The Epigenetics Revolution

We all recognise that different people seem to respond to stress in different ways. Some people seem fairly robust. Others can react really badly to the same stressful situation, even developing depression. Mice from different inbred strains are like this as well. Researchers exposed two different strains to mildly stressful stimuli. After the stressful situation, the researchers assessed the behaviour of the mice in some of the tests which mimic certain aspects of human depression. One strain was relatively non-anxious, whereas the other was relatively anxious. These strains were called B6 and BALB, but we’ll called them ‘chilled’ and ‘jumpy’, respectively, for convenience.

The researchers focused their studies on a region of the brain called the nucleus accumbens. This region plays a role in various emotionally important brain functions. These include aggression, fear, pleasure and reward. The researchers analysed the expression of various neurotrophic factors in the nucleus accumbens. The one that gave the most interesting results was a gene called Gdnf (glial cell-derived neurotrophic factor).

Stress caused an increase in expression of the Gdnf gene in the chilled mice. In the jumpy strain it caused a decrease in expression of the same gene. Now, different inbred strains of mice can have different DNA codes so the researchers analysed the promoter region, which controls the expression of Gdnf. The DNA sequence of the Gdnf promoter was identical in the chilled and the jumpy strains. But when the scientists examined the epigenetic modifications in this promoter, they found a difference. The histones of the jumpy mice had fewer acetyl groups than the histones of the chilled mice. As we’ve seen, low levels of histone acetylation are associated with low levels of gene expression, so this tied up well with the decreased Gdnf expression in the jumpy mice.

This led the scientists to wonder what had happened in the neurons of the nucleus accumbens. Why had the levels of histone acetylation dropped at the Gdnf gene in the jumpy mice? The scientists examined the levels of the enzymes that add or remove acetyl groups from histones. They found only one difference between the two strains of mice. A specific histone deacetylase (member of the class of proteins which removes acetyl groups) called Hdac2 was much more highly expressed in the neurons of the jumpy mice[215], compared with the chilled out mice.

Other researchers tested mice in a different model of depression, called social defeat. In these experiments, mice are basically humiliated. They’re put in an environment where they can’t get away from a bigger, scarier mouse, although they are removed before they come to any physical harm. Some mice find this really stressful; others seem to brush it off.

In the experiments adult mice underwent ten days of social defeat. At the end of this they were classified as either susceptible or resistant, depending on how well they bounced back from the experience. Two weeks later the mice were examined. The resistant mice had normal levels of corticotrophin-releasing hormone. This is the chemical released by the hypothalamus. It’s the one which ultimately stimulates the production of cortisol, the stress hormone. The susceptible mice had high levels of corticotrophin-releasing hormone and low levels of DNA methylation at the promoter of this gene. This was consistent with the high levels of expression from this gene. They also had low levels of Hdac2, and high levels of histone acetylation, which again fits with over-expression of the corticotrophin-releasing hormone[216].

It might seem odd that in one model system Hdac2 levels went up in the susceptible mice, whereas in another they went down. But it’s important with all these epigenetic events to remember that context is everything. There isn’t just one way in which Hdac2 levels (or those of any other epigenetic gene, for that matter) are controlled. The control will depend on the region of the brain and the precise signalling pathways that are activated in response to a stimulus.

The drugs do work

There’s more evidence supporting a significant role for epigenetics in responses to stress. The naturally jumpy B6 mice were the ones with the increased expression of Hdac2 in the nucleus accumbens, and decreased expression from the Gdnf gene. We can treat these mice with SAHA, the histone deacetylase inhibitor. SAHA treatment leads to increased acetylation of the Gdnf promoter. This is associated with increased expression of the Gdnf gene. The crucial finding is that the treated mice stop being jumpy and become chilled instead[217] – changing the histone acetylation levels of the gene changed the mouse’s behaviour. This supports the idea that histone acetylation is really important in modulating the responses of these mice to stress.