The Epigenetics Revolution (19 page)
Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
But this creates a paradox. Azim Surani’s experiments showed that the male and female pronuclei aren’t functionally equivalent; we need one of each to create a new mammal. This is known as a parent-of-origin effect, because it essentially shows that there are ways for a zygote and its daughter cells to distinguish between chromosomes from the mother and father. This isn’t a genetic effect, it is an epigenetic one, and so there must be some epigenetic modifications that do get transmitted from one generation to the next.
In 1987 the Surani lab published one of the first papers to give an insight into this mechanism. They hypothesised that parent-of-origin effects could be caused by DNA methylation. At that time, this was really the only chromatin modification that had been identified, so it was an excellent place to start. The researchers created genetically modified mice. These mice contained an extra piece of DNA that could get inserted randomly anywhere in the genome. The DNA sequence of this extra bit wasn’t particularly important to the experimenters. What was important was that they could easily measure how much DNA methylation was present on this sequence, and whether the amount of methylation was transmitted faithfully from parent to offspring.
Azim Surani and his colleagues examined seven lines of mice with this random insertion. In one of the seven lines, something very odd happened. When a mother passed on the inserted DNA, it was always heavily methylated in her offspring. But when a male mouse passed it on to his offspring, the mouse pups always ended up with low methylation of this foreign DNA.
Figure 7.3
demonstrates this.
Figure 7.3
demonstrates this.
Black represents the methylated inserted DNA, whereas white represents unmethylated DNA. Fathers always give their offspring white, unmethylated DNA whereas mothers always give their offspring black, methylated DNA. In other words, the methylation in the offspring is dependent on the
sex
of the parent who passed the inserted DNA onto them. It’s not dependent on what the methylation was like in the parent. For example, a ‘black’ male will always have offspring with ‘white’ DNA.
sex
of the parent who passed the inserted DNA onto them. It’s not dependent on what the methylation was like in the parent. For example, a ‘black’ male will always have offspring with ‘white’ DNA.
What this paper from Azim Surani
7
, and another published at the same time
8
, demonstrated was that when mammals create eggs and sperm, they somehow manage to barcode the DNA in these cells. It’s as if the chromosomes carry little flags. The chromosomes in sperm carry little flags that say, ‘I’m from Dad’ and the chromosomes in eggs carry little flags that say, ‘I’m from Mum’. DNA methylation is the fabric that these flags are made from.
7
, and another published at the same time
8
, demonstrated was that when mammals create eggs and sperm, they somehow manage to barcode the DNA in these cells. It’s as if the chromosomes carry little flags. The chromosomes in sperm carry little flags that say, ‘I’m from Dad’ and the chromosomes in eggs carry little flags that say, ‘I’m from Mum’. DNA methylation is the fabric that these flags are made from.
Figure 7.3
Mice generated in which a particular foreign piece of DNA was either methylated or not methylated. Black represents methylated DNA, and white represents unmethylated. When a mother passed on this foreign DNA, the DNA was always heavily methylated (black) in her offspring, regardless of whether she herself had been ‘black’ or ‘white’. The opposite was found for males, whose offspring always had unmethylated ‘white’ DNA. This was the first experimental demonstration that some regions of the genome can be marked to indicate if they were inherited via the maternal or the paternal line.
Mice generated in which a particular foreign piece of DNA was either methylated or not methylated. Black represents methylated DNA, and white represents unmethylated. When a mother passed on this foreign DNA, the DNA was always heavily methylated (black) in her offspring, regardless of whether she herself had been ‘black’ or ‘white’. The opposite was found for males, whose offspring always had unmethylated ‘white’ DNA. This was the first experimental demonstration that some regions of the genome can be marked to indicate if they were inherited via the maternal or the paternal line.
The description that is used for this is imprinting – the chromosomes have been imprinted with information about which parent they came from originally. Imprinting and parent-of-origin effects are something we will explore in more detail in the next chapter.
What was happening to the foreign DNA in the experiments, which kept changing its methylation status as it was transmitted from parent to offspring? It had, quite by chance, got inserted into a region of the mouse DNA that carried one of these flags. As a consequence, the foreign DNA also started getting DNA methylation flags stuck to it when it was passed down the generations.
The fact that only one of seven mouse lines showed this effect suggested that not all of the genome carries these flags. If the whole genome was marked in this way, we would have expected that all the lines that were tested would show the effect. In fact, the one in seven rate suggests that these flagged regions are the exception, not the rule.
