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

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.

Figure 1. NR3C1 region: promoter of exon 1D and promoter of exon 1F

Note. CpG numbering taken from Palma-Gudiel et al. (2015). Boxes around CpG site numbers represent NGFI-A transcription factor binding sites according to McGowan et al. (2009).

Figure 2. Primary latent change score models

Note. * represents freely estimated parameter. PC1–2 = DNA-based Principal Components used to account for potential population stratification.

Figure 3. Depiction of NR3C1 change over time separately by maltreatment and comparison children

Note. Average methylation across multiple CpG sites (exon 1_D CpGs 3–5, 7–10 & exon 1_F CpGs 27–29) is presented separately for maltreated and comparison children. * = p < .05, ns = p > .05. The graph represents multiple analyses to better understand study results. Maltreated children n = 134, Comparison group n = 126.