46 · see citing works
“such as the anterior pituitary and the adrenal gland [3], as well as throughout the different neural tube derived tissues throughout the human brain [15] supporting the latter hypothesis.”
BackgroundSelf-citation
Epigenetic Changes Associated with Different Types of Stressors and Suicide
Dee, G., Ryznar, R. J., & Dee, C. (2023) · Cells · doi:10.3390/cells12091258 · Cited by 48 · see citing works
“When examining chronic stress, the literature demonstrated increased methylated changes in exon 17 of Nr3c1 in the amygdala (a fear-processing region) and no changes in the hippocampus or the pituitary and adrenal glands [34,36,37].”
BackgroundInfluential
Hippocampal NR3C1 DNA methylation can mediate part of preconception paternal stress effects in rat offspring
Niknazar, S., Nahavandi, A., Peyvandi, A. A., Peyvandi, H., Roozbahany, N. A., & Abbaszadeh, H. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.02.014 · Cited by 40 · see citing works
Child maltreatment and NR3C1 exon 1F methylation, link with deregulated hypothalamus-pituitary-adrenal axis and psychopathology: A systematic review
Wadji, D. L., Tandon, T., Ketcha Wanda, G. J. M., Wicky, C., Dentz, A., Hasler, G., Morina, N., & Martin-Soelch, C. (2021) · Child Abuse & Neglect · doi:10.1016/j.chiabu.2021.105304 · Cited by 40 · see citing works
Glucocorticoid receptor gene expression and promoter CpG modifications throughout the human brain
Cao-Lei, L., Suwansirikul, S., Jutavijittum, P., Mériaux, S. B., Turner, J. D., & Muller, C. P. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.07.022 · Cited by 39 · see citing works
“, 2012), and the rat homolog (exon 17) had a similar negative correlation with both total GR and the corresponding exon 17 transcript (Witzmann et al., 2012).”
BackgroundResultSelf-citation
Hormonal and nutritional regulation of postnatal hypothalamic development
Sominsky, L., Jasoni, C. L., Twigg, H., & Spencer, S. J. (2018) · Journal of Endocrinology · doi:10.1530/joe-17-0722 · Cited by 34 · see citing works
“However, chronic stress has no effect on PVN methylation or glucocorticoid receptor expression, despite effects at pituitary and adrenal (Witzmann et al. 2012).”
Background
A Systems Biology-Based Investigation into the Pharmacological Mechanisms of Wu Tou Tang Acting on Rheumatoid Arthritis by Integrating Network Analysis
Zhang, Y., Wang, D., Tan, S., Xu, H., Liu, C., & Lin, N. (2013) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2013/548498 · Cited by 33 · see citing works
“NR3C1, named as glucocorticoid receptor, has a dual mode of action, as a transcription factor that binds to glucocorticoid response elements and as amodulator of other transcription factors [56].”
Background
Acquired Glucocorticoid Resistance Due to Homologous Glucocorticoid Receptor Downregulation: A Modern Look at an Age-Old Problem
Spies, L.-M. L., Verhoog, N. J. D., & Louw, A. (2021) · Cells · doi:10.3390/cells10102529 · Cited by 34 · see citing works
“[86] indicate that chronic, rather than acute stress, resulted in increased methylation of the promoter of exon 17 in peripheral tissues.”
