The Epigenetics Revolution (34 page)
Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
The other theory is that the tumour suppressors that become repressed epigenetically are somehow targeted in this process. It’s not just random bad luck, these genes are actually at a higher than average risk of epigenetic silencing.
In recent years, as we’ve had the technology to profile the epigenetic modifications in more and more cell types, and at higher and higher resolutions, the field has shifted in favour of the second model. There are a set of genes that seem to be rather prone to getting themselves switched off epigenetically.
At first this seems incredibly counter-intuitive. Why on earth would billions of years of evolution leave us with cellular systems that render us prone to cancerous changes? Well, we have to put this in context. Most evolutionary pressures are connected with the drive to leave behind as many offspring as possible. For a human to reach reproductive age, it’s incredibly important that early development occur as efficiently as possible. After all, you can’t reproduce if you never make it past the embryo stage. Once we’ve reached reproductive age and had the opportunity to reproduce, there is little to be gained in evolutionary terms in us staying alive for several decades afterwards.
Evolution has favoured cellular mechanisms that promote effective early growth and development, including the production of multiple different tissue types. Many of these tissue types contain reservoirs of stem cells which are specific to that tissue. Our bodies need these for tissue growth as we mature, and for tissue regeneration following injury. The fates and identities of these tissue-specific stem cells are controlled by the precise patterns of epigenetic modifications. By using epigenetic modifications to control gene expression, the cells keep some flexibility. They have the potential to change into more specialised cells, for example. Perhaps even more importantly when considering cancer, the epigenetic modifications also allow cells to divide to form more stem cells. This is why we don’t run out of skin cells, or bone marrow cells, even if we live to be a hundred years old.
This requirement for gene expression patterns that aren’t completely set in stone is probably why epigenetic repression of tumour suppressor genes is not a random process. We can’t have things two ways. Regulatory systems that allow cells to be flexible are inevitably also systems that allow cells to go wrong. In evolutionary terms, it’s the price we have to pay for our Goldilocks scenario. Our epigenetic pathways make sure some of our cells aren’t completely pluripotent or completely differentiated. Instead, they are just right, hovering somewhere near the top of Waddington’s epigenetic landscape, but ready to roll down at any time.
Peter Laird, who like Peter Jones is based at the University of Southern California, has shown the knock-on effects of this system in cancer cells. His team analysed patterns of DNA methylation in cancer cells, especially focusing on the promoters of tumour suppressor genes. Tumour suppressor genes whose histones are methylated by the EZH2 complex in ES cells were twelve times as likely to have abnormally high levels of DNA methylation as those genes that aren’t targeted by EZH2. Peter Laird described this effect very elegantly, saying, ‘reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation [sic].’
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This is consistent with the idea that there is a stem cell aspect to cancer. If cells are locked into a stem cell-like state, where they can’t differentiate into cells at the bottom of the epigenetic landscape, they will be very dangerous because they will always be able to keep on dividing to form yet more cells like themselves.
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This is consistent with the idea that there is a stem cell aspect to cancer. If cells are locked into a stem cell-like state, where they can’t differentiate into cells at the bottom of the epigenetic landscape, they will be very dangerous because they will always be able to keep on dividing to form yet more cells like themselves.
Jean-Pierre Issa has described the genes that are epigenetically silenced in colon cancer as the gatekeepers. They are frequently genes whose normal role is to move the cells away from self-renewal, and into fully differentiated cell types. Inactivation of these genes in cancer locks the cells in a self-renewing stem cell-like state. This creates a population of cells that are able to keep dividing, keep accumulating further epigenetic changes and mutations, and keep inching towards a full-blown cancer state
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When we visualise the cells in Waddington’s landscape, it’s quite difficult to visualise the ones that linger somewhere near the top. That’s because instinctively we know that that’s a really unstable place to be. A ball that has started rolling down a slope is always likely to keep going, unless something can hold it back. And even if such a ball does come to a halt, there’s always the chance it will start moving again, rolling on down that hill.
What holds cells in this teetering position? In 2006, a group headed by Eric Lander at the Broad Institute in Boston, found at least part of the answer. A key set of genes in ES cells, the pluripotent cells we have come to know so well, were found to have a really strange histone modification pattern. These were genes that were very important for controlling if an ES cell stayed pluripotent, or differentiated. Histone H3K4 was methylated at these genes, which normally is associated with switching on gene expression. H3K27 was also methylated. This is normally associated with switching off gene expression. So, which modification would turn out to be stronger? Would the genes be switched on or off?
The answer turned out to be both. Or neither, depending on which way we look at it. These genes were in a state called ‘poised’. Given the slightest encouragement – a change in culture conditions that pushed cells towards differentiation for example – one or other of these methylations was lost. The gene was fully switched on, or strongly repressed, depending on the epigenetic modification
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This is really important in cancer. Stephen Baylin is the third person, along with Peter Jones and Jean-Pierre Issa, who has done so much to make epigenetic therapies a reality. He has shown that these poised histone modifications are found in early cancer stem cells and are really significant for setting the DNA methylation patterns in cancer cells
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Of course, other events must also be taking place. Many people do not develop cancer, no matter what age they live to. Something must happen in the people who do develop cancer, which results in the normal stem cell pattern getting subverted and hardened so that the cells are locked into their aggressively and abnormally proliferative state. We know that environment can have a substantial impact on cancer risk (just think of the hugely increased risk of lung cancer in smokers) but we’re not clear on how or if the environment intersects with these epigenetic processes.
