The Epigenetics Revolution (21 page)
Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
There’s another way in which patients can inherit PWS or AS. Some patients with these disorders have two totally normal copies of chromosome 15. There are no deletions, and no other mutations of any type, and yet the children develop the conditions. To understand how this can be, it’s helpful to think back to the mice who inherited both copies of chromosome 11 from one parent. Some of the same researchers who unravelled the story of the PWS deletion showed that in certain examples of this condition, the children have two normal copies of chromosome 15. The trouble is, they’ve inherited both from their mother, and none from their father. This is known as uniparental disomy – one parent contributing two chromosomes
13
. In 1991, a team from the Institute of Child Health in London showed that some cases of AS were caused by the opposite form of uniparental disomy to PWS. The children had two normal copies of chromosome 15, but had inherited both from their father
14
.
13
. In 1991, a team from the Institute of Child Health in London showed that some cases of AS were caused by the opposite form of uniparental disomy to PWS. The children had two normal copies of chromosome 15, but had inherited both from their father
14
.
This reinforced the notion that PWS and AS are each examples of epigenetic diseases. The children with uniparental disomy of chromosome 15 had inherited exactly the right amount of DNA, they just hadn’t inherited it from each parent. Their cells contained all the correct genes, in all the correct amounts, and yet still they suffered from these severe disorders.
It’s important that we inherit this fairly small region of chromosome 15 in the right way because this region is normally imprinted. There are genes in this region that are only expressed from either the maternal or the paternal chromosome. One of these genes is called
UBE3A
. This gene is important for normal functioning in the brain, but it’s only expressed from the maternally inherited gene in this tissue. But what if a child doesn’t inherit a copy of
UBE3A
from its mother? This could happen if both copies of
UBE3A
came from the father, because of uniparental disomy of chromosome 15. Alternatively, the child might inherit a copy of chromosome 15 from its mother which lacked the
UBE3A
gene, because part of the chromosome had been lost.
UBE3A
. This gene is important for normal functioning in the brain, but it’s only expressed from the maternally inherited gene in this tissue. But what if a child doesn’t inherit a copy of
UBE3A
from its mother? This could happen if both copies of
UBE3A
came from the father, because of uniparental disomy of chromosome 15. Alternatively, the child might inherit a copy of chromosome 15 from its mother which lacked the
UBE3A
gene, because part of the chromosome had been lost.
In these cases, the child can’t express UBE3A protein in its brain, and this leads to the development of the symptoms of Angelman syndrome.
Conversely, there are genes that are normally only expressed from the paternal version of this stretch of chromosome 15. This includes a gene called
SNORD116
, but others may also be important. The same scenario applies as for
UBE3A
, but replace the word maternal with paternal. If a child doesn’t inherit this region of chromosome 15 from its father, it develops Prader-Willi syndrome.
SNORD116
, but others may also be important. The same scenario applies as for
UBE3A
, but replace the word maternal with paternal. If a child doesn’t inherit this region of chromosome 15 from its father, it develops Prader-Willi syndrome.
There are other examples of imprinting disorders in humans. The most famous is called Beckwith-Wiedemann syndrome, again named after the people who first described it in the medical literature
15
,
16
. This disorder is characterised by over-growth of tissues, so that the babies are born with over-developed muscles including the tongue, and a range of other symptoms
17
. This condition has a slightly different mechanism to the ones described above. When imprinting goes wrong in Beckwith-Wiedemann syndrome, both the maternal and paternal copies of a gene on chromosome 11 get switched on, when normally only the paternally-derived version should be expressed. The key gene seems to be
IGF2
, which codes for the growth factor protein that we met earlier, on mouse chromosome 7. By expressing two copies of this gene, rather than just one, twice as much IGF2 protein as normal is produced and the foetus grows too much.
15
,
16
. This disorder is characterised by over-growth of tissues, so that the babies are born with over-developed muscles including the tongue, and a range of other symptoms
17
. This condition has a slightly different mechanism to the ones described above. When imprinting goes wrong in Beckwith-Wiedemann syndrome, both the maternal and paternal copies of a gene on chromosome 11 get switched on, when normally only the paternally-derived version should be expressed. The key gene seems to be
IGF2
, which codes for the growth factor protein that we met earlier, on mouse chromosome 7. By expressing two copies of this gene, rather than just one, twice as much IGF2 protein as normal is produced and the foetus grows too much.
