The Epigenetics Revolution (38 page)
Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
Many of the techniques used until very recently looked for the presence of DNA methylation. They often couldn’t distinguish between unmethylated DNA and 5-hydroxymethylated DNA. This means that many of the papers which refer to decreased DNA methylation may actually have been detecting increased 5-hydroxymethylation without knowing it. It’s currently unproven, but it may be that instead of actually demethylating DNA, as reported in some of the behavioural studies, neurons really convert 5-methylcytosine to 5-hydroxymethylcytosine. The techniques for studying 5-hydroxymethylcytosine are still under development but we do know that neurons contain higher levels of this chemical than any other cell type
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Remember, remember
Despite these controversies, research is continuing into the importance of epigenetic modifications in brain function. One area that is attracting a lot of attention is the field of memory. Memory is an incredibly complex phenomenon. Both the hippocampus and a region of the brain called the cortex are involved in memory, but in different ways. The hippocampus is mainly involved in consolidating memories, as our brains decide what we are going to remember. The hippocampus is fairly plastic in the way that it operates, and this seems to be associated with transient changes in DNA methylation, again through fairly uncharacterised mechanisms. The cortex is used for longer-term storage of memories. When memories are stored in the cortex, there are prolonged changes in DNA methylation.
The cortex is like a hard drive on a computer with gigabytes of storage. The hippocampus is more like the RAM (random access memory) chip, where data are temporarily processed before being deleted, or transferred to the hard drive for permanent storage. Our brain separates out different functions to selected cell populations in different anatomical regions. This is why memory loss is rarely all-encompassing. Depending on the clinical condition, for example, either one of short-term or long-term memory may be relatively lost or remain relatively intact. It makes a lot of sense for these different functions to be separated in our brains. Just try to imagine life if we remembered everything that ever happened – the phone number that we dialled only once, every word a dull stranger said to us on a train, or the canteen menu from a wet Wednesday three years ago.
The complexity of our memory systems is one of the reasons why it is quite a difficult area to study, because it can be difficult to set up experiments where we are absolutely sure which aspects of memory our experimental techniques are actually addressing. But one thing we know for sure is that memory involves long-term changes in gene expression, and in the way neurons make connections with one another. And that again leads to the hypothesis that epigenetic mechanisms may play a role.
In mammals, both DNA methylation and histone modifications play a role in memory and learning. Rodent studies have shown that these changes may be targeted to very specific genes in discrete regions of the brain, as we have come to expect. For example, the DNA methyltransferase proteins DNMT3A and DNMT3B increase in expression in the adult rat hippocampus in a particular learning and memory model. Conversely, treating these rats with a DNA methyltransferase inhibitor such as 5-azacytidine blocks memory formation and affects both the hippocampus and the cortex
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A particular histone acetyltransferase (protein which adds acetyl groups to histones) gene is mutated in a human disorder called Rubinstein-Taybi syndrome. Mental retardation is a frequent symptom in this disease. Mice with a mutant version of this gene also have low levels of histone acetylation in the hippocampus, as we would predict. They also have major problems in long-term memory processing in the hippocampus
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. When these mice were treated with SAHA, the histone deacetylase inhibitor, acetylation levels in the hippocampus went up, and the memory problems improved
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. When these mice were treated with SAHA, the histone deacetylase inhibitor, acetylation levels in the hippocampus went up, and the memory problems improved
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SAHA can inhibit many different histone deacetylases, but in the brain some of its targets seem to be more important than others. The two most highly expressed enzymes of this class are HDAC1 and HDAC2. These differ in the ways they are expressed in the brain. HDAC1 is predominantly expressed in neural stem cells, and in a supportive, protective population of non-neurons called glial cells. HDAC2 is predominantly expressed in neuronal cells
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, so it’s unsurprising that this is the histone deacetylase that is most important in learning and memory.
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, so it’s unsurprising that this is the histone deacetylase that is most important in learning and memory.
