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Epigenetics: Far-reaching effects
far right DR ANDREJS LIEPINS/SCIENCE PHOTO LIBRARY main. JELLYFISH PICTURES/SCIENCE PHOTO LIBRARY left, meyer/tendance floue
Through the generations Can epigenetic traits be transmitted to an organism’s offspring? In plants, the answer is a definitive yes. A particular flower shape found in some toadflax plants is faithfully passed on between generations, yet it does not appear to involve any difference in DNA sequence. This “peloric” flower form, which has been known for more than 200 years, turns out to be caused by silencing of a gene through DNA methylation. Evidence for transgenerational effects in animals is scarce, but does exist. Take the agouti mice described on page iv, whose coat colour varies from yellow through to brown, depending on the methylation status of a pigmentation gene. Crossing two mice of the same colour generates once more the complete range of coat colours, suggesting that the epigenetic marks are not reliably transmitted to offspring. But careful analysis shows that yellow parents have more yellow pups than average, suggesting a small tendency for this epigenetic trait to be passed on, although the effect is lost in later generations. The same pattern is seen with another mouse gene that causes a kinked tail. The conclusion from these thorough studies in mice is that epigenetic inheritance does exist, but that it is a weak effect lost after one generation. So what about us? Might the epigenetic consequences of starvation, neglect or disease be inherited across human generations? One study showed that people with a grandparent who went through a famine as a teenager died earlier, on average, if they were the same sex as the starved grandparent. The implication is that the experience of starvation changed the epigenome and that this effect was faithfully transmitted over two generations to compromise the health of the grandchildren. Studies of this kind are statistical and retrospective, so it is hard to investigate what is going on at a molecular level. Besides, it is difficult to rule out that these effects were transmitted through culture rather than epigenetics. Large-scale mapping of human epigenomes in relation to experience and disease is under way and may help resolve this conundrum. The possibility that characteristics acquired during an individual’s lifetime are epigenetically memorised and transmitted to the next generation has led to a revival in some quarters of the hitherto discredited theory of evolution known as Lamarckism. The consensus view, supported by a mountain of evidence, is still that evolution proceeds by natural selection among genetic variants that arise by accident. Nevertheless, epigenetic mechanisms could conceivably play some minor evolutionary role. vi | NewScientist | 5 January 2013
”Epigenetic changes in the womb may have lifelong consequences”
Epigenetics and disease
Generation game: the effects of culture and inheritance can be hard to disentangle
A purely epigenetic disease would be one in which the epigenome is altered without any accompanying change to DNA sequences. In practice it is difficult to prove that DNA mutations have not also played a role, but some disorders may well be purely epigenetic. For instance, a congenital disorder called BeckwithWiedemann syndrome involves the malfunctioning of a gene encoding a signalling molecule called IGF2, which encourages fetal growth (see page iii). The copy of this gene derived from the father is normally expressed, while the copy from the mother is silenced, or “imprinted”, by DNA methylation. When the maternal gene is not properly silenced, too much IGF2 leads to an abnormally large fetus, congenital malformations and childhood tumours. In many cases no mutation in the DNA sequence can be detected and the risk of recurrence in affected families is lower than would be expected if a genuine genetic mutation is involved. Some cases of Beckwith-Wiedemann syndrome may therefore have an epigenetic origin. Assisted-reproduction technologies such as IVF appear to slightly increase the likelihood of Beckwith-
far-reaching effects As epigenetic changes to genes can be profound and durable, it is entirely likely they are involved in human disease. So far, faulty epigenetic programming has been implicated in some congenital disorders and in certain cancers. But the jury is still out as to whether epigenetic susceptibility to disease can be passed on to future generations
