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Epigenetic slate stays dirty
THIS WEEK
Sins of the fathers Andy Coghlan
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 – 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, DOI:
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’s 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 – which genes are switched “Changes in mouse DNA on or off, and when it happens caused by depression are (see diagram, right). Every cell in passed down to their the body contains the same DNA pups and grand-pups” but epigenetic settings on cells in the bone and blood, for example, 10.1016/j.biopscych.2010.05.036). mean the tissues do very different According to classical genetics, jobs. The epigenetic consequences this shouldn’t be possible because of a huge range of environmental epigenetic marks on sperm and factors are under investigation, egg cells are supposed to be from exposure to drugs, “wiped clean” both before and chemicals and hormones, to the just after fertilisation, then reset impact of poor maternal care in in the new embryo. However, infancy, and the likelihood that Mansuy’s team found that the they are as heritable as DNA. relevant genes were over or underSo far, most epigenetic research methylated in the sperm of has focused on cancer because stressed males and in the brains epigenetic marks unique to cancer and germ lines, eggs or sperm of cells may set them apart from their offspring. “This provides healthy tissue. Now it’s the turn of proof that the changes in DNA psychiatric illness. The latest methylation are heritable,” results will be presented this week says Mansuy. in Washington DC at the annual Jonathan Mill of the Institute meeting of the American Society of Psychiatry, London, is one of for Human Genetics (ASHG). a few who are not yet convinced. The most compelling evidence “Evidence is mounting that for the epigenetic heritability of stress can produce enduring 8 | NewScientist | 6 November 2010
Marc Debnam/stone/getty
A little thing called methylation means the genetic slate isn’t wiped clean for the next generation
behavioural changes in rodents associated with epigenetic changes in specific gene regions,” says Mill. “But more research is needed before we can conclude that these effects are purely epigenetic in nature,” he says. Evidence for epigenetic effects in psychiatric illness is piling up. What’s 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, DOI: 10.1016/j. biopsych.2008.11.028). People with schizophrenia and bipolar disorder also have abnormally low levels of BDNF. Likewise, Michael Meaney and colleagues at McGill University in Montreal, Canada, found that in pups of mice bred to withhold maternal affection GAD1, a gene
In this section n Uniting gravity with nature’s other forces, page 10 n Cold-climate biogas on the cards, page 14 n Chronicles of a mothbot, page 22
Down the generations Epigenetic changes caused by the environment can affect which genes are turned
on and off. Could these changes be passed on to your children too?
DNA
METHYL GROUPS
HISTONE PROTEIN STRAND
DNA
Enzymes attach chemical caps called methyl groups to cytosine, one of the four base units that make up DNA
Methyl and other groups can also be added to protein strands on histones, components of disc-shaped proteins that serve as molecular cotton reels for DNA
METHYL GROUPS
DNA
Chromosome
Methylation can promote or decrease the activity of a gene so that genes throughout the body and throughout life can be activated at different stages of development
–Like grandad, like dad, like son–
vital for producing the brain found that IGF2, a particular neurotransmitter GABA was gene linked with embryonic suppressed. This substance is growth, was under-methylated vital for regulating emotion, and in these women. people with schizophrenia Last year, a study by Mill on produce too little of it (The Journal post-mortem brains revealed a of Neuroscience, DOI: 10.1523/ possible explanation: that underjneurosci.1039-10.2010). methylation of IGF2 is linked to Diet appears to play a part too. lower brain size and weight and One of the most famous studies that this, in turn, could be linked linking diet with schizophrenia with schizophrenia. The link followed the fate of Dutch women with the Dutch famine suggests who were pregnant during a that lack of methylation could prolonged famine at the end of simply be down to a diet lacking the second world war. The studies, in methyl-rich food, such as to be updated at the ASHG folate, during pregnancy, meeting this week by Ezra Susser when the brain is undergoing of Columbia University in New “It is a bridge between York, showed that girls born to what’s hard-wired into our these women had twice the usual DNA and what’s modifiable risk of developing schizophrenia. by the environment” A study published last year
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’s not to say it will be easy, though it transpires that antipsychotic drugs for conditions like bipolar disorder actually work by affecting epigenetic patterns. “The trouble is that these drugs are ‘dirty’, in that they often affect the whole genome and so could have side effects,” says Mill. “Targeting a specific gene in a specific part of the brain could be more difficult.” There are also simpler, behavioural interventions that could work. Recent studies by
Margaret Morris and Jayanthi Maniam of the University of New South Wales in Australia have shown that “comfort” food and opportunities for exercise reversed epigenetic abnormalities in rats caused by early-life stress (Psychoneuroendocrinology, DOI: 10.1016/j.psyneuen.2010.05.012). 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. “It can provide a bridge between what’s hard-wired in our DNA and what’s modifiable through the environment,” says Mill. “Once we understand the epigenome, we’ll understand more about the genome itself.” n 6 November 2010 | NewScientist | 9