Mice whose neurons over-express Hdac2 have poor long-term memory, even though their short-term memory is fine. Mice whose neurons don’t express any Hdac2 have excellent memories. These data show us that Hdac2 has a negative effect on memory storage. The neurons which over-expressed Hdac2 formed far fewer connections than normal, whereas the opposite was true for the neurons lacking Hdac2. This supports our model of epigenetically-driven changes in gene expression ultimately altering complex networks in the brain. SAHA improves memory in the mice that over-express Hdac2, presumably by dampening down its effects on histone acetylation and gene expression. SAHA also improves memory in normal mice
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In fact, increased acetylation levels in the brain seem to be consistently associated with improved memory. Learning and memory both improved in mice kept in conditions known as environmentally enriched. This is a fancy way of saying they had access to two running wheels and the inside of a toilet roll. The histone acetylation levels in the hippocampus and cortex were increased in the mice in the more entertaining surroundings. Even in these mice, the histone acetylation levels and memory skills improved yet further if they were treated with SAHA
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We can see a consistent trend emerging. In various different model systems, learning and memory improve when animals are treated with DNA methyltransferase inhibitors, and especially with histone deacetylase inhibitors. As we saw in the last chapter, there are drugs licensed in both these classes, such as 5-azacytidine and SAHA, respectively. It’s very tempting to speculate about taking these anti-cancer drugs and using them in conditions where memory loss is a major clinical problem, such as Alzheimer’s disease. Perhaps we might even use them as general memory enhancers in the wider population.
Unfortunately, there are substantial difficulties in doing this. These drugs have side-effects which can include severe fatigue, nausea and a higher risk of infections. These side-effects are considered acceptable if the alternative is an inevitable and fairly near-term death from cancer. But they might be considered less acceptable for treating the early stages of dementia, when the patient still has a relatively reasonable quality of life. And they would certainly be unacceptable for the general population.
There is an additional problem. Most of these drugs are really bad at getting into the brain. In many of the rodent experiments, the drugs were administered directly into the brain, and often into very defined regions such as the hippocampus. This isn’t a realistic treatment method for humans.
There are a few histone deacetylase inhibitors that do get into the brain. A drug called sodium valproate has been used for decades to treat epilepsy, and clearly must be getting into the brain in order to do this. In recent years, we have realised that this compound is also a histone deacetylase inhibitor. This would be extremely encouraging for trying to use epigenetic drugs in Alzheimer’s disease but unfortunately, sodium valproate only inhibits histone deacetylases very weakly. All the animal data on learning and memory have shown that stronger inhibitors work much better than weak ones at reversing these deficits.
It’s not just in disorders like Alzheimer’s disease that epigenetic therapies could be useful if we manage to develop suitable drugs. Between 5 and 10 per cent of regular users of cocaine become addicted to the drug, suffering from uncontrollable cravings for this stimulant. A similar phenomenon occurs in rodents, if animals are allowed unlimited access to the drug. Addiction to stimulants such as cocaine is a classic example of inappropriate adaptations by memory and reward circuits in the brain. These maladaptations are regulated by long-lasting changes in gene expression. Changes in DNA methylation, and in how methylation is read by MeCP2, underpin this addiction. This happens via a set of poorly understood interactions which include signalling factors, DNA and histone modifying enzymes and readers, and miRNAs. Related pathways also underpin addiction to amphetamines
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If we return to the starting point of this chapter, it’s clear that there’s a major need to stop children who have suffered early trauma from developing into adults with a substantially higher than normal risk of mental illness. It’s very appealing to think we might be able to use epigenetic drug therapies to improve their life chances. Unfortunately, one of the problems in designing therapies for children who have been abused or neglected is that it’s actually pretty difficult to identify those who will be permanently damaged as adults, and those who will have healthy, happy and fulfilled lives. There are enormous ethical dilemmas around giving drugs to children, when we can’t be sure if an individual child actually needs the treatment. In addition, clinical trials to determine if the drugs actually do any good would need to last for decades, which makes them economically almost a non-starter for any pharmaceutical company.
But we mustn’t end on too negative a note. Here’s a great story about an epigenetic event and behaviour. There is a gene called
Grb10
that is involved in various signalling pathways. It’s an imprinted gene, and the brain only expresses the paternally inherited copy. If we switch off this paternal copy, the mouse can’t produce any Grb10 protein, and the animals develop a very odd phenotype. They nibble off the face fur and whiskers of other mice in the same cage. This is a sort of aggressive grooming, a bit like a pecking order in chickens. In addition, if faced with a big mouse that they don’t know, the
Grb10
mutant mice don’t back away – they stand their ground
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.