The opposite phenotype to Beckwith-Wiedemann syndrome is a condition called Silver-Russell syndrome
18
,
19
. Children with this disorder are characterised by retarded growth before and after birth and other symptoms associated with late development
20
. Most cases of this condition are also caused by problems in the same region of chromosome 11 as in Beckwith-Wiedemann syndrome, but in Silver-Russell syndrome IGF2 protein expression is depressed, and the growth of the foetus is dampened down.
18
,
19
. Children with this disorder are characterised by retarded growth before and after birth and other symptoms associated with late development
20
. Most cases of this condition are also caused by problems in the same region of chromosome 11 as in Beckwith-Wiedemann syndrome, but in Silver-Russell syndrome IGF2 protein expression is depressed, and the growth of the foetus is dampened down.
The epigenetic imprint
So, imprinting refers to a situation where there is expression of only one member of a pair of genes, and the expression may be either maternal or paternal. What controls which gene is switched on? It probably isn’t surprising to learn that DNA methylation plays a really big role in this. DNA methylation switches genes off. Therefore, if a paternally-inherited region of a chromosome is methylated, the paternally-derived genes in this region will be repressed.
Let’s take the example of the
UBE3A
gene which we encountered in the discussion of Prader-Willi and Angelman syndromes. Normally, the copy inherited from the father contains methylated DNA and the gene is switched off. The copy inherited from the mother doesn’t have this methylation mark, and the gene is switched on. Something similar happens with
Igf2r
in mice. The paternal version of this is usually methylated, and the gene is inactive. The maternal version is non-methylated and the gene is expressed.
UBE3A
gene which we encountered in the discussion of Prader-Willi and Angelman syndromes. Normally, the copy inherited from the father contains methylated DNA and the gene is switched off. The copy inherited from the mother doesn’t have this methylation mark, and the gene is switched on. Something similar happens with
Igf2r
in mice. The paternal version of this is usually methylated, and the gene is inactive. The maternal version is non-methylated and the gene is expressed.
While a role for DNA methylation may not have come as a shock, it may be surprising to learn that it is often not the gene body that is methylated. The part of the gene that codes for protein is epigenetically broadly the same when we compare the maternal and paternal copies of the chromosome. It’s the region of the chromosome that
controls
the expression of the gene that is differently methylated between the two genomes.
controls
the expression of the gene that is differently methylated between the two genomes.
Imagine a night-time summer party in a friend’s garden, beautifully lit by candles scattered between the plants. Unfortunately, this lovely ambience is constantly ruined because the movement of the guests keeps triggering a motion detector on a security system and turning on a floodlight. The floodlight is too high on the wall to be able to cover it, but finally it dawns on the guests that they don’t need to cover the light. They need to cover the sensor that is triggering the light’s activity. This is very much what happens in imprinting.
The methylation, or lack of it, is on regions known as imprinting control regions (ICRs). In some cases, imprinting control is very straightforward to understand. The promoter region of a gene is methylated on the gene inherited from one parent, and not on the one from the other. This methylation keeps a gene switched off. This works when there is a single gene in a chromosome region that is imprinted. But many imprinted genes are arranged in clusters, all very close to one another in a single stretch on one chromosome. Some of the genes in the cluster will be expressed from the maternally-derived chromosome, others from the paternally-derived one. DNA methylation is still the key feature, but other factors help it to carry out its function.
The imprinting control region may operate over long distances, and certain stretches may bind large proteins. These proteins act like roadblocks in a city, insulating different stretches on a chromosome from one another. This gives the imprinting process an additional level of sophistication, by inserting diversions between different genes. Because of this, an imprinting control region may operate over many thousands of base-pairs, but it doesn’t mean that every single gene in those thousands of base-pairs is affected the same way. Different genes in a particular imprinted stretch of chromatin may loop out from their chromosome to form physical associations with each other, so that repressed genes huddle together in a sort of chromatin knot. Activated genes from the same stretch of chromosome may cling together in a different bundle
21
.
21
.