Background
Longitudinal changes in glucocorticoid receptor exon 1F methylation and psychopathology after military deployment
Schür, R. R., Boks, M. P., Rutten, B. P. F., Daskalakis, N. P., de Nijs, L., van Zuiden, M., Kavelaars, A., Heijnen, C. J., Joëls, M., Kahn, R. S., et al. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.150 · Cited by 31 · see citing works
Where does transcription start? 5′-RACE adapted to next-generation sequencing
Leenen, F. A. D., Vernocchi, S., Hunewald, O. E., Schmitz, S., Molitor, A. M., Muller, C. P., & Turner, J. D. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1328 · Cited by 28 · see citing works
Self-citation
Epigenetic modification of glucocorticoid receptor promoter I7 in maternally separated and restraint-stressed rats
Park, S. W., Lee, J. G., Seo, M. K., Ly, N. N., Lee, C. H., Cho, H. Y., Hein, L. T., Choi, A. J., Kim, G.-M., & Kim, Y. H. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.04.024 · Cited by 26 · see citing works
Fifty Years of Advances in Neuroendocrinology
Russell, J. A. (2018) · Brain and Neuroscience Advances · doi:10.1177/2398212818812014 · Cited by 26 · see citing works
“These studies on brain DNA seem to be problematic as methylation of genes of interest cannot be assumed to be stable through life (Witzmann et al., 2012), while the rationale for assuming that leukocyte DNA marks necessarily report about epigenetic modification of the same genes expressed in the…”
Background
Early Life Stress, Nicotinic Acetylcholine Receptors and Alcohol Use Disorders
Holgate, J. Y., & Bartlett, S. E. (2015) · Brain Sciences · doi:10.3390/brainsci5030258 · Cited by 26 · see citing works
“A growing number of studies have provided evidence suggesting that ELS causes epigenetic changes in gene transcription of the GRs contributing to disruptions in the mesolimbic pathway [76–88].”
Background
Prenatal risk factors for depression: a critical review of the evidence and potential mechanisms
Braithwaite, E., Murphy, S. E., & Ramchandani, P. G. (2014) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174414000324 · Cited by 26 · see citing works
“This results in an over-active stress response, as usually activation of the GR receptor initiates the negative feedback loop of the HPA axis, and ‘turns off’ cortisol release.(99) Exposure to early postnatal stress also results in increased methylation of the NR3C1 gene and subsequent downregulation of its expression…”
Background
Endothelial glucocorticoid receptor promoter methylation according to dexamethasone sensitivity
Mata‐Greenwood, E., Jackson, P. N., Pearce, W. J., & Zhang, L. (2015) · Journal of Molecular Endocrinology · doi:10.1530/jme-15-0124 · Cited by 21 · see citing works
“In sum, we found signiﬁcant differences in GR promoter methylation that result in differential GR 5 0 UTR mRNA isoform expression, and these differences further characterize DEX-sensitive and DEX-resistant HUVECs.”
Background
Adverse Maternal Exposures, Methylation of Glucocorticoid-Related Genes and Perinatal Outcomes: A Systematic Review
Nagarajan, S., Seddighzadeh, B., Baccarelli, A., Wise, L. A., Williams, M. A., & Shields, A. E. (2016) · Epigenomics · doi:10.2217/epi.16.9 · Cited by 20 · see citing works
DNA Methylation and Demethylation Underlie the Sex Difference in Estrogen Receptor Alpha in the Arcuate Nucleus
Cortes, L. R., Cisternas, C. D., Cabahug, I. N. K. V., Mason, D., Ramlall, E. K., Castillo‐Ruiz, A., & Forger, N. G. (2021) · Neuroendocrinology · doi:10.1159/000519671 · Cited by 19 · see citing works
Convergent actions of stress and stimulants via epigenetic regulation of neural circuitry
Murphy, M. D., & Heller, E. A. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.10.001 · Cited by 18 · see citing works
“Rodent studies also show that acute stress-induced DNAme sensitizes subjects to the effects of future stress exposure [44,45].”
Background
Glucocorticoid receptor signaling in leukocytes after early life adversity
Elwenspoek, M. M. C., Hengesch, X., Leenen, F. A. D., Sias, K., Fernandes, S. B., Schaan, V., Mériaux, S. B., Schmitz, S., Bonnemberger, F., Schächinger, H., et al. (2019) · Development and Psychopathology · doi:10.1017/s0954579419001147 · Cited by 18 · see citing works
Self-citation
A Tissue Comparison of DNA Methylation of the Glucocorticoid Receptor Gene (Nr3c1) in European Starlings
Siller, S., & Rubenstein, D. R. (2019) · Integrative and Comparative Biology · doi:10.1093/icb/icz034 · Cited by 17 · see citing works
“Indeed, changes in DNA methylation of Nr3c1 are associated with plasticity of the HPA axis and may directly impact an individual’s long-term stress response (Szyf et al. 2005; Witzmann et al. 2012).”
