Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
The Epigenetics Revolution (10 page)
But if a reader with any sort of background in neurogenetics read this article, two things probably struck them immediately. The first was that it’s very unusual – not unheard of but pretty uncommon – for girls to present with such severe autism. This is much more common in boys. The second thing that would have struck them was that this case sounded exactly the same as a rare genetic disorder called Rett syndrome, right down to the normal early development and the timing and types of symptoms. It’s just coincidence that the symptoms of Rett syndrome, and indeed of most types of autism, first start becoming obvious at around the same age as when infants are typically given the MMR vaccination.
But what does this have to do with epigenetics? In 1999, a group led by the eminent neurogeneticist Huda Zoghbi at the Baylor College of Medicine in Houston, Texas showed that the majority of cases of Rett syndrome are caused by mutations in
MeCP2
, the gene which encodes the reader of methylated DNA. The children with this disorder have a mutation in the
MeCP2
gene which means that they don’t produce a functional MeCP2 protein. Although their cells are perfectly capable of methylating DNA correctly, the cells can’t read this part of the epigenetic code properly.
MeCP2
, the gene which encodes the reader of methylated DNA. The children with this disorder have a mutation in the
MeCP2
gene which means that they don’t produce a functional MeCP2 protein. Although their cells are perfectly capable of methylating DNA correctly, the cells can’t read this part of the epigenetic code properly.
The severe clinical symptoms of children with the
MeCP2
mutation tell us that reading the epigenetic code properly is very important. But they also tell us other things. Not all the tissues of girls with Rett syndrome are equally affected, so perhaps this particular epigenetic pathway is more important in some tissues than others. Because the girls develop severe mental retardation, we can deduce that having the right amount of normal MeCP2 protein is really important in the brain. Given that these children seem to be fairly unaffected in other tissues such as liver or kidney, perhaps MeCP2 activity isn’t as important in these tissues. It could be that DNA methylation itself isn’t so critical in these organs, or maybe these tissues contain other proteins in addition to MeCP2 that can read this part of the epigenetic code.
MeCP2
mutation tell us that reading the epigenetic code properly is very important. But they also tell us other things. Not all the tissues of girls with Rett syndrome are equally affected, so perhaps this particular epigenetic pathway is more important in some tissues than others. Because the girls develop severe mental retardation, we can deduce that having the right amount of normal MeCP2 protein is really important in the brain. Given that these children seem to be fairly unaffected in other tissues such as liver or kidney, perhaps MeCP2 activity isn’t as important in these tissues. It could be that DNA methylation itself isn’t so critical in these organs, or maybe these tissues contain other proteins in addition to MeCP2 that can read this part of the epigenetic code.
Long-term, scientists, physicians and families of children with Rett syndrome would dearly love to be able to use our increased understanding of the disease to help us find better treatments. This is a huge challenge, as we would be trying to intervene in a condition that affects the brain as a result of a gene mutation that is present throughout development, and beyond.
One of the most debilitating aspects of Rett syndrome is the profound mental retardation that is an almost universal symptom. Nobody knew if it would be possible to reverse a neurodevelopmental problem such as mental retardation once it had become established, but the general feeling about this wasn’t optimistic. Adrian Bird remains a major figure in our story. In 2007 he published an astonishing paper in
Science
, in which he and his colleagues showed that Rett syndrome could be reversed, in a mouse model of the disease.
Science
, in which he and his colleagues showed that Rett syndrome could be reversed, in a mouse model of the disease.
Adrian Bird and his colleagues created a cloned strain of mice in which the
Mecp2
gene was inactivated. They used the types of technologies pioneered by Rudolf Jaenisch. These mice developed severe neurological symptoms, and as adults they exhibited hardly any normal mouse activities. If you put a normal mouse in the middle of a big white box, it will almost immediately begin to explore its surroundings. It will move around a lot, it will tend to follow the edges of the box just like a normal house mouse scurrying along by the skirting boards, and it will frequently rear up on its back legs to get a better view. A mouse with the
Mecp2
mutation does very few of these things – put it in the middle of a big white box and it will tend to stay there.
Mecp2
gene was inactivated. They used the types of technologies pioneered by Rudolf Jaenisch. These mice developed severe neurological symptoms, and as adults they exhibited hardly any normal mouse activities. If you put a normal mouse in the middle of a big white box, it will almost immediately begin to explore its surroundings. It will move around a lot, it will tend to follow the edges of the box just like a normal house mouse scurrying along by the skirting boards, and it will frequently rear up on its back legs to get a better view. A mouse with the
Mecp2
mutation does very few of these things – put it in the middle of a big white box and it will tend to stay there.
