Childhood Abuse Affects Regulation of Glucocorticoid Receptor Expression

Jacquelyn K Beals, PhD

February 23, 2009

February 23, 2009 — Regulation of the glucocorticoid receptor gene, NR3C1, in hippocampal samples from suicide victims who suffered childhood abuse differs from its regulation in suicide victims with no such abuse history and in control individuals, according to a new study published online February 22 in Nature Neuroscience.

Animal research indicates that maternal behavior affects the expression of hippocampal glucocorticoid receptors. The current study supports these findings on epigenetic regulation of NR3C1 and shows that life events can influence the epigenetic state of certain genomic regions in humans, possibly influencing susceptibility to psychopathology.

Glucocorticoid receptors are probably located "in every tissue in the body, although at varying levels, depending upon the developmental stage," said senior author Michael J. Meaney, PhD, professor, Department of Psychiatry and Department of Neurology & Neurosurgery, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada, in an email to Medscape Pathology & Lab Medicine.

The study focused on the hippocampus because "expression of the glucocorticoid receptor gene in the hippocampus is dynamic and associated with psychopathology," Dr. Meaney explained.

NR3C1 occupies more than 80 kilobases on human chromosome 5. An "untranslated region" at 1 end of the gene contains 11 variants and determines gene expression in specific tissues. One variant — exon 1F — is homologous to a region of the rat gene whose expression is affected by maternal behavior.

"The homolog of this variant in the rat is active in all brain regions that we have studied," said Dr. Meaney, "but that still leaves us short of being able to say that it is expressed throughout the [central nervous system]. There are about 5 or so...variants expressed in each region that we have studied in the rat, and the homolog of relevance [rat exon 17, homologous to human exon 1F] is...not the only one that is differentially affected by maternal care."

Subnormal Expression of Glucocorticoid Receptor

Based on observations that people with severe depression demonstrate lower expression of glucocorticoid receptors, investigators expected that individuals who committed suicide would have subnormal expression of the glucocorticoid receptor and untranslated region 1F.

Hippocampal samples obtained from the Quebec Suicide Brain Bank were of suicide victims with childhood abuse history (n = 12) and suicide victims without such a history (n = 12). Control samples (n = 12) were from subjects who died suddenly of non–suicide related causes. DNA and RNA were extracted from tissue sample homogenates.

A significant difference in glucocorticoid receptor expression was found for the 3 groups (F = 3.17; P = .05). Levels of glucocorticoid receptor mRNA were significantly lower in suicide victims who suffered childhood abuse compared with suicide victims without such abuse or control individuals (P < .05). Glucocorticoid receptor mRNA levels did not differ between nonabused suicide victims and control individuals (P > .05).

Analysis of expression of transcripts containing exon 1F determined that mRNA levels differed between groups (F = 3.58; P < .05), with significantly less expression in samples from suicide victims having childhood abuse history than in either of the other groups (P < .05).

Investigators also analyzed DNA methylation, as rat studies indicate that the "rat homolog of the exon 1F NR3C1 promoter, the exon 17 region, is differentially methylated as a function of variations in maternal care."

"Our evidence suggests that maternal care (licking of the rat pup) activates a series of intra-cellular signals in hippocampal neurons," explained Dr. Meaney. "We know that maternal care is associated with changes in CpG methylation that are somewhat site-specific and rely upon the binding of [the transcription factor] NGFI-A to the promoter."

Methylation May Influence NR3C1 Promoter Expression

CpG methylation is a recognized epigenetic mechanism that decreases gene expression by affecting the binding of transcription factors. The authors hypothesize that DNA methylation influences NR3C1 promoter expression by altering the binding of NGFI-A.

In this study, the percentage of methylated sites in the NR3C1 promoter region varied significantly between groups (F = 3.47; P < .05). Once again, significant differences were found between suicide victims with a history of childhood abuse and suicide victims with no abuse history (P = .05) or control individuals (P < .05). Interestingly, methylation was not global but site-specific.

Coauthor Moshe Szyf, PhD, professor, Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada, told Medscape Pathology & Lab Medicine: "[O]ur hypothesis is that sequence-specific transacting factors that are activated by cellular signaling pathways in neurons deliver DNA modification enzymes to specific positions in genes. Understanding how exposure to adverse social environment triggers these pathways is obviously extremely important," Dr. Szyf added," but we are not there yet."

The data indicate greater site-specific methylation of the promoter 1F in suicide victims who suffered childhood abuse, suggesting an interaction between methylation, binding of transcription factors, and glucocorticoid receptor gene expression.

Steven E. Hyman, MD, professor of neurobiology, Harvard Medical School, Boston, and provost of Harvard University, Cambridge, Massachusetts, also commented via email to Medscape Pathology & Lab Medicine. "This work is fairly convincing because it corroborates predictions made from the rodent models that Meaney and others have studied for more than a decade," he said.

"It is also consistent with physiological experiments in living humans...showing that individuals with a history of abuse have a greater cortisol and autonomic response to stress than control populations," noted Dr. Hyman. "While the mechanisms by which abuse produces later behavioral symptoms will likely prove multifarious and complex, this research...has shown that 'lived experience' can produce epigenetic regulation," he said, "[which is] something that was not initially expected."

Dr. Meaney, Dr. Szyf, and Dr. Hyman have disclosed no relevant financial relationships.

Nat Neurosci. Published online February 22, 2009.

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