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Editorial: Epigenetics can take us towards a saner future

A little thing called methylation means that parental neglect, or eating a poor diet, could lead to depression or schizophrenia two generations later

WHAT if your bad habits mean that your children and even their children end up with a psychiatric disorder? That is one of the implications of a study in rodents that suggests poor diet and parental neglect can leave their mark on the genes of your children and your children鈥檚 children.

A cryptic epigenetic code added to the DNA of mice shows for the first time that changes in gene activity can pass down three generations. It is likely that the same mechanisms are at work in humans.

Epigenetics deals with the regulation of gene activity within a cell 鈥� which genes are switched on or off, and when it happens (see diagram). Every cell in the body contains the same DNA but epigenetic settings on cells in the bone and blood, for example, mean the tissues do very different jobs. The epigenetic consequences of a huge range of environmental factors are under investigation, from exposure to drugs, chemicals and hormones, to the impact of poor maternal care in infancy, and the likelihood that they are as heritable as DNA.

So far, most epigenetic research has focused on cancer because epigenetic marks unique to cancer cells may set them apart from healthy tissue. Now it鈥檚 the turn of psychiatric illness. The latest results will be presented this week in Washington DC at the annual meeting of the (ASHG).

The most compelling evidence for the epigenetic heritability of psychiatric illness comes from a recent study of male mice made depressed by exposure to stress and lack of maternal care during the first two weeks after birth. Isabelle Mansuy at the University of Zurich, Switzerland, and colleagues found that two generations of offspring born to these mice were also depressed and anxious 鈥� even though they were raised with the usual levels of maternal care and attention.

Crucially, depressed males appeared to have passed down to their pups and grand-pups telltale epigenetic chemical marks on key brain genes, and on sperm cells (Biological Psychiatry, ).

鈥淐hanges in mouse DNA caused by depression are passed down to their pups and grand-pups鈥�

According to classical genetics, this shouldn鈥檛 be possible because epigenetic marks on sperm and egg cells are supposed to be 鈥渨iped clean鈥� both before and just after fertilisation, then reset in the new embryo. However, Mansuy鈥檚 team found that the relevant genes were over or under-methylated in the sperm of stressed males and in the brains and germ lines, eggs or sperm of their offspring. 鈥淭his provides proof that the changes in DNA methylation are heritable,鈥� says Mansuy.

of the Institute of Psychiatry, London, is one of a few who are not yet convinced. 鈥淓vidence is mounting that stress can produce enduring behavioural changes in rodents associated with epigenetic changes in specific gene regions,鈥� says Mill. 鈥淏ut more research is needed before we can conclude that these effects are purely epigenetic in nature,鈥� he says.

Evidence for epigenetic effects in psychiatric illness is piling up. What鈥檚 more, there appear to be critical points in life when epigenetic effects are more likely to kick in because of major hormonal changes: in the womb, just after birth, adolescence, and middle age.

For example, when infant rats were raised by stressed and abusive mothers, David Sweatt and his colleagues at the University of Alabama in Birmingham found that maltreatment lasting just a week was enough to trigger epigenetic changes. These changes partially deactivated the gene for brain derived neurotrophic factor (BDNF), a substance important for memory formation and emotional balance in rats and humans. Sweatt found these epigenetic changes on the BDNF gene in both the abusive adult rats and their offspring (Biological Psychiatry, ). People with schizophrenia and bipolar disorder also have abnormally low levels of BDNF.

Likewise, and colleagues at McGill University in Montreal, Canada, found that in pups of mice bred to withhold maternal affection GAD1, a gene vital for producing the brain neurotransmitter GABA was suppressed. This substance is vital for regulating emotion, and people with schizophrenia produce too little of it (The Journal of Neuroscience, ).

Diet appears to play a part too. One of the most famous studies linking diet with schizophrenia followed the fate of Dutch women who were pregnant during a prolonged famine at the end of the second world war. The studies, to be updated at the ASHG meeting this week by of Columbia University in New York, showed that girls born to these women had twice the usual risk of developing schizophrenia. A study published last year found that IGF2, a particular gene linked with embryonic growth, was under-methylated in these women.

Last year, a study by Mill on post-mortem brains revealed a possible explanation: that under-methylation of IGF2 is linked to lower brain size and weight and that this, in turn, could be linked with schizophrenia. The link with the Dutch famine suggests that lack of methylation could simply be down to a diet lacking in methyl-rich food, such as folate, during pregnancy, when the brain is undergoing critical growth and development.

The good news, however, is that there might be ways to treat or even prevent psychiatric disorders, not least because epigenetic marks on genes are potentially reversible. That鈥檚 not to say it will be easy, though it transpires that antipsychotic drugs for conditions like bipolar disorder actually work by affecting epigenetic patterns. 鈥淭he trouble is that these drugs are 鈥榙irty鈥�, in that they often affect the whole genome and so could have side effects,鈥� says Mill. 鈥淭argeting a specific gene in a specific part of the brain could be more difficult.鈥�

There are also simpler, behavioural interventions that could work. Recent studies by of the University of New South Wales in Australia have shown that 鈥渃omfort鈥� food and opportunities for exercise reversed epigenetic abnormalities in rats caused by early-life stress (Psychoneuroendocrinology, ).

Epigenetics is in its infancy, but has the potential to lead to new treatments for psychiatric disorders, as well as helping us understand how the environment impacts on our genes. 鈥淚t can provide a bridge between what鈥檚 hard-wired in our DNA and what鈥檚 modifiable through the environment,鈥� says Mill. 鈥淥nce we understand the epigenome, we鈥檒l understand more about the genome itself.鈥�

鈥淚t is a bridge between what鈥檚 hard-wired into our DNA and what鈥檚 modifiable by the environment鈥