Child abuse changes stress gene expression

Recent research by Patrick O McGowan and his team at McGill University, Montreal, have found a link between abuse in early childhood and epigenetic modification of genes resulting in an increased stress response and sensitivity. Epigenetic modification causes a change in gene expression causing a change in phenotype yet no change in the DNA sequence due to an environmental factor, which is in this situation abuse during childhood.

Published this year, the study analysed the difference in hippocampal glutocortide coding NR3C1 gene expression in 12 suicide victims who experienced childhood abuse, 12 who experienced no childhood abuse and 12 control subjects who died in accidental circumstances. The NR3C1 gene, a promoter for glucocorticoid receptors involved in dampening stress response, indirectly influences the levels of production ACTH in the hypothalamic-pituitary-adrenal axis (HPA axis). ACTH is the primary actor upon the HPA axis stress response, with an increase in pituitary production of ACTH increasing the stress response, and subsequently harmful functions, of the HPA axis.

When comparing suicide victims who had experienced abuse in their childhood to those who had not, it was found that there was an epigenetic modification of the expression of the NR3C1 gene resulting in a reduced HPA glucocortide receptor expression and increased ACTH response. This, in effect, causes the victims to have a far higher sensitivity to stress and elevated levels of stress symptoms. This modification of the NR3C1 gene resulted in increased methylation of the exox 1F NR3C1 promoter.

Similar decreases in glucocortide receptor function can be observed in infants whose mothers experienced a mood disorder during pregnancy (Oberlander, TF et al 2008. Differences in the methylation of the NR3C1 gene of a similar fashion have also been associated with schizophrenia and bipolar disorder (Perlman, W. et al 2004).

Improvements in understanding of the genetic basis of anxiety disorders and the effect of childhood abuse may assist in finding appropriate treatments and screening methods for this affliction.

McGowan P, Sasaki A, D’Alessio A, Dymov S, Labonte B, Szyf M, Turecki G. & Meaney M. 2009, ‘Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse’, Nature Neuroscience, vol. 12, no. 3, pp. 342-348

Perlman W, Webster M, Kleinman J, Weickert C 2004, ‘Reduced glucocorticoid and estrogen receptor alpha messenger ribonucleic acid levels in the amygdala of patients with major mental illness’, Biological Psychiatry, Vol. 56, no. 11, pp. 844-852

Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM.

2008, ‘Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses’, Epigenetics, Vol. 3, no. 2, pp. 97-106