Sins of the fathers Andy Coghlan
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 – 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, DOI:
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’s 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 – which genes are switched “Changes in mouse DNA on or off, and when it happens caused by depression are (see diagram, right). Every cell in passed down to their the body contains the same DNA pups and grand-pups” but epigenetic settings on cells in the bone and blood, for example, 10.1016/j.biopscych.2010.05.036). mean the tissues do very different According to classical genetics, jobs. The epigenetic consequences this shouldn’t be possible because of a huge range of environmental epigenetic marks on sperm and factors are under investigation, egg cells are supposed to be from exposure to drugs, “wiped clean” both before and chemicals and hormones, to the just after fertilisation, then reset impact of poor maternal care in in the new embryo. However, infancy, and the likelihood that Mansuy’s team found that the they are as heritable as DNA. relevant genes were over or underSo far, most epigenetic research methylated in the sperm of has focused on cancer because stressed males and in the brains epigenetic marks unique to cancer and germ lines, eggs or sperm of cells may set them apart from their offspring. “This provides healthy tissue. Now it’s the turn of proof that the changes in DNA psychiatric illness. The latest methylation are heritable,” results will be presented this week says Mansuy. in Washington DC at the annual Jonathan Mill of the Institute meeting of the American Society of Psychiatry, London, is one of for Human Genetics (ASHG). a few who are not yet convinced. The most compelling evidence “Evidence is mounting that for the epigenetic heritability of stress can produce enduring 8 | NewScientist | 6 November 2010
Marc Debnam/stone/getty
A little thing called methylation means the genetic slate isn’t wiped clean for the next generation
behavioural changes in rodents associated with epigenetic changes in specific gene regions,” says Mill. “But more research is needed before we can conclude that these effects are purely epigenetic in nature,” he says. Evidence for epigenetic effects in psychiatric illness is piling up. What’s 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, DOI: 10.1016/j. biopsych.2008.11.028). People with schizophrenia and bipolar disorder also have abnormally low levels of BDNF. Likewise, Michael Meaney and colleagues at McGill University in Montreal, Canada, found that in pups of mice bred to withhold maternal affection GAD1, a gene
In this section n Uniting gravity with nature’s other forces, page 10 n Cold-climate biogas on the cards, page 14 n Chronicles of a mothbot, page 22
Down the generations Epigenetic changes caused by the environment can affect which genes are turned
on and off. Could these changes be passed on to your children too?
DNA
METHYL GROUPS
HISTONE PROTEIN STRAND
DNA
Enzymes attach chemical caps called methyl groups to cytosine, one of the four base units that make up DNA
Methyl and other groups can also be added to protein strands on histones, components of disc-shaped proteins that serve as molecular cotton reels for DNA
METHYL GROUPS
DNA
Chromosome
Methylation can promote or decrease the activity of a gene so that genes throughout the body and throughout life can be activated at different stages of development
–Like grandad, like dad, like son–
vital for producing the brain found that IGF2, a particular neurotransmitter GABA was gene linked with embryonic suppressed. This substance is growth, was under-methylated vital for regulating emotion, and in these women. people with schizophrenia Last year, a study by Mill on produce too little of it (The Journal post-mortem brains revealed a of Neuroscience, DOI: 10.1523/ possible explanation: that underjneurosci.1039-10.2010). methylation of IGF2 is linked to Diet appears to play a part too. lower brain size and weight and One of the most famous studies that this, in turn, could be linked linking diet with schizophrenia with schizophrenia. The link followed the fate of Dutch women with the Dutch famine suggests who were pregnant during a that lack of methylation could prolonged famine at the end of simply be down to a diet lacking the second world war. The studies, in methyl-rich food, such as to be updated at the ASHG folate, during pregnancy, meeting this week by Ezra Susser when the brain is undergoing of Columbia University in New “It is a bridge between York, showed that girls born to what’s hard-wired into our these women had twice the usual DNA and what’s modifiable risk of developing schizophrenia. by the environment” A study published last year
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’s not to say it will be easy, though it transpires that antipsychotic drugs for conditions like bipolar disorder actually work by affecting epigenetic patterns. “The trouble is that these drugs are ‘dirty’, in that they often affect the whole genome and so could have side effects,” says Mill. “Targeting a specific gene in a specific part of the brain could be more difficult.” There are also simpler, behavioural interventions that could work. Recent studies by
Margaret Morris and Jayanthi Maniam of the University of New South Wales in Australia have shown that “comfort” food and opportunities for exercise reversed epigenetic abnormalities in rats caused by early-life stress (Psychoneuroendocrinology, DOI: 10.1016/j.psyneuen.2010.05.012). 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. “It can provide a bridge between what’s hard-wired in our DNA and what’s modifiable through the environment,” says Mill. “Once we understand the epigenome, we’ll understand more about the genome itself.” n 6 November 2010 | NewScientist | 9