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,