Background
Epigenetic landscape of stress surfeit disorders: Key role for DNA methylation dynamics
Gatta, E., Saudagar, V., Auta, J., Grayson, D. R., & Guidotti, A. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.08.002 · Cited by 17 · see citing works
An Epigenetic Perspective on Lifestyle Medicine for Depression: Implications for Primary Care Practice
Lee, J. S., Jaini, P. A., & Papa, F. J. (2020) · American Journal of Lifestyle Medicine · doi:10.1177/1559827620954779 · Cited by 17 · see citing works
Maternal Deprivation of Lewis Rat Pups Increases the Severity of Experi-mental Periodontitis in Adulthood
Breivik, T., Gundersen, Y., Murison, R., Turner, J. D., Muller, C., Gjermo, P., & Opstad, K. (2015) · Open Dentistry Journal · doi:10.2174/1874210601509010065 · Cited by 17 · see citing works
“Gr transcripts have previously been correlated with the sum of methylation throughout the 17 promoter, but not with single CpG dinucleotides [78, 79].”
BackgroundSelf-citation
Evaluating the Challenges and Reproducibility of Studies Investigating DNA Methylation Signatures of Psychological Stress
Zhang, Y., & Liu, C. (2022) · Epigenomics · doi:10.2217/epi-2021-0190 · Cited by 17 · see citing works
Behavioral Epigenetics: Perspectives Based on Experience-Dependent Epigenetic Inheritance
Pang, Y.-Y., Lu, R. J.-H., & Chen, P. (2019) · Epigenomes · doi:10.3390/epigenomes3030018 · Cited by 16 · see citing works
“Similarly, in a mouse model, NGFI-A was inhibited when the DNA methylation state was altered by variations in maternal care during the postpartum period [17].”
Background
Characterization of stress response involved in chicken myopathy
Kang, S. W., Kidd, M. T., Kadhim, H. J., Shouse, S. A., Orlowski, S., Hiltz, J. Z., ANTHONY, N. B., Kuenzel, W. J., & Kong, B. C. (2020) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2020.113526 · Cited by 14 · see citing works
Effects of lactational and/or in utero exposure to environmental contaminants on the glucocorticoid stress-response and DNA methylation of the glucocorticoid receptor promoter in male rats
Desaulniers, D. M., Xiao, G.-H., & Cummings‐Lorbetskie, C. (2013) · Toxicology · doi:10.1016/j.tox.2013.03.006 · Cited by 14 · see citing works
Increases in Bdnf DNA Methylation in the Prefrontal Cortex Following Aversive Caregiving Are Reflected in Blood Tissue
Duffy, H. B. D., & Roth, T. L. (2020) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2020.594244 · Cited by 14 · see citing works
Impact of acute stress exposure on genome-wide DNA methylation
Miller, M., McAfee, C. A., Brown, R., Sears, S., Krautkramer, C., Gogia, R., Wylie, D., Josephs, R. A., & Champagne, F. A. (2025) · Scientific Reports · doi:10.1038/s41598-025-09299-y · Cited by 10 · see citing works
“Though plasticity in the epigenome in response to acute stress has been demonstrated experimentally in the brain using animal models 14,15,30 there has been limited exploration of these effects in humans 20,21 .”
