While the human genome sequence has transformed our understanding of human biology, it isn’t just the sequence of your DNA that matters, but also how you use it! How are some genes activated and others are silenced? How is this controlled? The answer is epigenetics. Epigenetics has been a hot topic for research over the past decade as it has become clear that aberrant epigenetic control contributes to disease (particularly to cancer). Epigenetic alterations are heritable through cell division, and in some instances are able to behave similarly to mutations in terms of their stability. Importantly, unlike genetic mutations, epigenetic modifications are reversible and therefore have the potential to be manipulated therapeutically. It has also become clear in recent years that epigenetic modifications are sensitive to the environment (for example diet), which has sparked a large amount of public debate and research. This course will give an introduction to the fundamentals of epigenetic control. We will examine epigenetic phenomena that are manifestations of epigenetic control in several organisms, with a focus on mammals. We will examine the interplay between epigenetic control and the environment and finally the role of aberrant epigenetic control in disease. All necessary information will be covered in the lectures, and recommended and required readings will be provided. There are no additional required texts for this course. For those interested, additional information can be obtained in the following textbook. Epigenetics. Allis, Jenuwein, Reinberg and Caparros. Cold Spring Harbour Laboratory Press. ISBN-13: 978-0879697242 | Edition: 1
7.4 Hypomethylation genome-wide in cancer
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En provenance du cours de The University of Melbourne
Epigenetic Control of Gene Expression
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Week 7 - Cancer Epigenetics
This week we’ll bring together much of what we’ve learned in previous weeks of the course, to understand how the epigenome is affected, and can also affect, cancer development and progression. We’ll then go on to discuss the potential therapeutic benefits that can come from using epigenetic biomarkers, and targeting epigenetic modifiers in cancer.
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Dr. Marnie BlewittHead, Molecular Medicine Laboratory
Walter and Eliza Hall Institute of Medical Research
Okay, so now we're going to start thinking about genome-wide DNA
hypomethylation. So the low level of methylation that's
found approximately genome-wide. We're going to think about this occurring
in two particular contexts. At repetitive regions, and at CpG poor promoters.
So as I said, what we've spent the first
couple of lectures thinking about is the difference at CpG islands, and then
briefly, the difference at CpG island shores, or imprint control regions.
But actually in general the genome is not made up of CpG islands.
Most of the genome is made up of these intergenic intervals or repetitive
elements or other places where in general you would find that the
CpGs were methylated in a normal cell. But in cancer, as a general rule of thumb
these regions tend to become hypomethylated, so they have less
methylation than you would see, in a normal cell.
So why would this occur? Well, really this hypomethylation has a
consequence depending on where it's happening.
So, the actual outcome for the cell depends on where it's found.
But historically hypomethylation, genome-wide hypomethylation was the very
first epigenetic abnormality to be found. It was found back in the early 80s, back in
about 1983. We now know that if you've looked
through lots and lots and lots of tumour samples, genome-wide hypomethylation
occurs to some extent in every tumour. So, it's a very very common thing that
happens and it seems to happen quite early in tumourigenesis.
So it happens early and progresses with time.
And this is similar to what I said for CPG island hypermethylation, is that it
progresses with time, and it's a very common event.
So these epigenetic mistakes in cancer are not restricted in any way to one
particular tumour type, but rather they are a general rule for cancer in general.
So we'll think about the consequence of this hypomethylation.
First of all with regards to repeats, or repetitive elements.
And second, with regards to CpG poor promoters.
But at this stage I want to point out that really it's the repeats that are the
most important. So the hypomethylation that occurs is
most commonly occurring at repeats. And is rarer anywhere else.
So what I mentioned when we spoke about DNA methylation way back in week one was
that one of the functions of DNA methylation was to maintain genomic stability.
In other words to make sure that
genetically the genome was normal and we didn't lose chromosomes,
gain chromosomes or have illegitimate recombinations between chromosomes when
they shouldn't occur. So then if you have hypomethylation of
repeats or indeed intergenic intervals, the regions that aren't necessarily
repetitive but are between genes, then what you end up having the
consequence of this are Illegitimate recombination between repeats.
And so you can see here this results in things like reciprocal translocations
between two different chromosomes the blue and the black chromosomes shown here.
This happens because recombination
normally can only happen between regions that have genetic identity.
So say for example between a chromosome 2 and a chromosome 2.
However, if repeats have large tracks that are identical or very similar, and
of course by their very name they do have large regions that are repetitive
and are similar to other places in the genome.
The recombination could in theory happen because of alignment between these repeats.
Now, in a normal cell, this recombination
wouldn't happen because the repeats would be heavily methylated and also they'd be
heterchromatonized. So recombination not only needs genetic
identity or genetic similarity, but secondly needs open chromatin,
euchromatin, and then recombination can occur.
Otherwise, the DNA is too densely packaged for recombination to occur.
But in the context of cancer we have hypomethylation of these repetitive
elements or the intergenic regions. They align, they misalign, and then an
illegitimate recombination can occur because they are not densely packaged
down into heterochromatin. We know that the repeats can also be
activated because of the hypomethylation. This means that the repeats have the
capacity to actually make a copy of themselves.
And jump around the genome or transpose. This can result in consequent problems
where they jump into, because of course they may disrupt the coding region of a
gene but it also may activate neighbouring genes.
So, if you think about the examples that we gave in week five, the axin fused
allele or the agouti viable yellow allele, this was a repeat that sat within
a gene or upstream of a gene. And in those cases those very strong
promoters, the cryptic promoters, were activated in some instances, and they had
aberrant outcomes for the surrounding genes. In this case, the agouti genes or the
axin gene. So if you have hypomethylation of the
repeats then either they jump or they just have their promoters becoming
active, then this can lead to transcriptional aberration in the
surrounding regions. The overall outcome is that you have
additional deletions in cancer, you have insertions so you gain parts of chromosomes.
