Childhood abuse, promoter methylation of leukocyte NR3C1 and the potential modifying effect of emotional support

Written by Shields AE, Wise LA, Ruiz-Narvaez EA et al.

Over the past decade, several epigenetics studies have emerged linking various forms of childhood adversity with an altered hypothalamic–pituitary–adrenal axis stress response in humans [1,2]. Among the genes in the stress pathway, the glucocorticoid receptor gene, NR3C1, has been shown to be hypermethylated in response to various forms of early life psychosocial stress, such as physical or emotional abuse [3] or parental loss [4]. Increased methylation of NR3C1 is associated with a range of deleterious outcomes, including depression [5], borderline personality disorder [6,7] and cancer [8–10].
Nearly all methylation studies conducted on NR3C1 have focused on the CpG island located within the proximal promoter region, particularly in exon 1F and the 1F promoter. Epigenetics research to date has tended to focus on methylation in CpG islands, which are small stretches of unmethylated DNA found in the promoters of a handful of human genes [11], because methylation in these regions is assumed to have the greatest functional significance [12]. However, more recent research has shown that the majority of functionally important DNA methylation occurs not in CpG islands, but in CpG island shores, which are genomic regions located within 2 kb of a CpG island [13]. Our prior research suggests that DNA methylation at the CpG island shore located within the proximal promoter of NR3C1 is sensitive to environmental stressors [14–16], and thus may be a suitable candidate for methylation studies of external and internal stressors. None of the published studies demonstrating a link between early life psychosocial stressors and epigenetic modification within the proximal promoter region of NR3C1 have explored CpG island shores as a more sensitive or functional methylation site for psychosocial stress.

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