The impact of imprinting varies from tissue to tissue. The placenta is particularly rich in expression of imprinted genes. This is what we would expect from our model of imprinting as a means of balancing out the demand on maternal resources. The brain also appears to be very susceptible to imprinting effects. It’s not so clear why this should be the case. It’s harder to reconcile parent-of-origin control of gene expression in the brain with the battle for nutrients we’ve been considering so far. Professor Gudrun Moore of University College London has made an intriguing suggestion. She has proposed that the high levels of imprinting in the brain represent a post-natal continuation of the war of the sexes. She has speculated that some brain imprints are an attempt by the paternal genome to promote behaviour in young offspring that will stimulate the mother to continue to drain her own resources, for example by prolonged breast-feeding
22
.
22
.
The number of imprinted genes is quite low, rather less than 1 per cent of all protein-coding genes. Even this small percentage won’t be imprinted in all tissues. In many cells the expression from the maternally and paternally-derived copies will be the same. This is not because the methylation pattern is different between the tissues but because cells vary in the ways that they ‘read’ this methylation.
The DNA methylation patterns on the imprinting control regions are present in all the cells of the body, and show which parent transmitted which copy of a chromosome. This tells us something very revealing about imprinted regions. They must evade the reprogramming that takes place after the sperm and egg fuse to form the zygote. Otherwise, the methylation modifications would be stripped off and there would be no way for the cell to work out which parent had donated which chromosome. Just as the IAP retrotransposons stay methylated during zygotic reprogramming, mechanisms have evolved to protect imprinted regions from this broad-brush removal of methylation. It’s not really very clear how this happens, but it’s essential for normal development and health.
You put your imprint on, you take your imprint off …
Yet this presents us with a bit of a problem. If imprinted DNA methylation marks are so stable, how do they change as they are transmitted from parent to offspring? We know that they do, because of Azim Surani’s experiments with mice that we encountered in the previous chapter. These showed how methylation of a sequence monitored for experimental purposes changed as it was passed down the generations. This was the experiment that was described using the mice with ‘black’ and ‘white’ DNA in the previous chapter.
In fact, once scientists recognised that parent-of-origin effects exist, they predicted that there must be a way to reset the epigenetic marks, even before they knew what these marks were. Let’s consider chromosome 15, for example. I inherited one copy from my mother and one from my father. The
UBE3A
imprinting control region from my mother was unmethylated, whereas the same region on the chromosome from my father was methylated. This ensured appropriate expression patterns of UBE3A protein in my brain.
UBE3A
imprinting control region from my mother was unmethylated, whereas the same region on the chromosome from my father was methylated. This ensured appropriate expression patterns of UBE3A protein in my brain.
When my ovaries produce eggs, each egg inherits just one copy of chromosome 15, which I will pass on to a child. Because I’m a woman, each copy of chromosome 15 must carry a maternal mark on
UBE3A
. But one of my copies of chromosome 15 has been carrying the paternally-derived mark I inherited from my father. The only way I can make sure that I pass on chromosome 15 with the correct maternal mark to my children is if my cells have a way of removing the paternal mark and replacing it with a maternal one.
UBE3A
. But one of my copies of chromosome 15 has been carrying the paternally-derived mark I inherited from my father. The only way I can make sure that I pass on chromosome 15 with the correct maternal mark to my children is if my cells have a way of removing the paternal mark and replacing it with a maternal one.
A very similar process would have to take place when males produce sperm. All maternally-derived modifications would need to be stripped off the imprinted genes, and paternally derived ones put on in their place. This is indeed exactly what happens. It’s a very restricted process which only takes place in the cells that give rise to the germ line.
The general principle is shown diagrammatically in
Figure 8.3
.
Figure 8.3
.
Following fusion of the egg and sperm the blastocyst forms, and most regions of the genome become reprogrammed. The cells begin to differentiate, forming the precursors to the placenta and also the various cell types of the body. So, at this point the cells that had been part of the ICM are all marching to the developmental drumbeat, heading down the various troughs in Waddington’s epigenetic landscape. But a very small number (less than 100) begin to march to a different beat. In these cells a gene called
Blimp1
switches on. Blimp1 protein sets up a new cascade in signalling, which stops the cells heading towards their somatic dead-ends. These cells start travelling back up Waddington’s trenches
23
. They also lose the imprinted marks which told the cell which parent donated which of a pair of chromosomes.
Blimp1
switches on. Blimp1 protein sets up a new cascade in signalling, which stops the cells heading towards their somatic dead-ends. These cells start travelling back up Waddington’s trenches
23
. They also lose the imprinted marks which told the cell which parent donated which of a pair of chromosomes.
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