Chronic stress increases DNA methylation of the GR promoter in the central nucleus of the amygdala of female rats
Louwies, T., & Meerveld, B. G. (2022) · Neurogastroenterology & Motility · doi:10.1111/nmo.14377 · Cited by 11 · see citing works
Methylation of glucocorticoid receptor gene promoter modulates morphine dependence and accompanied hypothalamus–pituitary–adrenal axis dysfunction
Zhu, J., Zhu, F., Zhao, N., Mu, X. N., Li, P., Wang, W. T., Liu, J., & Ma, X. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23913 · Cited by 11 · see citing works
“For instance, hippocampal GR was found to mediate the negative feedback inhibition of the HPA axis (Jacobson and Sapolsky, 1991) and the persistent alteration of HPA axis function induced by multiple environmental factors (Feldman and Weidenfeld, 1999; Witzmann et al., 2012; Zhang et al., 2013).”
Background
Epigenetic Mechanisms of Perinatal Programming: Translational Approaches from Rodent to Human and Back
McGowan, P. O. (2014) · Advances in neurobiology · doi:10.1007/978-1-4939-1372-5_17 · Cited by 11 · see citing works
“A recent study has challenged the idea that GR17 transcript is regulated by DNA methylation of the NGFI-A response element in rats exposed to stress paradigms that lead to altered NGFI-A levels, though stress does appear to modulate the methylation of other CG sites within the GR17 promoter (Witzmann et al. 2012).”
Background
Mucosal RNA and protein expression as the next frontier in IBS: abnormal function despite morphologically intact small intestinal mucosa
Rodiño‐Janeiro, B. K., Pardo‐Camacho, C., Santos, J., & Martínez, C. (2019) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00186.2018 · Cited by 10 · see citing works
“In this line, a link has also been shown between early life experiences (abuse, maternal care) in rodents and humans and epigenetic alterations in the NR3C1 and brain-derived neurotrophic factor genes (109, 110, 138), characterized by neurobehavioral changes, a sensitized stress response, glucocorticoid resistance, in…”
Background
A Glimpse Into the Sexual Dimorphisms in Major Depressive Disorder Through Epigenetic Studies
Cahill, B., Poelker-Wells, S., Prather, J. F., & Li, Y. (2021) · Frontiers in Neural Circuits · doi:10.3389/fncir.2021.768571 · Cited by 9 · see citing works
“In general, social deﬁcits are hard to recapitulate within CVS paradigms without the combination of social stressors (Witzmann et al., 2012; Viana Borges et al., 2019).”
Background
The influence of aging on the methylation status of brain‐derived neurotrophic factor gene in blood
Ihara, K., Fuchikami, M., Hashizume, M., Okada, S., Kawai, H., Obuchi, S., Hirano, H., Fujiwara, Y., Hachisu, M., Kim, H., et al. (2018) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.4927 · Cited by 9 · see citing works
Linking the psychosocial aetiology and neurobiology of unipolar depression.
Coulter, L., Ibrahimi, M., Patel, R. J., & Agius, M. A. (2017) · PubMed · Cited by 9 · see citing works
The impact of parental and developmental stress on DNA methylation in the avian hypothalamic–pituitary–adrenal axis
Siller, S., Heidinger, B. J., Westneat, D. F., Solomon, J. W., & Rubenstein, D. R. (2024) · Molecular Ecology · doi:10.1111/mec.17291 · Cited by 8 · see citing works
A preferential switch between placental GR exon 1 promoter variants in the presence of maternal asthma or inflammation upregulates GRα D isoforms
Saif, Z., Meakin, A. S., & Clifton, V. L. (2021) · Placenta · doi:10.1016/j.placenta.2021.03.013 · Cited by 6 · see citing works
The significance of DNA methylation of the NR3C1 gene encoding the glucocorticoid receptor for developing resilience in individuals exposed to early life stress
Forum, D. M. K., Bjerregaard, C., & Thomsen, P. H. (2025) · Nordic Journal of Psychiatry · doi:10.1080/08039488.2024.2436987 · Cited by 6 · see citing works
Sex-dependent and -independent regulation of thyrotropin-releasing hormone expression in the hypothalamic dorsomedial nucleus by negative energy balance, exercise, and chronic stress