There may also be an aspect of pure bad luck in who develops cancer. We probably all have random fluctuations in the levels, activity or localisation of proteins that target, write, interpret and erase our epigenetic codes. And there are the non-coding RNAs too.
The 3´ UTRs of both
DNMT3A
and
DNMT3B
mRNA contain binding sites for a family of miRNAs called miR-29. Normally, these miRNAs will bind to the
DNMT3A
and
DNMT3B
mRNA molecules and down-regulate them. In lung cancer, the levels of these miRNAs drop and as a consequence
DNMT3A
and
DNMT3B
mRNA and subsequently protein expression is elevated. This is likely to increase the amount of de novo methylation of susceptible tumour suppressor promoters
37
.
DNMT3A
and
DNMT3B
mRNA contain binding sites for a family of miRNAs called miR-29. Normally, these miRNAs will bind to the
DNMT3A
and
DNMT3B
mRNA molecules and down-regulate them. In lung cancer, the levels of these miRNAs drop and as a consequence
DNMT3A
and
DNMT3B
mRNA and subsequently protein expression is elevated. This is likely to increase the amount of de novo methylation of susceptible tumour suppressor promoters
37
.
It is likely that there will also be feedback loops between miRNAs and the epigenetic enzymes they control, if one component of the pathway becomes mis-regulated. This will reinforce abnormal control mechanisms in the cell, leading to yet another vicious cycle, and is shown in
Figure 11.4
. In this example, a miRNA regulates a specific epigenetic enzyme, which itself modifies the promoter of the miRNA. In this case, the epigenetic enzyme creates a repressive modification.
Figure 11.4
. In this example, a miRNA regulates a specific epigenetic enzyme, which itself modifies the promoter of the miRNA. In this case, the epigenetic enzyme creates a repressive modification.
Figure 11.4
A positive feedback loop which constantly drives down expression of a miRNA which would normally control expression of an epigenetic enzyme that creates a repressed chromatin state.
A positive feedback loop which constantly drives down expression of a miRNA which would normally control expression of an epigenetic enzyme that creates a repressed chromatin state.
There is still much that we need to understand if we are to develop the next generation of epigenetic drugs to treat cancer patients. We need to know which drugs will work best in which diseases and which patients will benefit the most. We want to be able to work this out in advance, so that we don’t have to hope for the best when running large numbers of clinical trials. At least 5-azacytidine and SAHA have given us the comfort of knowing that epigenetic therapy is possible in cancer, even if improvements are needed.
As we shall see in the next chapter, epigenetic problems are not restricted to cancer. But sadly we are even further away from knowing how to use epigenetic therapies in one of the greatest unmet clinical needs in the western world – psychiatric disease.
The mind is its own place, and in itself can make a Heaven of Hell, a Hell of Heaven.
John Milton
One of the most noticeable publishing trends of the last ten years has been the rise and rise of the ‘misery memoir’. In this genre, the authors recount the tough times of their childhood and how they have risen above them to be successful and fulfilled individuals. The genre can be sub-divided into two categories. The first is the poor-but-happy tale, the ‘we had nothing but we had love’ story. The second, which may or may not also include poverty, tends to be much more disturbing. It focuses on harrowing tales of childhood neglect and childhood abuse, and some of these memoirs have been hugely successful.
A Child Called It
by Dave Pelzer, possibly the most famous of this category of books, spent over six years on the
New York Times
bestsellers list.
A Child Called It
by Dave Pelzer, possibly the most famous of this category of books, spent over six years on the
New York Times
bestsellers list.
A substantial amount of their appeal seems to lie in the triumph-over-adversity aspects of these memoirs. Readers seem to take heart from the stories of individuals who, despite a terrible start in life, finally grow up to be happy, well-balanced adults. We applaud those who become winners ‘against the odds’.
This tells us something quite revealing. It shows that, as a society, we believe that early childhood events are extremely important in influencing adult life. It also shows that we believe that it is very difficult to get over the effects of early trauma. As a readership, we possibly value these successful survivors because of what we perceive as their relative rarity.
In many ways, we are correct in our assumptions as it is true that dreadful early childhood experiences really can have a dramatic impact on adult life. There are all sorts of ways in which this has been measured and the precise figures may vary from study to study. Despite this, certain clear trends have emerged. Childhood abuse and neglect result in adults with a three times greater risk of suicide than the general population. Abused children are at least 50 per cent more likely than the general population to suffer from serious depression as adults, and will find it much harder to recover from this illness. Adults who were subjected to childhood abuse and neglect are also at significantly higher risk of a range of other conditions including schizophrenia, eating disorders, personality disorders, bipolar disease and generalised anxiety. They are also more likely to abuse drugs or alcohol
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An abusive or neglectful environment when young is clearly a major risk factor for the development of later neuropsychiatric disorders. We are so aware of this as a society that sometimes we almost forget to question why this should be the case. It just seems self-evident. But it’s not. Why should events that lasted for two years, for example, still have adverse consequences for that individual several decades later?
One explanation that is often given is that the children are ‘psychologically damaged’ by their early experiences. Whilst true, this isn’t that helpful a statement. The reason why it’s not helpful is that the phrase ‘psychologically damaged’ isn’t really an explanation at all – it’s a description. It sounds quite convincing but on certain levels it doesn’t really tell us anything.
Any scientist addressing this problem will want to take this description and probe it at another level. What are the molecular events that underlie this psychological damage? What happens in the brains of the abused or neglected children, that leaves them so prone to mental health problems as adults?
There is sometimes resistance to this approach from other disciplines, which work within different conceptual frameworks.
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