The Epigenetics Revolution

The later group used a mouse model of early-life stress. In this model, baby mice were taken away from their mothers for three hours a day, for the first ten days of their lives. Just like the baby rats that hadn’t been licked or groomed much, these babies developed into ‘high-stress’ adults. Cortisol levels were increased in these mice, especially in response to mild stress, just like the relatively neglected rats.

The researchers working on the mice studied the arginine vasopressin gene. Arginine vasopressin is secreted by the hypothalamus, and stimulates secretion from the pituitary. It is shown in Figure 12.1. The stressed-out mice, those that had suffered separation from their mothers in early life, had decreased DNA methylation of the arginine vasopressin gene. This resulted in increased production of arginine vasopressin, which stimulated the stress response[210].

^{Figure 12.2 Strong nurturing of baby rats sets up a cascade of molecular events that result in increased expression of the cortisol receptor in the brain. This increased expression makes the brain very effective at responding to cortisol and down-regulating stress responses via the negative feedback loop described in Figure 12.1.}

The rat and mouse experimental studies show us two important things. The first is that when early life events lead to adult stress, there is probably more than one gene involved. Both the cortisol receptor gene and the arginine vasopressin gene can contribute to this phenotype in rodents.

Secondly, the studies also show us that a particular class of epigenetic modification is not in itself good or bad. It’s where the modification happens that matters. In the rat model, the decreased DNA methylation of the cortisol receptor gene is a ‘good’ thing. It leads to increased production of this receptor, and a general dampening down of the stress response. In the mouse model, the decreased DNA methylation of the arginine vasopressin gene is a ‘bad’ thing. It leads to increased expression of this hormone and a stimulation of the stress response.

The decreased DNA methylation of the arginine vasopressin gene in the mouse model occurred through a different route to the one used in the rat hippocampus to activate the cortisol receptor gene.

In the mouse studies, separation from the mother triggered activity of the neurons in the hypothalamus. This set off a signalling cascade that affected the MeCP2 protein. MeCP2 is the protein we met in Chapter 4, which binds to methylated DNA and helps repress gene expression. It’s also the gene which is mutated in Rett syndrome, the devastating neurological disorder. Adrian Bird has shown that the MeCP2 protein is incredibly highly expressed in neurons[211].

Normally, MeCP2 protein binds to the methylated DNA at the arginine vasopressin gene. But in the stressed baby mice, the signalling cascade mentioned in the previous paragraph adds a small chemical group called a phosphate to the MeCP2 protein and because of this MeCP2 falls off the arginine vasopressin gene. One of the important roles of MeCP2 is attracting other epigenetic proteins to where it is bound on a gene. These are proteins that all cooperate to add more and more repressive marks to that region of the genome. When the phosphorylated MeCP2 falls off the arginine vasopressin gene, it can no longer recruit these different epigenetic proteins. Because of this, the chromatin loses it repressive marks. Activating modifications get put on instead, such as high levels of histone acetylation. Ultimately, even the DNA methylation is permanently lost.

Amazingly this all happens in the mice in the first ten days after birth. After that, the neurons essentially lose their plasticity. The DNA methylation pattern that’s in place at the end of this stage becomes the stable pattern at this location. If the DNA methylation levels are low, this will normally be associated with abnormally high expression of the arginine vasopressin gene. In this way, the early life events trigger epigenetic changes which get effectively ‘stuck’. Because of this, the animal continues to be highly stressed, with abnormal hormone production, long after the initial stress has vanished. Indeed, the response continues long after the animal would even normally ‘care’ about whether or not it has its mother’s company. After all, mice are not renowned for hanging about to look after their ageing parents.

In the depths