The Epigenetics Revolution (43 page)
Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
So far, we could be forgiven for thinking that honeybees and higher organisms, including us and our mammalian relatives, all use DNA methylation in the same way. It’s certainly true that changes in DNA methylation are associated with alterations in developmental processes in both humans and honeybees. It’s also true that mammals and honeybees both use DNA methylation in the brain during memory processing.
But oddly enough, honeybees and mammals use DNA methylation in very different ways. A carpenter has a saw in his toolbox and uses it to build a book case. An orthopaedic surgeon has a saw on his operating trolley and uses it to amputate a leg. Sometimes, the same bit of kit can be used in very different ways. Mammals and honeybees both use DNA methylation as a tool, but during the course of evolution they’ve employed it very differently.
When mammals methylate DNA, they usually methylate the promoter regions of genes, and not the parts that code for amino acids. Mammals also methylate repetitive DNA elements and transposons, as we saw in Emma Whitelaw’s work in
Chapter 5
. DNA methylation in mammals tends to be associated with switching off gene expression and shutting down dangerous elements like transposons that might otherwise cause problems in our genomes.
Chapter 5
. DNA methylation in mammals tends to be associated with switching off gene expression and shutting down dangerous elements like transposons that might otherwise cause problems in our genomes.
Honeybees use DNA methylation in a completely different way. They don’t methylate repetitive regions or transposons, so they presumably have other ways of controlling these potentially troublesome elements. They methylate CpG motifs in the stretches of genes that encode amino acids, rather than in the promoter regions of genes. Honeybees don’t use DNA methylation to switch off genes. In honeybees, DNA methylation is found on genes that are expressed in all tissues, and also on genes that tend to be expressed by many different insect species. DNA methylation acts as a fine-tuning mechanism in honeybee tissues. It modulates the activity of genes, turning the volume slightly up or down, rather than acting as an on-off switch
10
. Patterns of DNA methylation are also strongly correlated with control of mRNA splicing in honeybee tissues. However, we don’t yet know how this epigenetic modification actually influences the way in which a message is processed
11
.
10
. Patterns of DNA methylation are also strongly correlated with control of mRNA splicing in honeybee tissues. However, we don’t yet know how this epigenetic modification actually influences the way in which a message is processed
11
.
We’re really only just beginning to unravel the subtleties of epigenetic regulation in honeybees. For example, there are 10,000,000 CpG sites in the honeybee genome, but less than 1 per cent of these are methylated in any given tissue. Unfortunately, this low degree of methylation makes analysing the effects of this epigenetic modification very challenging. The effects of
Dnmt3
knockdown show that DNA methylation is very important in honeybee development. But, given that DNA methylation is a fine-tuning mechanism in this species, it’s likely that
Dnmt3
knockdown results in a number of individually minor changes in a relatively large number of genes, rather than dramatic changes in a few. These types of subtle alterations are the most difficult to analyse, and to investigate experimentally.
Dnmt3
knockdown show that DNA methylation is very important in honeybee development. But, given that DNA methylation is a fine-tuning mechanism in this species, it’s likely that
Dnmt3
knockdown results in a number of individually minor changes in a relatively large number of genes, rather than dramatic changes in a few. These types of subtle alterations are the most difficult to analyse, and to investigate experimentally.
Honeybees aren’t the only insect species that has developed a complex society with differing forms and functions for genetically identical individuals. This model has evolved independently several times, including in different species of wasps, termites, bees and ants. We don’t yet know if the same epigenetic processes are used in all these cases. Shelley Berger from the University of Pennsylvania, whose work on ageing we encountered in
Chapter 13
, is involved in a large collaboration focusing on ant genetics and epigenetics. This work has already shown that at least two species of ants also can methylate the DNA in their genomes. The expression of different epigenetic enzymes varies between different social groups in the colonies
12
. These data tentatively suggest that epigenetic control of colony members may prove to be a mechanism that has evolved more than once in the social insects.
Chapter 13
, is involved in a large collaboration focusing on ant genetics and epigenetics. This work has already shown that at least two species of ants also can methylate the DNA in their genomes. The expression of different epigenetic enzymes varies between different social groups in the colonies
12
. These data tentatively suggest that epigenetic control of colony members may prove to be a mechanism that has evolved more than once in the social insects.