Grb10
that is involved in various signalling pathways. It’s an imprinted gene, and the brain only expresses the paternally inherited copy. If we switch off this paternal copy, the mouse can’t produce any Grb10 protein, and the animals develop a very odd phenotype. They nibble off the face fur and whiskers of other mice in the same cage. This is a sort of aggressive grooming, a bit like a pecking order in chickens. In addition, if faced with a big mouse that they don’t know, the
Grb10
mutant mice don’t back away – they stand their ground
30
.
Switching off
Grb10
in the brain results in what might sound like a rather impressive, kick-ass kind of a mouse. It maybe even seems odd that this gene is normally switched on in the brain. Wouldn’t mice that switched off
Grb10
be the butchest, most successful mice? Actually, it’s more likely that they’d be the mice most likely to get themselves beaten up. There are a lot of mice in the world, and they encounter each other pretty frequently. It pays to recognise when you are out-gunned.
Grb10
in the brain results in what might sound like a rather impressive, kick-ass kind of a mouse. It maybe even seems odd that this gene is normally switched on in the brain. Wouldn’t mice that switched off
Grb10
be the butchest, most successful mice? Actually, it’s more likely that they’d be the mice most likely to get themselves beaten up. There are a lot of mice in the world, and they encounter each other pretty frequently. It pays to recognise when you are out-gunned.
When the
Grb10
gene is switched off in the brain, it’s like a bad Friday night for the mouse. Let’s put this in human terms so we can see why. You’re down the pub when a person twice your size and all muscle knocks against you and you spill your pint.
Grb10
gene is switched off in the brain, it’s like a bad Friday night for the mouse. Let’s put this in human terms so we can see why. You’re down the pub when a person twice your size and all muscle knocks against you and you spill your pint.
When this gene is switched off, it’s as if you have a friend next to you who says, ‘Go on, you can take him/her, don’t wimp out.’ We all know how badly those scenarios tend to play out. So let’s end this chapter by raising a cheer for imprinted
Grb10
, the gene that likes to say, ‘Leave it mate, it’s not worth it.’
Grb10
, the gene that likes to say, ‘Leave it mate, it’s not worth it.’
I guess I don’t so much mind being old, as I mind being fat and old.
Benjamin Franklin
Time moves forward, we age. It’s inevitable. And as we get older, our bodies change. Once we’re past our mid-thirties most of us would agree that it gets harder and harder to sustain the same level of physical performance. It doesn’t matter if it’s how fast we can run, how far we can cycle before needing to stop for a break, or how quickly we recover from a big night out. The older we get, the harder everything seems to become. We develop new aches and pains, and succumb more easily to annoying little infections.
Ageing is something we are good at recognising in the people around us. Even quite small children can tell the difference between the young and the very old, even if they are a bit hazy on everyone in the middle. Adults can easily tell the difference between a 20-year-old and a 40-something individual, or between two people who are 40 and 65.
We can categorise individuals instinctively into approximate age groups not because they give off an intrinsic radio signal about the number of years they have been on earth, but because of the physical signs of ageing. These include the loss of fat beneath the skin, making our features more drawn and less ‘fresh-faced’. There are the wrinkles, the fall in muscle tone, that slight curvature to the spine.
The growth of the cosmetic surgery industry appears to be relentless and shows how desperate we can be to fight the symptoms of ageing. Figures released in 2010 showed that in the top 25 countries covered in a survey by the International Society of Aesthetic Plastic Surgery, there were over eight and a half million surgical procedures carried out in 2009, and about the same number of non-surgical procedures, such as Botox and dermoabrasion. The United States topped the list, with Brazil and China fighting for second place
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As a society, we don’t seem to mind really about the number of years we’ve been alive, but we dislike intensely the physical decline that accompanies them. It’s not just the trivial stuff either. One of the greatest risk factors for developing cancer is simply being old. The same is true for conditions such as Alzheimer’s disease and stroke.
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