In
Chapter 6
we saw that sometimes animals do inherit acquired characteristics from their parents. The work of Emma Whitelaw, amongst others, shows us that some epigenetic modifications do indeed get passed between parent and offspring, via the sperm and the egg. This type of inheritance is pretty rare, but it does strengthen our belief that there must be some epigenetic modifications that are special. They don’t get replaced when the egg and sperm fuse to form the zygote. So, although the vast majority of the mammalian genome does get reset when the egg and the sperm fuse, a small percentage of it is immune from this reprogramming.
Chapter 6
we saw that sometimes animals do inherit acquired characteristics from their parents. The work of Emma Whitelaw, amongst others, shows us that some epigenetic modifications do indeed get passed between parent and offspring, via the sperm and the egg. This type of inheritance is pretty rare, but it does strengthen our belief that there must be some epigenetic modifications that are special. They don’t get replaced when the egg and sperm fuse to form the zygote. So, although the vast majority of the mammalian genome does get reset when the egg and the sperm fuse, a small percentage of it is immune from this reprogramming.
The epigenetics arms race
Only 2 per cent of our genome codes for proteins. A massive 42 per cent is composed of retrotransposons. These are very odd sequences of DNA, which probably originated from viruses in our evolutionary past. Some retrotransposons are transcribed to produce RNA and this can affect the expression of neighbouring genes. This can have serious consequences for cells. If it drives up expression of genes that cause cells to proliferate too aggressively, for example, this may nudge cells towards becoming cancerous.
There’s a constant arms race in evolution, and mechanisms have evolved in our cells to control the activity of these types of retrotransposons. One of the major mechanisms that cells use is epigenetic. The retrotransposon DNA gets methylated by the cell, turning off retrotransposon RNA expression. This prevents the RNA disrupting expression of neighbouring genes. One particular class, known as IAP retrotransposons, seems to be a particular target of this control mechanism.
During reprogramming in the early zygote, the methylation is removed from most of our DNA. But IAP retrotransposons are an exception to this. The reprogramming machinery has evolved to skip these rogue elements and leave the DNA methylation marks on them. This keeps the retrotransposons in an epigenetically repressed state. This has probably evolved as a mechanism to reduce the risk that potentially dangerous IAP retrotransposons will get accidentally re-activated.
This is relevant because the two best-studied examples of transgenerational inheritance of non-genetic features are the
agouti
mouse and the
Axin
Fu
mouse, which we met in the previous chapter. The phenotypes in both these models are a consequence of the methylation levels of an IAP retrotransposon upstream of a gene. The DNA methylation levels in the parent get passed on to the offspring, and so does the phenotype caused by the expression levels of the retrotransposon
9
.
agouti
mouse and the
Axin
Fu
mouse, which we met in the previous chapter. The phenotypes in both these models are a consequence of the methylation levels of an IAP retrotransposon upstream of a gene. The DNA methylation levels in the parent get passed on to the offspring, and so does the phenotype caused by the expression levels of the retrotransposon
9
.
We met other examples of transgenerational inheritance of acquired characteristics in
Chapter 6
, including the effects of nutrition on subsequent generations, and the transgenerational effects of environmental pollutants such as vinclozolin. Researchers are exploring the hypothesis that these environmental stimuli create epigenetic changes in the chromatin of the gametes. These alterations are probably in regions that are protected from reprogramming during early development after the egg and sperm fuse.
Chapter 6
, including the effects of nutrition on subsequent generations, and the transgenerational effects of environmental pollutants such as vinclozolin. Researchers are exploring the hypothesis that these environmental stimuli create epigenetic changes in the chromatin of the gametes. These alterations are probably in regions that are protected from reprogramming during early development after the egg and sperm fuse.
Like John Gurdon, Azim Surani has continued to work highly productively in a field that he pioneered. His work has been focused on how and why eggs and sperm barcode their DNA so that a molecular memory is passed on to the next generation. A large amount of Azim Surani’s initial pioneering work was dependent on manipulating mammalian nuclei by using tiny pipettes to transfer them between cells. Technically, this is a refined version of the methods that John Gurdon used so successfully fifteen years earlier. It’s oddly pleasing to consider that Professor Surani is now based at the research institute in Cambridge that is named after Professor Gurdon, and that they frequently bump into each other in the corridors and the coffee room.
Nobody will ever win the Battle of the Sexes. There’s just too much fraternising with the enemy.