Vargas, Y., de Oca, M. P.-M., Sánchez‐Jaramillo, E., Jaimes-Hoy, L., Sánchez-Islas, E., Uribe, R. M., Joseph‐Bravo, P., & Charli, J. (2022) · Brain Research · doi:10.1016/j.brainres.2022.148083 · Cited by 5 · see citing works
Epigenetic Mechanisms of Blood-Pressure Regulation
Markel, А. L., & Redina, O. E. (2018) · Molecular Biology · doi:10.1134/s0026893317050120 · Cited by 5 · see citing works
Epigenetic Modification of the Hypothalamic-Pituitary-Adrenal (HPA) Axis During Development in the House Sparrow (Passer Domesticus)
Siller, S., Westneat, D. F., Heidinger, B. J., Solomon, J. W., & Rubenstein, D. R. (2023) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2023.114336 · Cited by 3 · see citing works
Epigenetics
Turner, J. D., Kirschner, S. A., Molitor, A. M., Evdokimov, K., & Muller, C. P. (2015) · Elsevier eBooks · doi:10.1016/b978-0-08-097086-8.14142-x · Cited by 3 · see citing works
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The Social Environment and Epigenetics in Psychiatry
McGowan, P. O., Sasaki, A., & Roth, T. L. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-417114-5.00026-7 · Cited by 2 · see citing works
Neuroendocrine-immune Interactions in Major Depressive Disorder: Glucocorticoids and Glucocorticoid Receptors
Weston, F. I., Sforzini, L., Cattaneo, A., & Pariante, C. M. (2023) · Masterclass in neuroendocrinology · doi:10.1007/978-3-031-21358-8_6 · Cited by 1 · see citing works
The Light Side of Preterm Behavioral Epigenetics
Provenzi, L., Borgatti, R., & Montirosso, R. (2016) · Advances in medical diagnosis, treatment, and care (AMDTC) book series · doi:10.4018/978-1-4666-9992-2.ch006 · Cited by 1 · see citing works
Psychosocial Impact of Epigenetics in Pediatrics
Gong, X., & Rubin, L. P. (2019) · Springer eBooks · doi:10.1007/978-3-319-55530-0_100 · Cited by 1 · see citing works
Effects of early-life adversity on the adult phenotype in European starlings
Gott, A. (2018) · Cited by 1 · see citing works
The impact of aversive caregiving on DNA methylation in blood and the prefrontal cortex
Duffy, H. B. D. (2025) · Library, Museums and Press - UDSpace (University of Delaware) · doi:10.58088/kse7-3e24 · Cited by 1 · see citing works
The Social Environment and Epigenetics in Psychiatry 26 CHAPTER
McGowan, P. O., Sasaki, A., & Roth, T. L. (2014)
The Epigenome: Possible Mechanisms by which Early Life Stress May Prime Vulnerability towards Substance Use Disorder
Lewis, C. R. (2015)
Psychosocial Impact of Epigenetics in Pediatrics
Gong, X., & Rubin, L. P. (2017) · Springer eBooks · doi:10.1007/978-3-319-31143-2_100-1
Violence conjugale : incidences et corrélats psychobiologiques sur des dyades mère-enfant = Intimate partner violence : psychobiological impacts and correlates on mother-child dyads
Wadji, D. L. (2022) · doi:10.51363/unifr.lth.2022.011
NR3C1 Methylation and Perceived Parenting as Joint Predictors of the Development of Loneliness in Adolescence
Koopmans, Y., Nelemans, S. A., Claes, S. J., Bijttebier, P., Bosmans, G., Noortgate, W. V. D., Leeuwen, K. G. V., & Goossens, L. (2025) · Journal of Adolescence · doi:10.1002/jad.70012
A Fifth-Order Adaptive Network Model of the Role of Epigenetic Modification Caused by Early Life Stressors in Borderline Personality Disorder
Vukmirović, J., Huber, A., Hendrikse, S. C. F., & Jan Treur, A. (2026) · Studies in computational intelligence · doi:10.1007/978-3-032-13592-6_34
IMPACT DE L’HYPERCORTICISME SUR L’AXE GONADOTROPE FEMELLE
Ayrout, M. (2018) · doi:10.70675/194a6ff5z99f6z4ef0z800ez5473528e7a30
Association between chronic stress and the epigenome: Exploration of psychological and biological stress
Miller, M. A., Brown, R. D., Krautkramer, C., Gogia, R., Fritz, H., Wylie, D., Kinney, K. L., & Champagne, F. A. (2026) · PLoS ONE · doi:10.1371/journal.pone.0346517
“Studies in animal models demonstrate that chronic stress exposure induces changes in gene expression and DNAm of stress-related genes [10,11].”

