Dynamic stress-related epigenetic regulation of the glucocorticoid receptor gene promoter during early development: The role of child maltreatment

Parent, Justin; Parade, Stephanie H.; Laumann, Laura E.; Ridout, Kathryn K.; Yang, Bao-Zhu; Marsit, Carmen J.; Seifer, Ronald; Tyrka, Audrey R.

doi:10.1017/s0954579417001298

Cited by 72Child Abuse and TraumaEpigenetics and DNA MethylationStress Responses and Cortisol

Dynamic stress-related epigenetic regulation of the glucocorticoid receptor gene promoter during early development: The role of child maltreatment

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Parent, Justin, Parade, Stephanie H., Laumann, Laura E., Ridout, Kathryn K., Yang, Bao-Zhu, Marsit, Carmen J., Seifer, Ronald, Tyrka, Audrey R.·2017·Development and Psychopathology

DOI 10.1017/s0954579417001298PMC PMC5726533

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Abstract

Epigenetics processes may play a vital role in the biological embedding of early environmental adversity and the development of psychopathology. Accumulating evidence suggests that maltreatment is linked to methylation of the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), which is a key regulator of the hypothalamus-pituitary-adrenal axis. However, prior work has been exclusively cross-sectional, greatly constraining our understanding of stress-related epigenetic processes over time. In the current study, we examined the effect of maltreatment and other adversity on change in NR3C1 methylation among at-risk preschoolers to begin to characterize within-child epigenetic changes during this sensitive developmental period. Participants were 260 preschoolers (3-5 years old, 53.8% female), including 51.5% with moderate to severe maltreatment in the past 6 months. Child protection records, semistructured interviews, and parent reports were used to assess child stress exposure. Methylation of exons 1D and 1F of NR3C1 via saliva DNA were measured at two time points approximately 6 months apart. Results indicate that maltreated children evidence higher baseline levels of NR3C1 methylation, significant decreases in methylation over time, and then at follow-up, lower levels of methylation, relative to nonmaltreated preschoolers. Findings from the current study highlight the complex nature of stress-related epigenetic processes during early development.

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In preschoolers, mean methylation of the NR3C1 promoter 1D region positively predicted childhood maltreatment at baseline but negatively predicted the change in methylation and maltreatment at follow-up.
“The mean methylation of the promoter 1 D region positively predicted childhood maltreatment at baseline (also evaluated over a six month period), but negatively predicted the change in methylation and maltreatment at follow-up”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Parent et al., 2017
The Results (Primary analyses; page unavailable) report that maltreatment status positively predicted baseline mean NR3C1 exon 1D methylation and negatively predicted its change over six months. The citing sentence reverses the predictor and outcome: the paper does not report that methylation predicted maltreatment. Lower 1D methylation at follow-up was only marginally significant. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Maltreated children display increased NR3C1 promoter methylation after trauma and decreased promoter methylation at later follow-up stages.
“suggesting that maltreated children display increased NR3C1 promoter methylation after trauma and decreased promoter methylation at later follow-up stages (Parent et al., 2017)”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Parent et al., 2017

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The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention
Schiele, M. A., Gottschalk, M. G., & Domschke, K. (2020) · Clinical Psychology Review · doi:10.1016/j.cpr.2020.101830 · Cited by 156 · see citing works
Incorporating epigenetic mechanisms to advance fetal programming theories
Conradt, E., Adkins, D. E., Crowell, S. E., Raby, K. L., Diamond, L. M., & Ellis, B. (2018) · Development and Psychopathology · doi:10.1017/s0954579418000469 · Cited by 60 · see citing works

Giucocorticoid-Insensitive Bronchial Asthma
Lee, T. H., & Leung, D. Y. M. (2008) · Blackwell Science Ltd eBooks · doi:10.1002/9780470694923.ch33
[Medicinal activation and inhibition of function of glucocorticoid receptors as the basis for regulation of the glucocorticoid effect].
Pp, G. (1994) · PubMed · Cited by 1 · see citing works
Study on the Relationship Between Sensitivity to Glucocorticoid and Glucocorticoid Receptor Isoform in Patients with Idiopathic Thrombocytopenia Purpura
Zhu, Q. H. (2007) · Chinese Journal of Thrombosis and Hemostasis
Heterogeneity of Binding Sites for Glucocorticoid and the Glucocorticoid-Receptor Complex in Rat Livers
Muramatsu, M., Tanaka, M., Fujita, A., et al. (1984) · The Japanese Journal of Pharmacology · doi:10.1254/jjp.36.87 · Cited by 1 · see citing works
The role of the glucocorticoid receptor and its impact on steroid response in moderate-severe COVID-19 patients
Aliska, G., Nafrialdi, N., Lie, K. C., Setiabudy, R., Putra, A. E., Widyahening, I. S., & Harahap, A. R. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.175555 · Cited by 7 · see citing works

Authors: Parent, J., Parade, S. H., Laumann, L. E., Ridout, K. K., Yang, B.-Z., Marsit, C. J., Seifer, R., & Tyrka, A. R.
Affiliations: Florida International University (US)
Brown University (US)
Butler Hospital (US)
Yale University (US)
Emory University (US)
Corresponding author: Tyrka, Audrey R.
ORCID: Parent, Justin
Parade, Stephanie H.
Laumann, Laura E.
Ridout, Kathryn K.
Yang, Bao-Zhu
Marsit, Carmen J.
Seifer, Ronald
Tyrka, Audrey R.
Venue: Development and Psychopathology
Publisher: Cambridge University Press (CUP)
Published: 2017-11-22
Volume: 29
Issue: 5
Pages: 1635-1648
ISSN: 0954-5794 (ISSN-L)
1469-2198
DOI: 10.1017/s0954579417001298
PMC: PMC5726533
OpenAlex: W2770616513
Cited by: 72
References: 74
Citations by year: 2026: 5 · 2025: 3 · 2024: 8 · 2023: 9 · 2022: 5 · 2021: 8 · 2020: 24 · 2019: 3 · 2018: 7
FWCI: 11.51
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.cambridge.org/core/terms (unspecified)
Locations: Development and Psychopathology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Mental Health (R25MH101076, R01MH083704)
Topics: Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: child abuse, glucocorticoid receptor, NR3C1, DNA methylation, epigenetic regulation, childhood adversity, preschool children, hypothalamic-pituitary-adrenal axis, biological embedding, sensitive period, stress exposure
MeSH terms: Child Abuse, Child Development, Child, Preschool, Exons, Female, Humans, Hypothalamo-Hypophyseal System, Male, Pituitary-Adrenal System, Receptors, Glucocorticoid, DNA Methylation

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Dynamic stress-related epigenetic regulation of the glucocorticoid receptor gene promoter during early development: The role of child maltreatment

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