Henry Kissinger
The laboratory stick insect
Carausius morosus
is a very popular pet. As long as it has a few privet leaves to munch on it will be perfectly content, and after a few months it will begin to lay eggs. In due course, these will hatch into perfect little baby stick insects, looking just like miniature versions of the adults. If one of these baby stick insects is removed as soon as it is born, and kept in a tank on its own, then it too will lay eggs which will hatch into little stick insects in their turn. This is despite the fact that it has never mated.
Carausius morosus
is a very popular pet. As long as it has a few privet leaves to munch on it will be perfectly content, and after a few months it will begin to lay eggs. In due course, these will hatch into perfect little baby stick insects, looking just like miniature versions of the adults. If one of these baby stick insects is removed as soon as it is born, and kept in a tank on its own, then it too will lay eggs which will hatch into little stick insects in their turn. This is despite the fact that it has never mated.
Stick insects frequently reproduce this way. They are using a mechanism known as parthenogenesis, from the Greek for ‘virgin birth’. Females lay fertile eggs without ever mating with a male, and perfectly healthy little stick insects emerge from these eggs. These insects have evolved with special mechanisms to ensure that the offspring have the correct number of chromosomes. But these chromosomes all came from the mother.
This is very different from mice and humans, as we saw in the last chapter. For us and our rodent relatives, the only way to generate live young is by having DNA from both a mother and a father. It’s tempting to speculate that stick insects are highly unusual but they’re not. We mammals are the exceptions. Insects, fish, amphibians, reptiles and even birds all have a few species that can reproduce parthenogenetically. It’s we mammals who can’t. It’s our class in the animal kingdom which is the odd one out, so it makes sense to ask why this is the case. We can begin by looking at the features which are found only in mammals. Well, we have hair, and we have three bones in our middle ear. Neither of these characteristics is found in the other classes, but it seems unlikely these are the key features that have led us to abandon virgin birth. For this issue there is a much more important characteristic.
The most primitive examples of mammals are the small number of creatures like the duck-billed platypus and the echidna, which lay eggs. After them, in terms of reproductive complexity, are the marsupials such as the kangaroo and the Tasmanian devil, which give birth to very under-developed young. The young of these species go through most of their developmental stages outside the mother’s body, in her pouch. The pouch is a glorified pocket on the outside of the body.
By far the greatest numbers of our class are called placental (or eutherian) mammals. Humans, tigers, mice, blue whales – we all nourish our young in the same way. Our offspring undergo a really long developmental phase inside the mother, in the uterus. During this developmental stage, the young get their nourishment via the placenta. This large, pancake-shaped structure acts as an interface between the blood system of the foetus and the blood system of the mother. Blood doesn’t actually flow from one to the other. Instead the two blood systems pass so closely to one another that nutrients such as sugars, vitamins, minerals and amino acids can pass from the mother to the foetus. Oxygen also passes from the mother’s blood to the foetal blood supply. In exchange, the foetus gets rid of waste gases and other potentially harmful toxins by passing them back into the mother’s circulation.
It’s a very impressive system, and allows mammals to nurture their young for long periods during early development. A new placenta is created in each pregnancy and the code for its production isn’t carried by the mother. It’s all coded for by the foetus. Think back yet again to our model of the early blastocyst in
Chapter 2
. All the cells of the blastocyst are descendants of the fertilised single-cell zygote. The cells that will ultimately become the placenta are the tennis ball cells on the outside of the blastocyst. In fact, one of the earliest decisions that cells make as they begin to roll down Waddington’s epigenetic landscape is whether they are turning into future placental cells, or future body cells.
Chapter 2
. All the cells of the blastocyst are descendants of the fertilised single-cell zygote. The cells that will ultimately become the placenta are the tennis ball cells on the outside of the blastocyst. In fact, one of the earliest decisions that cells make as they begin to roll down Waddington’s epigenetic landscape is whether they are turning into future placental cells, or future body cells.
We can’t escape our (evolutionary) past
While the placenta is a great method for nourishing a foetus, the system has ‘issues’. To use business or political speech, there’s a conflict of interest, because in evolutionary terms, our bodies are faced with a dilemma.
This is the evolutionary imperative for the male mammal, phrased anthropomorphically:
This pregnant female is carrying my genes in the form of this foetus. I may never mate with her again. I want my foetus to get as big as possible so that it has the greatest chance of passing on my genes.
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