Epigenetics and Stress: “The moving finger writes; and, having writ, moves on.” – Omar Khayyam

There is a well-known connection between early life stress (ELS) and depression that develops in adolescence or the adult years. Individuals with severe ELS suffer from an up to three-fold higher incidence of depression as adults, a risk seen both in humans and in animal models. What has remained mysterious is the mechanism by which childhood stresses can propagate over decades to promote this risk many years later. A new publication in the journal Nature Neuroscience reveals that markings on our chromosomes are a key factor in establishing and maintaining the ELS effects.

DNA is our genetic material and it contains roughly 30,000 genes. These genes encode proteins, and proteins perform critical functions that our cells need to grow, survive, and reproduce. Unless we acquire mutations, our DNA blueprint passes unchanged from generation to generation of our cells as they divide during our lifetime. However, while the sequences of the genes are relatively unchanging, the expression of any single gene can be highly variable and is controlled at many levels. Consequently, even though human cells share the same set of genes, for any particular gene the timing of its expression, which cells produce it, and what amount of protein is made can vary significantly between individuals. These differences in protein expression can produce wide variations in biological outcomes, thus our physical and mental characteristics are not as simple as just having or not having a certain gene. One of the important mechanisms for regulating gene expression is dependent on the packing of DNA in chromosomes. Chromosomes form when DNA associates with a group of proteins known collectively as histones. The DNA is wrapped around balls of histones to protect the DNA and control the expression of genes. Part of the control, called epigenetic regulation, is via chemical modifications added to the histones or the DNA that increase or decrease the expression of nearby genes. These modifications are added by certain enzymes (the “writers”) and remain on the histones unless removed by other enzymes (the “erasers”). Collectively, the sum of all our histone and DNA modifications is referred to as our epigenome.

This new study used a mouse model of ELS to look at the nucleus accumbens, a region of the brain that is involved in depression and the stress response. Specifically, they looked at one type of histone modification called H3K79me2. This modification is added by the writer enzyme Dot1l and removed by the eraser enzyme Kdm2b. To examine the role of the H3K79me2 modification the authors of the study manipulated the levels of Dot1l or Kdm2b in the nucleus accumbens of mice. Increasing Dot1l, which results in more H3K79me2, caused depression-like behaviors while increasing Kdm2b to remove H2K79me2 reversed the effect. Additionally, the overall pattern of genes expressed in the nucleus accumbens of mice with high levels of Dot1l resembled the pattern seen in ELS mice. These data suggest that histone modifications that are written into our epigenome during childhood in response to stress may persist and predispose us to depression later in life. The histone modifications are like detour signs on a highway. Once they are in place the signs alter the normal flow of traffic, and the flow will stay altered unless the signs are removed. On a hopeful note, the authors also tested mice with a compound that inhibits Dot1l. Mice treated with the compound during a 10-day stress exposure had lower levels of H3K79me2 than control mice and performed better on social interactions in subsequent stress situations. Eventually, perhaps there will be medications that can be taken during stressful situations to prevent unwanted histone modifications from forming. Alternatively, there could be pharmaceuticals that are taken after ELS to erase the unwanted modifications and eliminate the negative stress effects. Either way, learning to manipulate our epigenome promises to have great value for our mental and physical health.

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