Lifelong Epigenetic Changes Induced by Early Life Stress

Post by D. Chloe Chung

What's the science?

Stress early in life (e.g., childhood) can make people more vulnerable to other stressors, and increase the likelihood of developing depression later in life. The nucleus accumbens, a brain region involved in stress-related behaviors that combines inputs from other limbic brain regions, can regulate the impact of stress on our behaviors. Previous animal studies have shown that stress occurring early in life can induce transcriptional changes in the nucleus accumbens and increase the susceptibility to stress later in life as well as depression risk in adulthood. However, the exact mechanisms that sustain these transcriptional changes induced by early life stress were not well understood. This week in Nature Neuroscience, Kronman and colleagues found that early life stress can lead to perpetual changes in a histone modification in a specific type of neuron in the nucleus accumbens.

How did they do it?

To create stress factors early in life, the authors separated the mouse pups from their mom and left them with little bedding materials for several hours per day for 8 days. For this entire period, control mouse pups stayed with their mom with a sufficient amount of bedding. Then, the authors used a proteomics approach to analyze histone modifications within the nucleus accumbens collected from mice at different developmental stages: 21 days (young), 35 days (adolescence), and 70 to 80 days (adulthood) after birth. The authors also analyzed the RNA sequencing dataset from their previous study on early life stress to find enzymes that may be involved in histone modification changes. To further understand the significance of these enzymes on vulnerability to stress later in life, the authors virally overexpressed or knocked down these enzymes in specific cells of the nucleus accumbens and evaluated stress-related behaviors of mice. Some of the stress-related behavioral assessments were (1) interaction with an aggressive mouse, (2) free roaming in an open field, and (3) forced swimming in water. The authors also explored the potential therapeutic value of modulating these enzymes by testing a small molecule drug that can inhibit one of the enzymes. Specifically, twice a day for 10 days, the authors injected this drug into the abdomen of mice that were exposed to early life stress. Along with control mice injected with a placebo (salt water), these mice were compared for their interaction with an aggressive mouse.

What did they find?

First, the authors found several persistent histone modifications caused by early life stress from their proteomics analysis, such as histone methylation that can suppress or activate gene expression depending on the amino acid being methylated. In particular, they found that dimethylation on the lysine residue 79 of the histone H3 protein (H3K79me2) was significantly altered in adult male mice that experienced early life stress. From RNA sequencing data, the authors identified multiple histone-modifying enzymes whose expression levels were significantly altered upon early life stress: DOT1 that can add methylation to H3K79, and KDM2B that can remove methylation from the site. Interestingly, these epigenetic changes and associated enzymes were enriched in dopamine D2 medium spiny neurons of the nucleus accumbens. The authors virally modulated the level of DOT1 or KDM2B in these D2 neurons of the nucleus accumbens and found that stress-related behaviors can change in both control mice and mice that experienced early life stress. Specifically, mice exposed to early life stress were corrected for their stress behaviors and behaved like normal mice upon knockdown of DOT1 or overexpression of KDM2B in D2 neurons. Conversely, increased DOT1 expression or decreased KDM2B expression in control mice made them display depressive behaviors similar to mice with early life stress.

The authors further revealed that the consequences of cell type-specific manipulation of DOT1 and KDM2B levels were also reflected in gene regulation patterns in D2 neurons. Taken together, these findings highlight the importance of DOT1L and H3K79me2 in sustaining the impact of early life stress on stress vulnerability later in life. In a preclinical investigation effort, the authors also showed that a DOT1L-inhibiting drug can correct stress-related behaviors in mice exposed to early life stress, hinting at the potential therapeutic value of modulating histone modification.

What’s the impact?

This study found a brain region and cell type-specific epigenetic mechanism by which early life stress can influence susceptibility to other stressors and depression later in life. Notably, this work elucidated both specific histone modifications and responsible enzymes that are involved in persistent epigenetic reprogramming caused by early life stress. Findings from this study suggest that it may be feasible to develop therapeutic strategies to modulate the epigenetic landscape and reverse depression and stress-related responses influenced by early life stress. Additional studies are required to establish this as a possibility. Future research should also investigate other independent or synergistic mechanisms that contribute to the link between early life stress and depression risk.

Kronman et al. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nature Neuroscience (2021). Access the original scientific publication here.