For now, however, most interest in the world outside epigenetics labs focuses on royal jelly, as this has a long history as a health supplement. It’s worth pointing out that there’s very little hard evidence to support this having any major effects in humans. The 10HDA, that Mark Bedford and his colleagues showed was a histone deacetylase inhibitor, can affect the growth of blood vessel cells
13
. Theoretically, this could be useful in cancer, as tumours rely on a good blood supply for continuing growth. However, we’re a very long way from showing that royal jelly can really fight off cancer, or aid human health in any other way. If there’s one thing we do already know, it’s that bees and humans are not the same epigenetically. Which is just as well, unless you’re a really big fan of the monarchy …
13
. Theoretically, this could be useful in cancer, as tumours rely on a good blood supply for continuing growth. However, we’re a very long way from showing that royal jelly can really fight off cancer, or aid human health in any other way. If there’s one thing we do already know, it’s that bees and humans are not the same epigenetically. Which is just as well, unless you’re a really big fan of the monarchy …
To see a world in a Grain of Sand,
And a Heaven in a Wild Flower,
Hold Infinity in the palm of your hand,
And eternity in an hour.
William Blake
Probably all of us are familiar with the guessing game ‘animal, vegetable or mineral’. The implicit assumption in the name of this game is that plants and animals are completely different from one another. True, they are both living organisms, but that’s where we feel the similarity ends. We may be able to get on board with the idea that somewhere back in the murky evolutionary past, humans and microscopic worms have a shared ancestor. But how often do we ever wonder about the biological heritage we share with plants? When do we ever think of carnations as our cousins?
Yet animals and plants are surprisingly similar in many ways. This is especially the case when we consider the most advanced of our green relatives, the flowering plants. These include the grasses and cereals that we rely on for so much of our basic food intake, and the broad-leaved plants, from cabbages to oak trees and from rhododendrons to cress.
Animals and the flowering plants are each made up of lots of cells; they are multicellular organisms. Many of these cells are specialised for particular functions. In the flowering plants these include cells that transport water or sugars around the plant, the photosynthesising cells of the leaves and the food storing cells of the roots. Like animals, plants have specialised cells which are responsible for sexual reproduction. The sperm nuclei are carried in pollen and fertilise a large egg cell, which ultimately gives rise to a zygote and a new individual plant.
The similarities between plants and animals are more fundamental than these visible features. There are many genes in plants which have equivalents in animals. Crucially, for our topic, plants also have a highly developed epigenetic system. They can modify histone proteins and DNA, just like animal cells can, and in many cases use very similar epigenetic enzymes to those used by animals, including humans.
These genetic and epigenetic similarities all suggest that animals and plants have common ancestors. Because of our common ancestry, we’ve inherited similar genetic and epigenetic tool kits.
Of course, there are also really important differences between plants and animals. Plants can create their own food, but animals can’t do this. Plants take in basic chemicals in the environment, especially water and carbon dioxide. Using energy from sunlight, plants can convert these simple chemicals into complex sugars such as glucose. Nearly all life on planet earth is dependent directly or indirectly on this amazing process of photosynthesis.
There are two other ways in which plants and animals are very different. Most gardeners know that you can take a cutting from a growing plant – maybe just a small shoot – and create an entire new plant from this. There are very few animals where this is possible, and certainly no advanced ones. True, if certain species of lizard lose their tail, the animal can grow a new one. But they can’t do this the other way around. We can’t grow a new lizard from a discarded bit of tail.
This is because in most adult animals the only genuinely pluripotent stem cells are the tightly controlled cells of the germline which give rise to eggs or sperm. But active pluripotent stem cells are a completely normal part of a plant. In plants these pluripotent stem cells are found at the tips of stems and the tips of roots. Under the right conditions, these stem cells can keep dividing to allow the plant to grow. But under other conditions, the stem cells will differentiate into specific cell types, such as flowers. Once such a cell has become committed to becoming part of a petal, for example, it can’t change back into a stem cell. Even plant cells roll down Waddington’s epigenetic landscape eventually.
The other difference between plants and animals is really obvious. Plants can’t move. When environmental conditions change, the plant must adapt or die. They can’t out-run or out-fly unfavourable climates. Plants have to find a way of responding to the environmental triggers all around them. They need to make sure they survive long enough to reproduce at the right time of year, when their offspring will have the greatest chance of making it as new individuals.
Contrast this with a species such as the European swallow (
Hirundo rustica
) which winters in South Africa. As summer approaches and conditions become unbearable the swallow sets off on an epic migration. It flies up through Africa and Europe, to spend the summer in the UK where it raises its young. Six months later, back it goes to South Africa.
Hirundo rustica
) which winters in South Africa. As summer approaches and conditions become unbearable the swallow sets off on an epic migration. It flies up through Africa and Europe, to spend the summer in the UK where it raises its young. Six months later, back it goes to South Africa.