And you even have these reciprocal translocations.
So, in general genomic instability.
So, what evidence do we have for this genomic instability?
There's actually quite a lot of evidence for DNA methylation being involved in
maintaining genomic stability and when its gone or low you get increased genomic instability.
If we think first about mouse models,
while I told you again in week three I believe, in X inactivation lectures that a
DNMT1 null embryo, an embryo that has no DNA methyltransferase 1,
the maintenance methyltransferase, will die around mid gestation,
you can actually make an adult mouse that has decreased or no levels of DNMT1 just
in particular tissues. So the animal doesn't immediately die
because you've only gotten rid of DNMT1 in a particular area.
Say, for example, just in the thymus. Or just in maybe the blood cells.
So you can look in these very restrictive ways to say what's the role
of DNA methylation in that particular organ.
And when you do that, you find that the animal ends up getting cancer.
If you get rid of DNA methylation, you find increased genomic
instability in that particular tissue, and then they end up with a particular
type of cancer. So this is good evidence that there's
genomic instability resulting from exactly the mutation that you made.
So you made sure there was no DNA methyltransferase, and this led to
genomic instability. You'll also remember that we spoke about
ICF syndromes, this immunodeficiency and cranio-facial defects syndrome.
In this case, it came from a mutation in DNMT3B in humans, so DNMT3B is one of the
de novo methyltransferases. And one of the characteristic features of
this particular disease is genomic instability.
And that's because of DNA hypomethylation a particular centromeric repeats.
So repeats that are found around the centromere.
But of course its from human cancer where
we see hypomethylation and genomic instability.
So other than this repeats where it's most common to have hypermethylation, you
can also see hypomethylation in other regions of the genome.
Although it's less frequent. I mentioned the imprint control regions earlier.
We went through an example of
hypermethylation, but they can also sometimes be hypomethylated
at other imprint control regions.
But we also see hypermethylation on occasion of CpG poor promoters.
So in other words, a CpG, a promoter which doesn't have a sufficient density
of CpGs to be considered a CpG island. So say, for example, shown here you can
see there are just a few CpGs in the promoter of this blue gene that I've
shown with the exons. So what can happen in these cases in
cancer is that the CpG poor promoters become hypomethylated in cancer.
And this is associated with activation of the associated genes.
Two examples are activation of the potent onco gene R-RAS in gastric cancer
because of the hypremethylation of its CpG poor promoter or hypomethylation of
MicroRNA miR21. In the case of hypomethylating a microRNA
and activating a microRNA, the effect that this will have in a cancer cell
really depends on what the function of that microRNA is, which protein, or which
RNA and then the consequent protein is it targeting?
In this case, miR21 targets the tumour suppressor PTEN, and so, if you then have
additional microRNA targeting PTEN, that means that you will have less PTEN
being expressed, and so it's a different way to end up silencing a tumour
suppressor through activation of the microRNA that targets the tumour suppressor.
Okay. So, this is one the secondary events in terms of hypomethylation, this
hypomethylation of CpG poor promoters. So, what I have told you in terms of DNA
methylation and cancer is that you both have hypomethylation genome-wide in one
hand and hypermethylation of the tumour suppressor genes.
So this really begs the question, what is the contribution of DNA methylation to cancer?
And say for example, if we wanted to
inhibit DNA methylation for therapeutic purpose, would it be good or bad when
they both, you've got both of these things going on at once.
And again, we now know a little bit about the role of DNA methylation in this way
because of particular mouse studies that have been performed.
And in these mouse studies, what they've been able to find is that yes, you do
have both hypermethylation of the tumour suppressor genes and hypomethylation
genome wide. But the driving role of DNA methylation
is context dependent. So that means that the functional outcome
of depleting DNMT1, for example, is context dependent. So, different tumours,
while all tumours tend to show CpG island hypermethylation and genome-wide
hypomethylation, different tumours have different dependencies on each of these
particular aberrant demethylation profiles.
So some tumours are driven by that tumour suppressor hypermethylation.
And that's what's making them continue to divide so rapidly.
In that case, if you remove some DNA methylation.
Then it ends up suppressing tumourigenesis.
So, those that are driven by tumour suppressor hypermethylation, if you can
reduce some of that hypermethylation a little bit, then you will reduce the
tumourigenicity. But, in contrast, some types of cancers
are driven by chromosomal instability, and in this case if you deplete DNA
methylation, you will have exacerbating the genome-wide hypomethylation which
contributes to genomic instability. And therefore it will enhance tumourigenesis.
And so this is what I mean by the role of
DNA methylation being context dependent. What's additionally complicated is that
if you then look at the stage of the tumour.
So not are there just these two different tumour types, those that are dependent on
the hypermethylation. Those that are dependent on the
hypomethylation, but the secondary effect that you need to consider is that
some tumours change their dependencies throughout their lifespan, if you like.
So very early in tumourigenesis, they may depend on one, say in the preneoplastic
state, and then very late, maybe at the invasion or metastasis stage, their
dependency will change. And this really has implications for the
effectiveness of epigenetic drugs, drugs targeting these epigenetic mistakes.
And so we need to think very hard about when is the most appropriate time to say,
for example, treat with a drug the inhibits DNA methylation.
Whether it might be effective late or early.
And this may need to be addressed, or will need to be addressed in every
individual type of tumour at different stages of disease.
In the next lecture we'll leave DNA methylation and move on to the other
epigenetic aberrations that are seen in cancer.
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