When Adrian Bird created his mouse strain with the
Mecp2
mutation, he also engineered it so that the mice would also be carrying a normal copy of
Mecp2
. However, this normal copy was silent – it wasn’t switched on in the mouse cells. The really clever bit of this experiment was that if the mice were given a specific harmless chemical, the normal
Mecp2
gene became activated. This allowed the experimenters to let the mice develop and grow up with no Mecp2 in their cells, and then at a time of the scientists’ choosing, the
Mecp2
gene could be switched on.
Mecp2
mutation, he also engineered it so that the mice would also be carrying a normal copy of
Mecp2
. However, this normal copy was silent – it wasn’t switched on in the mouse cells. The really clever bit of this experiment was that if the mice were given a specific harmless chemical, the normal
Mecp2
gene became activated. This allowed the experimenters to let the mice develop and grow up with no Mecp2 in their cells, and then at a time of the scientists’ choosing, the
Mecp2
gene could be switched on.
The results of switching on the
Mecp2
gene were extraordinary. Mice which previously just sat in the middle of the white box suddenly turned into the curious explorers that mice should be
6
. You can find clips of this on
YouTube
, along with interviews with Adrian Bird where he basically concedes that he really never expected to see anything so dramatic
7
.
Mecp2
gene were extraordinary. Mice which previously just sat in the middle of the white box suddenly turned into the curious explorers that mice should be
6
. You can find clips of this on
YouTube
, along with interviews with Adrian Bird where he basically concedes that he really never expected to see anything so dramatic
7
.
The reason this experiment is so important is that it offers hope that we may be able to find new treatments for really complex neurological conditions. Prior to the publication of this
Science
paper, there had been an assumption that once a complex neurological condition has developed, it is impossible to reverse it. This was especially presumed to be the case for any condition that arises developmentally, i.e. in the womb or in early infancy. This is a critical period when the mammalian brain is making so many of the connections and structures that are used throughout the rest of life. The results from the
Mecp2
mutant mice suggest that in Rett syndrome, maybe all the bits of cellular machinery that are required for normal neurological function are still there in the brain – they just need to be activated properly. If this holds true for humans (and at a brain level we aren’t really
that
different from mice) this offers hope that maybe we can start to develop therapies to reverse conditions as complex as mental retardation. We can’t do this the way it was done in the mouse, as that was a genetic approach that can only be used in experimental animals and not in humans, but it suggests that it is worth trying to develop suitable drugs that have a similar effect.
Science
paper, there had been an assumption that once a complex neurological condition has developed, it is impossible to reverse it. This was especially presumed to be the case for any condition that arises developmentally, i.e. in the womb or in early infancy. This is a critical period when the mammalian brain is making so many of the connections and structures that are used throughout the rest of life. The results from the
Mecp2
mutant mice suggest that in Rett syndrome, maybe all the bits of cellular machinery that are required for normal neurological function are still there in the brain – they just need to be activated properly. If this holds true for humans (and at a brain level we aren’t really
that
different from mice) this offers hope that maybe we can start to develop therapies to reverse conditions as complex as mental retardation. We can’t do this the way it was done in the mouse, as that was a genetic approach that can only be used in experimental animals and not in humans, but it suggests that it is worth trying to develop suitable drugs that have a similar effect.
DNA methylation is clearly really important. Defects in reading DNA methylation can lead to a complex and devastating neurological disorder that leaves children with Rett syndrome severely disabled throughout their lives. DNA methylation is also essential for maintaining the correct patterns of gene expression in different cell types, either for several decades in the case of our long-lived neurons, or in all daughters of a stem cell in a constantly-replaced tissue such as skin.
But we still have a conceptual problem. Neurons are very different from skin cells. If both cells types use DNA methylation to switch off certain genes, and to keep them switched off, they must be using the methylation at different sets of genes. Otherwise they would all be expressing the same genes, to the same extent, and they would inevitably then be the same types of cells instead of being neurons and skin cells.
The solution to how two cell types can use the same mechanism to create such different outcomes lies in how DNA methylation gets targeted to different regions of the genome in different cell types. This takes us into the second great area of molecular epigenetics. Proteins.