Many of a plant’s responses to the environment are linked to changes in cell fate. These include the change from being a pluripotent stem cell to becoming part of a terminally differentiated flower in order to allow sexual reproduction. Epigenetic processes play important roles in both these events, and interact with other pathways in plant cells to maximise the chance of reproductive success.
Not all plants use exactly the same epigenetic strategies. The best-characterised model system is an insignificant looking little flowering plant called
Arabidopsis thaliana
. It’s a member of the mustard family and looks like any nondescript weed you can find on any patch of wasteland. Most of the leaves grow close to the ground in a rosette shape. It produces small white flowers on a stem about 20–25 centimetres high. It’s been a useful model system for researchers because its genome is very compact, which makes it easy to sequence in order to identify the genes. There are also well-developed techniques for genetically modifying
Arabidopsis thaliana
. This makes it relatively straightforward for scientists to introduce mutations into genes to investigate their function.
Arabidopsis thaliana
. It’s a member of the mustard family and looks like any nondescript weed you can find on any patch of wasteland. Most of the leaves grow close to the ground in a rosette shape. It produces small white flowers on a stem about 20–25 centimetres high. It’s been a useful model system for researchers because its genome is very compact, which makes it easy to sequence in order to identify the genes. There are also well-developed techniques for genetically modifying
Arabidopsis thaliana
. This makes it relatively straightforward for scientists to introduce mutations into genes to investigate their function.
Arabidopsis thaliana
seeds typically germinate in early summer in the wild. The seedlings grow, creating the rosette of leaves. This is called the vegetative phase of plant growth. In order to produce offspring,
Arabidopsis thaliana
generates flowers. It is structures in the flowers that will generate the new eggs and sperm that will eventually lead to new zygotes, which will be dispersed in seeds.
seeds typically germinate in early summer in the wild. The seedlings grow, creating the rosette of leaves. This is called the vegetative phase of plant growth. In order to produce offspring,
Arabidopsis thaliana
generates flowers. It is structures in the flowers that will generate the new eggs and sperm that will eventually lead to new zygotes, which will be dispersed in seeds.
But here’s the problem for the plant. If it flowers late in the year, the seeds it produces will be wasted. That’s because the weather conditions won’t be right for the new seeds to germinate. Even if the seeds do manage to germinate, the tender little seedlings are likely to be killed off by harsh weather like frost.
The adult
Arabidopsis thaliana
needs to keep its powder dry. It has a much greater chance of lots of its offspring surviving if it waits until the next spring until it flowers. The adult plant can survive winter weather that would kill off a seedling. This is exactly what
Arabidopsis thaliana
does. The plant ‘waits’ for spring and only then does it produce flowers.
Arabidopsis thaliana
needs to keep its powder dry. It has a much greater chance of lots of its offspring surviving if it waits until the next spring until it flowers. The adult plant can survive winter weather that would kill off a seedling. This is exactly what
Arabidopsis thaliana
does. The plant ‘waits’ for spring and only then does it produce flowers.
The rites of spring
The technical term for this is vernalisation. Vernalisation means that a plant has to undergo a prolonged cold period (winter, usually) before it can flower. This is very common in plants with an annual life-cycle, especially in the temperate regions of the earth where the seasons are well-defined. Vernalisation doesn’t just affect broad-leaved plants like
Arabidopsis thaliana
. Many cereals also show this effect, especially crops like winter barley and winter wheat. In many cases, the prolonged period of cold needs to be followed by an increase in day length if flowering is to take place. The combination of the two stimuli ensures that flowering occurs at the most appropriate time of year.
Arabidopsis thaliana
. Many cereals also show this effect, especially crops like winter barley and winter wheat. In many cases, the prolonged period of cold needs to be followed by an increase in day length if flowering is to take place. The combination of the two stimuli ensures that flowering occurs at the most appropriate time of year.
Vernalisation has some very interesting features. When the plant first begins to sense and respond to cold weather, this may be many weeks or months before it starts to flower. The plant may continue to grow vegetatively through cell division during the cold period. When new seeds are produced, after the vernalisation of the parent plant, the seeds are ‘reset’. The new plants they produce from the seeds will themselves have to go through their own cold season before flowering
1
.
1
.
These features of vernalisation are all very reminiscent of epigenetic phenomena in animals. Specifically:
1. The plant displays some form of molecular memory, because the stimulus and the final event are separated by weeks or months. We can compare this with abnormal stress responses in adult rodents that were ‘neglected’ as infants.
2. The memory is maintained even after cells divide. We can compare this with animal cells that continue to perform in a certain way after a stimulus to the parent cell, such as in normal development or in cancer progression.
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