Read more: 鈥�Instant Expert 29: Epigenetics鈥�
As well as DNA methylation, other epigenetic mechanisms include chemical changes to the proteins that package DNA. These systems are not just responsible for such classic epigenetic phenomena as tortoiseshell cats, but are also involved in our development in the womb and the day-to-day regulation of our genes.
In fact, almost everything DNA does 鈥� including protein manufacture, replication of DNA before cells divide, and the repair of DNA damage 鈥� entails epigenetic systems of this kind. These mechanisms also offer a potential conduit for the world we live in to influence our genes, reviving the old nature or nurture debate
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How it works
DNA methylation was the first epigenetic mechanism to be appreciated, in the 1970s, but since then a plethora of other such chemical modifications have become apparent. Instead of changing DNA itself, many act through its associated proteins, called histones.
Histone proteins help to package the DNA of all complex life forms, including animals, plants and fungi, but excluding bacteria. The arrangement resembles beads on a string, except that the DNA is wrapped round the outside of the histone cluster rather than passing through a hole in the middle (see diagram). Importantly, histones have long protruding molecular tails with many possible sites for chemical modification.
As with DNA, histones can have methyl groups added to them, but also other chemical units, including phosphate groups, acetyl groups and even small proteins, such as ubiquitin. While DNA methylation turns genes off, histone methylation can enhance gene activity or silence it, depending on where on the tail the methyl group is added. Histone acetylation, on the other hand, almost always turns genes on. Altogether over 50 different types of modification have been identified, many of which we are still trying to decode.
How do these chemical changes exert their effects? For a gene to be active and churning out its protein, a series of manufacturing enzymes must bind to the DNA so that they can make an intermediary molecule called messenger RNA. Some epigenetic changes cause the DNA to become more tightly coiled up and inaccessible, stopping the enzymes from binding 鈥� turning the gene off, in other words. Changes that turn the gene on cause the DNA to physically open up so the manufacturing enzymes can bind to it.
These epigenetic systems are managed by proteins classed as writers, erasers or readers. Writers are the enzymes that put on the chemical marks, whereas erasers, as the name implies, remove them. And readers interpret marks by binding to the altered site and causing gene silencing or activation. For every type of epigenetic mark 鈥� methylation, phosphorylation, and so on 鈥� there is a specific set of proteins that writes, reads and erases it.
Window on the world
One of the most controversial aspects of epigenetics is the route it offers for the environment to influence our bodies and behaviour, rather than our genes. Bear in mind, though, that most epigenetic mechanisms discovered so far respond to constraints that are internal to the organism rather than external, including X-chromosome inactivation, gene imprinting and the regulation of gene expression during our time in the womb. In fact there is good recent evidence that the major determinant of initial DNA methylation patterns is the DNA sequence itself 鈥� suggesting our genes have the last word after all.
鈥淥ne of the most controversial aspects of epigenetics is the route it offers for the environment to influence us鈥�
In some cases, however, the environment has been found to influence DNA methylation patterns. The best example involves the effect of diet on an unusually coloured type of mouse called agouti. Normally, a litter of these mice has a range of coat colours from yellow to dark brown, thanks to the agouti gene. But if the pregnant mother is fed a diet high in certain vitamins and amino acids that are rich in methyl groups, she gives birth to more brown pups.
The high sensitivity of the agouti gene to methylation is due to a nearby 鈥渢ransposon鈥�; these are short DNA sequences that can be found randomly distributed through our genomes. When methylation is low, the transposon drives abnormally high expression of agouti, leading to yellow mice. Artificially increasing methylation, on the other hand, shuts down the transposon giving brown mice. While the methyl-rich diet would cause a modest increase in DNA methylation across the whole genome, only the transposon at the agouti locus appears hypersensitive to the increase.
So do environmental cues affect epigenetic systems in a more natural setting? We know that conditions during pregnancy, including maternal diet, have long-term health consequences for the offspring right into adult life. For instance, people whose mothers were malnourished during pregnancy are more prone to heart disease and diabetes as adults. Epigenetic mechanisms may be involved here, although the evidence so far is inconclusive.
Some see effects of this kind as evolutionarily adaptive: the offspring鈥檚 metabolism is prepared for a world where the going is tough, and excess calories need to be hoarded. Of course, if the going turns out to be easy, this would be counter-productive.
In one striking example, rat pups that are neglected by their mothers in the nest grow up to be skittish and timid adults. There is evidence that this is achieved through DNA methylation at a gene that regulates the response to stress.
Methylation, it is argued, turns down the 鈥渧olume control鈥� on the gene, resulting in permanent anxiety. According to the evolutionarily adaptive theory, this prepares the rats for a tough environment by making them more risk averse.
Perhaps most controversially, a has suggested similar profound effects in humans. This comes from post-mortem analyses of suicide victims who had been abused as children. The authors proposed that the abuse increased methylation in the corresponding human stress response gene, with lifelong adverse consequences. However, the study was small and the effects weak, so it is too soon to draw firm conclusions.
