Researchers from the University of Wisconsin–Madison have compared the whole genomes of children with very high-stress early lives to those of kids whose childhoods were relatively tranquil. They found scores of differences in how their genes function, differences that may point out avenues to better diagnosis and treatment of stress-related disorders.

“We know that early life stress and the development of psychiatric disorders are related. We want to know how one leads to the other. We were surprised to see so many differences between our two groups, but now we can start looking at those differences more carefully, with the end goal of designing interventions, therapies, or medications that could resolve or even prevent those problems,"

says Leslie Seltzer, a researcher at UW–Madison’s Waisman Center and a lead author on the study with neuroepigenetics researcher Ligia Papale.

DNA Methylation

Seltzer, Papale and collaborators collected saliva from 22 girls from 9 to 12 years old, and analyzed the samples to see which genes were actually at work managing biological processes.

They were looking for a molecular modification called methylation. In methylation, environmental changes spur the attachment of a particular molecule, called a methyl group, to susceptible sites on genes.

“What you eat, your life experiences, how much you exercise, all of these things can modify your DNA methylation levels. DNA methylation doesn’t change your DNA, but the presence or absence of DNA methylation can change the way your DNA is used and whether or how much genes are expressed."

says UW–Madison neurosurgery professor Reid Alisch, who studies the regulation of gene expression in disease, especially mental illness.

The researchers found 122 genes where methylation of the high-stressed kids' DNA differed from their low-stress peers. The team also looked at how genes were expressed.

In all, more than 1,400 genes showed a difference in expression connected to the amount of stress the girls had experienced, including a dozen of the differently methylated genes.

[caption id=“attachment_96405” align=“aligncenter” width=“680”] Overlap of differentially methylated and expressed genes. Venn diagram of the overlap between differentially methylated genes (N = 122) and differentially expressed genes (N = 1,405) with known stress-related genes tested within the gene universe (yellow; N = 4,327).
An asterisk indicates that the overlap is significant (Chi-square P-value < 0.05).
Credit: Ligia A. Papale et al. CC-BY[/caption]

The combination of different methylation and gene expression highlighted some genes known to play roles in mood and psychiatric disorders.

“Our analysis identified differences in genes that help regulate mood and attachment, such as those for oxytocin and serotonin receptors. Those are exciting because we may be seeing the mechanism via which childhood stress can cause social or behavioral problems. But we’ve also flagged a lot of genes whose jobs still aren’t clear. Now we know that they may deserve more study for playing a part in stress-related psychiatric disorders, or in the stress response itself,"

Seltzer says.

Lasting Changes

It’s also notable, Alisch says, that the methylation and gene expression differences persist as the girls age.

“What some people in the field weren’t sure about is whether molecular changes that occur during a stressful period very early in life are stable,” he says. “What we’re finding is that after 10 years or so there are still markers, like fossils in our genome, telling us there was a trauma here. And that trauma may make this individual more susceptible to a second trauma or, even worse, a behavioral change, later in life."

Seltzer began exploring the way childhood stress may alter gene expression seven years ago, when she was a postdoctoral researcher in the lab of UW–Madison psychology Professor Seth Pollak. One of the results of Pollak’s work on abuse, neglect, poverty and other challenges in the life of a child is, according to Alisch, a particularly useful method of characterizing the types and severity of stress through detailed interviews with both the children and their parents.

[caption id=“attachment_96404” align=“aligncenter” width=“680”]Characterization of the potential role(s) of DMLs on gene expression. Characterization of the potential role(s) of DMLs on gene expression.
Credit: Ligia A. Papale et al. CC-BY[/caption]

The new insight in this research is not the fact that stress and abuse can make changes in gene expression, as any person who is familiar with gene expression would make this assumption. What is new, rather,  is that the study suggests by comparing gene expression between a non-stressed child compared a stressed child, scientists can determine what genes play a role in stress related symptoms.

“Our hope is that we can use molecular approaches and maybe some of the genes defined here to sort of refine our diagnosis at the individual level. That could make diagnosis and treatment more precise for each individual,"

Alisch says.

The work was supported in part by the National Institute of Mental Health, a core grant to the Waisman Center from the National Institute of Child Health and Human Development, the Hartwell Foundation, a NARSAD Young Investigator Grant from the Brain & Behavioral Research Foundation, and the National Science Foundation.

Ligia A. Papale, Leslie J. Seltzer, Andy Madrid, Seth D. Pollak & Reid S. Alisch Differentially Methylated Genes in Saliva are linked to Childhood Stress Scientific Reports volume 8, Article number: 10785

Top Image: Michele Studer, Wellcome Images

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