ARTICLE IN BRIEF
Investigators identified altered DNA methylation levels in the glucocorticoid receptor (GR) gene, in the hippocampal tissue of suicide victims who had a known history of child abuse.
There was most certainly no mention of it in suicide notes. But scientists have found an unwritten message that could help explain the final act of desperation in people who kill themselves: an epigenetic fingerprint — a non-genetic (environmental) factor that may change gene expression without changing the original DNA sequence — seems to be a response to child abuse early in their lives.
The epigenetic changes triggered by the environment led to lifelong changes in the way the gene worked to make proteins that regulate the human stress response. It is possible that this epigenetic phenomenon had a role in an abused person's decision to die at their own hands. So suggests research by investigators at McGill University in Montreal, Canada.
Moshe Szyf, PhD, a professor in the department of pharmacology and therapeutics at McGill University, and his colleagues have for decades studied DNA methylation, first in cancer and more recently in the brains of people who committed suicide. In DNA methylation, the genome may be modified by addition of a methyl group, usually at the fifth cystine.
If DNA is the alphabet of the genome then methylation is akin to the punctuation marks, he explained. Whatever methylation occurs on the DNA will determine which parts of it are expressed. While DNA is inherited there is growing evidence that methylation is laid down during gestation. And now it turns out that these markers, or methylated punctuation marks on DNA — which block and sometimes promote expression of labeled DNA in certain instances — are sensitive to environmental influences throughout life.
“The environment is dynamic and DNA is static,” said Dr. Szyf. “DNA methylation provides a way for a person to adapt to his or her environment. DNA methylation can serve as a bridge between nature and nurture, a way social exposure can modulate DNA by changing its marks so that a person can adapt to changing environments.”
The Canadian investigators first became interested in DNA methylation when they studied the effect of maternal love on rats. Maternal behavior — licking and grooming pups — altered the development of the pup's stress response - directly through effects of gene transcription in one specific region in the brain. In fact, it was in these animal studies that Dr. Szyf and his colleague Michael Meaney, PhD, found altered DNA methylation levels in the glucocorticoid receptor (GR) gene, which regulates stress hormones. Other groups have told similar stories about the power of a mother's love or lack of it on the offspring's brain and behavior.
In the latest work, published earlier this year in Nature Neuroscience, the team worked with colleagues at the Quebec Suicide Brain Bank, focusing on hippocampal tissue. They identified samples from 12 people who had killed themselves and had a retrospective psychological autopsy — case histories showing a history of childhood abuse — that revealed a history of childhood abuse, an equal number of people who committed suicide without a known abuse history, and 12 others who died in accidents.
They looked specifically at the epigenetic difference in the neuron-specific glucocorticoid receptor NR3C1 promoter. The gene sits on chromosome five. They measured the expression of total glucocorticoid receptor and glucocorticoid receptor-1F using quantitative reverse transcriptase PCR on the RNA extracted from the hippocampal tissue. They found a significant decrease in the expression of glucocorticoid receptors and in the expression of transcripts containing the NR3C2 promoter. The decrease was found only in tissue samples from suicide victims with a history of childhood abuse, according to Dr. Szyf. There was no difference in the levels of the receptors or the promoter in the 12 suicide victims without a known history of abuse and those who died in car crashes or other accidents.
They also found a high degree of DNA methylation in the NR3C1 promoter region, again only in those who committed suicide and had a known childhood history of abuse. The scientists suspect that this increased methylation is intimately involved in the decreased expression of the glucocorticoid receptors. There is mounting evidence that decreases in hippocampal expression of glucocorticoid receptor enhance the effects of stress, Dr. Szyf said.
Measurements of glucocorticoids in the blood were much higher in the abused suicide victims, he added. (The hippocampus regulates hormone levels in the body.)
Admittedly, the scientists say that they have no idea when the methylation occurs. If they were to guess from animals, it would seem that the changes occur on the heels of maternal deprivation. But licking and grooming behavior in rats is a long way from the human expression and experience of love and nurturing.
Still, said Dr. Szyf, “this is the first study that links social environment to the genome.” He said that it may also explain many other adulthood diseases where epigenetics may have a hand in shaping the body's response to life experiences.
“This study offers an important insight into how early adverse life experience ‘gets under the skin,’ affecting critical areas of brain function that contribute to a life course of health or disease,” said Tim F. Oberlander, MD, FRCPC, a professor in the division of developmental pediatrics at the BC Children's Hospital Child and Family Research Institute at the University of British Columbia.
In a 2008 study published in the journal Epigenetics, Dr. Oberlander and his colleagues reported a correlation between exposure to maternal depressed mood in the third trimester of pregnancy and neonatal methylation status of glucocorticoid receptor gene in human umbilical cord blood. Newborns of depressed mothers had increased site-specific methylation of an NGFI-A (nerve growth factor induced) response element of glucocorticoid receptor 1F — the same location found by Dr. Szyf and colleagues in an animal model of maternal care-giving — and the increased methylation was linked to an enhanced cortisol stress response in infants at 3 months of age.
“Interestingly, while many mothers in our study had been treated with a selective serotonin re-uptake inhibitor antidepressant, like Prozac or Paxil, this did not make a difference to methylation levels, suggesting that such treatment did not ‘buffer’ or protect their children from the effects of the mothers' depressed mood.”
The study showed that antenatal maternal mood might transmit vulnerability for altered stress regulation from parent to child via an epigenetic modification of genomic regions critical to the development of stress regulation systems.
“For many years we have known that maternal mood during pregnancy is associated with impaired stress reactivity and an increased risk for mood disturbances during childhood and later across the life span,” Dr. Oberlander said. “Our findings showed that a mother's mood affects her infant in ways that go beyond inherited genes or exposure to medication during pregnancy. It provides critical clues to how early adverse life experience might work to ‘program’ — via ‘epigenetic mechanisms’ — the developing stress system that contributes to stress related disorders, like depression, later in life.”
Dr. Szyf added that the next step is to look at DNA methylation in adoption and even socioeconomically disadvantaged populations to see if other adverse events alter the expression of regions on the human genome.
While the investigators can't look at tissue slices from the brains of living people, they are hoping that their white blood cells will tell a similar story. “We want to understand how methylation marks are laid down and altered,” he said. “We believe that environment will feed into signaling pathways that will direct enzymes to certain genes that will remove or add methylation.”
Weaver IC, Cervoni N, Meaney MJ, et al. Epigenetic programming by maternal behavior. Nat Neurosci
McGowan PO, Sasaki A, Meaney MJ, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci
Oberlander TF, Weinberg J, Devlin AM, et al. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics