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

398 notes

The University of Melbourne

Epigenetic Control of Gene Expression

398 notes

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

À partir de la leçon

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.

7.1 Overview of cancer epigenetics7:13

7.2 Hypermethylation of CpG islands in cancer16:40

7.3 Hypermethylation of sets of CpG islands in cancer11:59

7.4 Hypomethylation genome-wide in cancer12:04

7.5 Altered histone modifications in cancer11:55

7.6 Long range epigenetic alterations in cancer and alterations to nuclear architecture10:25

7.7 Altered expression on piRNAs and long noncoding RNAs in cancer9:35

7.8 Mutations in epigenetic modifiers in cancer9:41

7.9 Drugs that target the epigenetic machinery as chemotherapeutics17:05

7.10 Extension lecture: Aging - Part 114:07

7.11 Extension lecture: Aging - Part 223:04

Rencontrer les enseignants

Dr. Marnie Blewitt
Head, 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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