Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse - PubMed (original) (raw)

Comparative Study

Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse

Patrick O McGowan et al. Nat Neurosci. 2009 Mar.

Abstract

Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A-inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.

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Figures

Figure 1

Figure 1

Hippocampal glucocorticoid receptor expression. (a,b) Mean ± s.e.m. expression levels of total glucocorticoid receptor (GR) mRNA (a) and glucocorticoid receptor 1F (GR1F) in 12 suicide victims with a history of childhood abuse, 12 nonabused suicide victims and 12 control subjects (b). Outliers excluded from analysis included n = 2 control subjects, n = 1 suicide victims with a history of childhood abuse for glucocorticoid receptor 1F and an additional n = 1 suicide victim with a history of childhood abuse, and n = 3 nonabused suicide victims for overall levels of glucocorticoid receptor. * indicates P < 0.05; n.s. indicates not statistically significant.

Figure 2

Figure 2

Methylation of the NR3C1 promoter in the hippocampus. Twenty clones were sequenced for each subject for methylation mapping. (a) Mean ± s.e.m. percentage of methylated clones for suicide victims with a history of childhood abuse (n = 12), suicide victims without a history of childhood abuse (n = 12) and controls (n = 12). The methylation percentage was calculated as the number of clones with at least one methylated CpG site divided by the total number of clones (* indicates P ≤ 0.05; n.s. indicates not statistically significant). (b) Methylation of the NR3C1 promoter region, showing the frequency of methylation observed at each CpG site for suicide victims with a history of childhood abuse, suicide victims with no history of childhood abuse and control subjects (*P < 0.05, **P < 0.001, abused suicides versus controls; &P < 0.05, &&P < 0.001, non-abused suicides versus controls; #P < 0.05, ##P < 0.001, abused suicides versus non-abused suicides; Bonferroni post hoc comparisons).

Figure 3

Figure 3

In vitro analysis of NR3C1 promoter methylation. (a) The relative position of the NR3C1 variant and the promoter sequence, showing the location of the CpG dinucleotides. The 255-bp (▼, solid underline) and 125-bp (∇, broken underline) deletion constructs are shown, along with specific CpG dinucleotides that were methylated in each deletion construct, as indicated by circles. Boxes represent known or putative canonical (solid-lined box) and noncanonical (broken-lined box) NGFI-A–binding sites, with the shaded area indicating the beginning of the exon. (b,c) Mean ± s.e.m. levels of luciferase expression in HEK293 cells. Results are shown after the subtraction of expression of the promoter in the antisense orientation. (b) The full NR3C1 promoter was either unmethylated (hGR) or completely patch methylated (hGR PatchM) and transfected in the presence or absence of NGFI-A. (c) The 255-bp and 125-bp NR3C1 deletion construct were either unmethylated (255 bp or 125 bp) or methylated (255 bp M or 125 bp M), as shown in a, and transfected either in the presence or absence of NGFI-A.

Figure 4

Figure 4

NGFI-A association with exon 1F NR3C1 promoter constructs. (a–c) Quantification of NR3C1 promoter immunoprecipitated with NGFI-A antibody and normalized to input DNA for the full human NR3C1 promoter (a), the 255-bp deletion construct (b) and the 125-bp deletion construct (c), each of which was either unmethylated or methylated and transfected in the presence or absence of NGFI-A. Data are presented as means ± s.e.m.

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