Wiedemann syndrome and other imprinting disorders. There is also a higher rate of such abnormalities in cloned animals. This suggests that there may be critical periods in early embryonic development when an altered environment can cause epigenetic errors. Epigenetic malfunction is also implicated in one of the commonest causes of death in the west: cancer. Tumours arise when cells are released from the constraints that normally stop them from dividing to produce daughter cells. Instead, they proliferate and form tumours. There is abundant evidence that the primary causes of this escape are genetic mutations, but for many years we have known that DNA methylation can also go awry in cancer. Indeed, sometimes epigenetic changes are suspected of being a primary cause of a tumour. For example, the gene MLH1, whose protein product is required to repair damage to DNA, is often mutated in colon cancer. But it can sometimes be found silenced by DNA methylation alone, without an apparent mutation. Drugs that remove DNA methylation reactivate MLH1 expression in the
cancer cells, suggesting that there is nothing intrinsically wrong with the gene except that it has been silenced epigenetically. In addition, some cancer-causing mutations in DNA exert their effects through secondary epigenetic changes: there is a fast-growing list of cancer mutations that alter the epigenetic machinery (that is, the readers, writers and erasers described on page v). For example, many myeloid cancers – which affect blood cells – have mutations in a gene called TET2. This gene encodes a protein that converts the methyl group on DNA to a hydroxymethyl group, which subsequently leads to loss of the methyl group, thereby preventing inappropriate gene silencing Conversely, in the absence of TET2, methylation levels climb too high, leading to silencing of critical genes. Perhaps the best evidence for the importance of epigenetics in cancer is that drugs targeting epigenetic processes can be effective anti-cancer agents. For example, the demethylating drug decitabine is used successfully to treat some chronic leukaemias, and drugs that inhibit the enzymes that erase acetyl groups from histones are also used in the clinic. It might be expected that perturbing epigenetic signals through the whole body in this way would result in profound side effects. In practice, tumour cells are often killed at doses that are relatively non-toxic, suggesting that epigenetic disturbances are the Achilles heel of certain cancers. With many more such epigenetic drugs in the pipeline, this is
surely a promising approach for anti-cancer therapy. Are there other diseases with epigenetic influences waiting to be discovered? We should know in a few years, as large-scale epigenomic mapping projects designed to answer this question are ongoing.
Leukemia: epigenetic changes are the Achilles heel of many cancers
5 January 2013 | NewScientist | vii
Through the generations Can epigenetic traits be transmitted to an organism’s offspring? In plants, the answer is a definitive yes. A particular flower shape found in some toadflax plants is faithfully passed on between generations, yet it does not appear to involve any difference in DNA sequence. This “peloric” flower form, which has been known for more than 200 years, turns out to be caused by silencing of a gene through DNA methylation. Evidence for transgenerational effects in animals is scarce, but does exist. Take the agouti mice described on page iv, whose coat colour varies from yellow through to brown, depending on the methylation status of a pigmentation gene. Crossing two mice of the same colour generates once more the complete range of coat colours, suggesting that the epigenetic marks are not reliably transmitted to offspring. But careful analysis shows that yellow parents have more yellow pups than average, suggesting a small tendency for this epigenetic trait to be passed on, although the effect is lost in later generations. The same pattern is seen with another mouse gene that causes a kinked tail. The conclusion from these thorough studies in mice is that epigenetic inheritance does exist, but that it is a weak effect lost after one generation. So what about us? Might the epigenetic consequences of starvation, neglect or disease be inherited across human generations? One study showed that people with a grandparent who went through a famine as a teenager died earlier, on average, if they were the same sex as the starved grandparent. The implication is that the experience of starvation changed the epigenome and that this effect was faithfully transmitted over two generations to compromise the health of the grandchildren. Studies of this kind are statistical and retrospective, so it is hard to investigate what is going on at a molecular level. Besides, it is difficult to rule out that these effects were transmitted through culture rather than epigenetics. Large-scale mapping of human epigenomes in relation to experience and disease is under way and may help resolve this conundrum. The possibility that characteristics acquired during an individual’s lifetime are epigenetically memorised and transmitted to the next generation has led to a revival in some quarters of the hitherto discredited theory of evolution known as Lamarckism. The consensus view, supported by a mountain of evidence, is still that evolution proceeds by natural selection among genetic variants that arise by accident. Nevertheless, epigenetic mechanisms could conceivably play some minor evolutionary role. vi | NewScientist | 5 January 2013
