How Does Stress Get Under the Skin? The Epigenetic Hypothesis
By: Yiwen Zhu and Khalil Zlaoui
In a previous blog post, we discussed how genes and environmental exposures, including experiences of stress and adversity, come together to shape risk for depression—wherein our susceptibility to environmental stress may differ depending on our genetic makeup. Can those same environmental stressors “get under the skin” and change how our genes function? In this post, we explore how the field of epigenetics is providing new insights into this question.
1. What is epigenetics?
Epigenetics is the field of study concerned with how external stimuli can influence behavior and lead to potentially heritable changes without modifying the actual DNA sequence. Think of epigenetics as a performance of a Beethoven’s symphony: you always have the same sheet music (DNA sequence), but each conductor adds their own unique annotations to that score (i.e., adagio to allegro), which ultimately change how the musical score is expressed. Epigenetic marks, just like those annotations, can change how our DNA functions and how our genes are expressed.
One of the most widely studied mechanisms of epigenetic regulation is DNA methylation (DNAm). DNAm is a phenomenon commonly found in a specific region of the genome that potentially regulates gene expression by adding components called “methyl groups” to DNA molecules.
2. What do we know about the epigenetics of adversity and depression? From animal models to human studies.
Interest in behavioral epigenetics boomed following a 2004 study in rats, which revealed that maternal care during the first week of life directly changed methylation levels of offspring at a gene known to be involved in stress response. In this study, offspring of nurturing mothers showed less fearful behavior compared to offspring of neglectful mothers—this behavior persisted into adulthood.
However perhaps more importantly, some pups in this study were given surrogate mothers after the first week of life and this change in maternal care reversed the methylation alterations previously induced by the lack of maternal care in the first week of life. Collectively, these findings suggested that epigenetic differences may be a biological mechanism linking this type of early life adversity to later behavioral responses. This study therefore raised the idea that it might be possible to potentially reverse or alter behavioral responses by programming DNAm.
Since then, many animal studies have been conducted to examine the relationship between psychosocial factors—such as maternal behavior or social deprivation—on risk for psychopathology. Some of our favorite reviews on this topic include papers by Peña et al. (2014), Nestler (2015), and Januar et al. (2015). These studies also inspired research in humans that focused on the methylation changes at particular genes that were thought to be implicated in psychopathology risk.
An increasingly more popular approach now used is the epigenome-wide association study (EWAS), which allows researchers to simultaneously examine methylation levels across thousands of genes. Findings from EWAS suggest that differences in methylation levels are predicted by environmental risk factors linked to psychopathology and are also predictive of mental health outcomes such as depression and suicidal risk. For example, a recent meta-analysis found robust evidence linking differential methylation patterns—particularly in genes regulating aspects of brain development—to risk for depression.
Current studies in the field are also investigating how the characteristics of exposure to adversity predict epigenetic patterns. As an example, a recent study conducted by our lab found that the developmental timing of exposure to childhood adversity was linked to differential methylation at various sites on the epigenome. In other words, there appeared to be sensitive periods when adversity was more impactful in shaping DNA methylation signatures. With the support of a Rising Star research award from One Mind, we are now extending this work, in an effort to better understand links between the timing of exposure to adversity, DNA methylation, and subsequent risk for depression.
To date, EWAS have provided interesting insights into how changes in the epigenomic landscape may alter cellular function and ultimately shape risk for depression. Yet, because most studies are limited by costs and therefore sample size, many results have not been successfully replicated. As we have noted in a previous blog post, replication is critical to move this science forward.
3. What’s the long-term potential for epigenetics research?
Psychiatric epigenetics research is a promising new field that could provide deeper insights into the biological underpinnings of mental disorders. EWAS allow for the identification of objective biomarkers, capturing both the consequences of exposure to adversity and the potential causes of depression. Such insights may ultimately create opportunities for early diagnosis and prevention of depression, well before the onset of symptoms. It may also pave the way for new opportunities to prevent the negative consequences of certain adverse life experiences, including exposure to adversity.
Epigenetic marks may also represent potential therapeutic targets that could be modified through innovative interventions in the future. Though more research is needed, technological advancements, such as epigenome editing, may one day allow for the targeting of epigenetic marks at specific sites in the genome to treat a wide range of disorders.
Although there is still a long way to go before we fully understand the underlying pathway linking environmental exposures to epigenetic changes and its long-term effects on mental health, epigenetics research opens up exciting new possibilities for intervention and prevention of mental illness. As a lab, we are excited to be continuing this work to learn not just whether the environment shapes epigenetic profiles, but where on the genome these changes occur, and when these changes happen. Such insights can then be used to prevent depression and improve the lives of people and families already suffering from depression.