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

  • Justin Parent (a1) (a2) (a3), Stephanie H. Parade (a1) (a2), Laura E. Laumann (a4), Kathryn K. Ridout (a1) (a4), Bao-Zhu Yang (a5), Carmen J. Marsit (a6), Ronald Seifer (a1) (a2) and Audrey R. Tyrka (a1) (a4)...

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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Corresponding author

Address correspondence and reprint requests to: Audrey R. Tyrka, Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI 02903; E-mail: audrey_tyrka@brown.edu.

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This research was supported by Grant R01 MH083704 (to A.R.T.) and R25 MH101076 (K.K.R.) from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIMH. We are grateful to the children and families who participated in this study, and we thank Hasbro Children's Hospital, Rhode Island Head Start, and the Rhode Island Department of Children, Youth, and Families for assisting in recruitment of study participants. We also thank Brittney Josefson and the numerous other research assistants who contributed to this project, and Asi Polly Gobin for data management. Isolation of DNA and genotyping were done in the laboratory of Joel Gelernter, MD, and we are grateful to Dr. Gelernter and his staff for their contribution.

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