”Epigenetic changes in the womb may have lifelong consequences”
Epigenetics and disease
Generation game: the effects of culture and inheritance can be hard to disentangle
A purely epigenetic disease would be one in which the epigenome is altered without any accompanying change to DNA sequences. In practice it is difficult to prove that DNA mutations have not also played a role, but some disorders may well be purely epigenetic. For instance, a congenital disorder called BeckwithWiedemann syndrome involves the malfunctioning of a gene encoding a signalling molecule called IGF2, which encourages fetal growth (see page iii). The copy of this gene derived from the father is normally expressed, while the copy from the mother is silenced, or “imprinted”, by DNA methylation. When the maternal gene is not properly silenced, too much IGF2 leads to an abnormally large fetus, congenital malformations and childhood tumours. In many cases no mutation in the DNA sequence can be detected and the risk of recurrence in affected families is lower than would be expected if a genuine genetic mutation is involved. Some cases of Beckwith-Wiedemann syndrome may therefore have an epigenetic origin. Assisted-reproduction technologies such as IVF appear to slightly increase the likelihood of Beckwith-
far-reaching effects As epigenetic changes to genes can be profound and durable, it is entirely likely they are involved in human disease. So far, faulty epigenetic programming has been implicated in some congenital disorders and in certain cancers. But the jury is still out as to whether epigenetic susceptibility to disease can be passed on to future generations
Wiedemann syndrome and other imprinting disorders. There is also a higher rate of such abnormalities in cloned animals. This suggests that there may be critical periods in early embryonic development when an altered environment can cause epigenetic errors. Epigenetic malfunction is also implicated in one of the commonest causes of death in the west: cancer. Tumours arise when cells are released from the constraints that normally stop them from dividing to produce daughter cells. Instead, they proliferate and form tumours. There is abundant evidence that the primary causes of this escape are genetic mutations, but for many years we have known that DNA methylation can also go awry in cancer. Indeed, sometimes epigenetic changes are suspected of being a primary cause of a tumour. For example, the gene MLH1, whose protein product is required to repair damage to DNA, is often mutated in colon cancer. But it can sometimes be found silenced by DNA methylation alone, without an apparent mutation. Drugs that remove DNA methylation reactivate MLH1 expression in the
cancer cells, suggesting that there is nothing intrinsically wrong with the gene except that it has been silenced epigenetically. In addition, some cancer-causing mutations in DNA exert their effects through secondary epigenetic changes: there is a fast-growing list of cancer mutations that alter the epigenetic machinery (that is, the readers, writers and erasers described on page v). For example, many myeloid cancers – which affect blood cells – have mutations in a gene called TET2. This gene encodes a protein that converts the methyl group on DNA to a hydroxymethyl group, which subsequently leads to loss of the methyl group, thereby preventing inappropriate gene silencing Conversely, in the absence of TET2, methylation levels climb too high, leading to silencing of critical genes. Perhaps the best evidence for the importance of epigenetics in cancer is that drugs targeting epigenetic processes can be effective anti-cancer agents. For example, the demethylating drug decitabine is used successfully to treat some chronic leukaemias, and drugs that inhibit the enzymes that erase acetyl groups from histones are also used in the clinic. It might be expected that perturbing epigenetic signals through the whole body in this way would result in profound side effects. In practice, tumour cells are often killed at doses that are relatively non-toxic, suggesting that epigenetic disturbances are the Achilles heel of certain cancers. With many more such epigenetic drugs in the pipeline, this is
surely a promising approach for anti-cancer therapy. Are there other diseases with epigenetic influences waiting to be discovered? We should know in a few years, as large-scale epigenomic mapping projects designed to answer this question are ongoing.
Leukemia: epigenetic changes are the Achilles heel of many cancers
5 January 2013 | NewScientist | vii