DNA has a friend
DNA is often described as if it’s a naked molecule, i.e. DNA and nothing else. If we visualise it at all in our minds, a DNA double helix probably looks like a very long twisty railway track. This is pretty much how we described it in the previous chapter. But in reality it’s actually nothing like that, and many of the great breakthroughs in epigenetics came about when scientists began to appreciate this fully.
DNA is intimately associated with proteins, and in particular with proteins called histones. At the moment most attention in epigenetics and gene regulation is focused on four particular histone proteins called H2A, H2B, H3 and H4. These histones have a structure known as ‘globular’, as they are folded into compact ball-like shapes. However, each also has a loose floppy chain of amino acids that sticks out of the ball, which is called the histone tail. Two copies of each of these four histone proteins come together to form a tight structure called the histone octamer (so called because it’s formed of eight individual histones).
It might be easiest to think of this octamer as eight ping-pong balls stacked on top of each other in two layers. DNA coils tightly around this protein stack like a long liquorice whip around marshmallows, to form a structure called the nucleosome. One hundred and forty seven base-pairs of DNA coil around each nucleosome.
Figure 4.3
is a very simplified representation of the structure of a nucleosome, where the white strand is DNA and the grey wiggles are the histone tails.
Figure 4.3
is a very simplified representation of the structure of a nucleosome, where the white strand is DNA and the grey wiggles are the histone tails.
If we had read anything about histones even just fifteen years ago, they would probably have been described as ‘packaging proteins’, and left at that. It’s certainly true that DNA has to be packaged. The nucleus of a cell is usually only about 10 microns in diameter – that’s 1/100th of a millimetre – and if the DNA in a cell was just left all floppy and loose it could stretch for 2 metres. The DNA is curled tightly around the histone octamers and these are all stacked closely on top of each other.
Certain regions of our chromosomes have an extreme form of that sort of structure almost all the time. These tend to be regions that don’t really code for any genes. Instead, they are structural regions such as the very ends of chromosomes, or areas that are important for separating chromosomes after DNA has been duplicated for cell division.
Figure 4.3
The histone octamer (2 molecules each of histones H2A, H2B, H3 and H4) stacked tightly together, and with DNA wrapped around it, forms the basic unit of chromatin called the nucleosome.
The histone octamer (2 molecules each of histones H2A, H2B, H3 and H4) stacked tightly together, and with DNA wrapped around it, forms the basic unit of chromatin called the nucleosome.
The regions of DNA that are really heavily methylated also have this hyper-condensed structure and the methylation is very important in establishing this configuration. It’s one of the mechanisms used to keep certain genes switched off for decades in long-lived cell types such as neurons.
But what about those regions that aren’t screwed down tight, where there are genes that are switched on or have the potential to be switched on? This is where the histones really come into play. There is so much more to histones than just acting as a molecular reel for wrapping DNA around. If DNA methylation represents the semi-permanent additional notes on our script of
Romeo and Juliet
, histone modifications are the more tentative additions. They may be like pencil marks, that survive a few rounds of photocopying but eventually fade out. They may be even more transient, like Post-It notes, used very temporarily.
Romeo and Juliet
, histone modifications are the more tentative additions. They may be like pencil marks, that survive a few rounds of photocopying but eventually fade out. They may be even more transient, like Post-It notes, used very temporarily.
A substantial number of the breakthroughs in this field have come from the lab of Professor David Allis at Rockefeller University in New York. He’s a trim, neat, clean-shaven American who looks much younger than his 60 years and is exceptionally popular amongst his peers. Like many epigeneticists, he began his career in the field of developmental biology. Just like Adrian Bird, and John Gurdon before him, David Allis wears his stellar reputation in epigenetics very lightly. In a remarkable flurry of papers in 1996, he and his colleagues showed that histone proteins were chemically modified in cells, and that this modification increased expression of genes near a specific modified nucleosome
8
.
8
.
The histone modification that David Allis identified was called acetylation. This is the addition of a chemical group called an acetyl, in this case to a specific amino acid named lysine on the floppy tail of one of the histones.
Figure 4.4
shows the structures of lysine and acetyl-lysine, and we can again see that the modification is relatively small. Like DNA methylation, lysine acetylation is an epigenetic mechanism for altering gene expression which doesn’t change the underlying gene sequence.
Figure 4.4
shows the structures of lysine and acetyl-lysine, and we can again see that the modification is relatively small. Like DNA methylation, lysine acetylation is an epigenetic mechanism for altering gene expression which doesn’t change the underlying gene sequence.
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