Epigenetic modification of glucocorticoid receptor promoter I7 in maternally separated and restraint-stressed rats
Park, S. W., Lee, J. G., Seo, M. K., Ly, N. N., Lee, C. H., Cho, H. Y., Hein, L. T., Choi, A. J., Kim, G.-M., & Kim, Y. H. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.04.024 · Cited by 26 · see citing works
Effects of Early Life Stress on Epigenetic Changes of the Glucocorticoid Receptor 17 Promoter during Adulthood
Seo, M. K., Kim, S.-G., Seog, D., Bahk, W., Kim, S.-H., Park, S. W., & Lee, J. G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176331 · Cited by 24 · see citing works
Methylation at the CpG island shore region upregulates Nr3c1 promoter activity after early-life stress
Bockmühl, Y., Patchev, A. V., Madejska, A., Hoffmann, A., Sousa, J. C., Sousa, N., Holsboer, F., Almeida, O. F. X., & Spengler, D. (2015) · Epigenetics · doi:10.1080/15592294.2015.1017199 · Cited by 117 · see citing works
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
de Rooij, S. R., Costello, P. M., Veenendaal, M. V. E., Lillycrop, K. A., Gluckman, P. D., Hanson, M. A., Painter, R. C., & Roseboom, T. J. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.09.010 · Cited by 52 · see citing works
Stimulus-dependent glucocorticoid receptor signalling in early-life stressed mice
Madejska, A. (2015) · Elektronische Hochschulschriften der LMU München (Ludwig-Maximilians-Universität München) · doi:10.5282/edoc.18546

Authors: Witzmann, S. R., Turner, J. D., Mériaux, S. B., Meijer, O. C., & Muller, C. P.
Affiliations: National Public Health Laboratory (NP)
Leiden University (NL)
Corresponding author: Muller, Claude P.
ORCID: Turner, Jonathan D.
Meijer, Onno C.
Muller, Claude P.
Venue: Epigenetics
Publisher: Informa UK Limited
Published: 2012-11-13
Volume: 7
Issue: 11
Pages: 1290-1301
ISSN: 1559-2294 (ISSN-L)
1559-2308
DOI: 10.4161/epi.22363
PMC: PMC3499330
OpenAlex: W2030896169
Cited by: 90
References: 49
Citations by year: 2026: 2 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 7 · 2018: 9 · 2017: 8 · 2016: 11 · 2015: 8 · 2014: 12 · 2013: 8
FWCI: 3.60
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Epigenetics (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Leiden Repository (Leiden University) (submittedVersion)
Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-sa)
Funders: Deutsche Forschungsgemeinschaft (GRK 1389/1, GRK 1389, 1389/1)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: glucocorticoid receptor, DNA methylation, epigenetic regulation, chronic stress, acute stress, NGFI-A, paraventricular nucleus, hippocampus, hypothalamic-pituitary-adrenal axis, perinatal programming, gene expression
MeSH terms: Animals, Corticosterone, Male, Paraventricular Hypothalamic Nucleus, Promoter Regions, Genetic, Receptors, Glucocorticoid, RNA, Messenger, Stress, Psychological, Rats, Sprague-Dawley, CpG Islands, DNA Methylation, Epigenesis, Genetic, Rats, Early Growth Response Protein 1

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Epigenetic regulation of the glucocorticoid receptor promoter 17in adult rats

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