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
6.8 Constitutional epimutation in humans - not transgenerational epigenetic inheritance
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From the course by The University of Melbourne
Epigenetic Control of Gene Expression
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From the lesson
Week 6 - Mechanisms of Environmental Influence on Epigenetic Control and Transgenerational Epigenetic Inheritance Through the Gametes
A look at the mechanisms underlying some of the observations we discussed in week 5, through the study of model organisms. We’ll learn about metastable epialleles, which have allowed the study of transgenerational epigenetics in mice, and provided some evidence for transgenerational epigenetics in mammals.
Meet the Instructors
Dr. Marnie BlewittHead, Molecular Medicine Laboratory
Walter and Eliza Hall Institute of Medical Research
So, we've not been through examples of transgenerational epigenetic inheritance
at metastable epiallele in mice, and we've thought about the two potential
mechanisms that have been considered and for which there had been data in the past.
So, either persistence of an epigenetic
mark through epigenetic reprogramming or transmission of some messenger molecule
and potentially an RNA. So, now I want to reconsider whether we
have data to support transgenerational epigenetic inheritance in humans.
So, in the first couple of lectures, we thought about the Overkalix data, and
really, as you know there isn't a lot of molecular data here.
So, we don't know whether or not this is transgenerational epigenetic inheritance.
The other example that's been in the
literature is that of constitutional epimutation of the MLH1 locus.
So, we're now going to consider this as whether or not this is transgenerational
epigenetic inheritance in humans. So, Lynch syndrome is a type of
hereditary cancer, it's hereditary nonpolyposis colorectal cancer.
So, HNPCC is its other name. We know that this particular type of
colorectal cancer is characterised by a micro satellite instability.
So, these are short repeats, and they are unstable in terms of their length.
So, they can either expand or contract. And so, this micro satellite instability
is usually caused by mutations in the mismatch repair genes.
And MLH1 is one example of a mismatch repair gene, although there are many others.
So, normally in patients of HNPCC,
they'll find one copy of one of their mismatch repair genes has a mutation.
And this predisposes them to develop Lynch syndrome later in life.
It's hereditary because it runs in families, and so, you can see many people
within the same family were predisposed to the syndrome,
because they've all inherited this particular mutation.
But in some cases of Lynch syndrome, what happens is that they can't find a mutation.
They still definitely have micro
satellite instability. They'll still have Lynch syndrome.
They'll still get colorectal cancer. And yet they'll still have micro
satellite instability, and yet you don't have a mutation.
So, in these cases what they have found in the past is that MLH1, one of the
genes involved, will be hypermethylated.
So, it has too much DNA methylation at the CpG island.
And you'll remember that DNA methylation at a CpG island it tends to be synonymous
with silencing. And indeed that's the case in these patients.
They've hypermethylated the CpG island of
MLH1 and it's no longer expressed from that allele.
So, now, instead of having a mutation of MLH1, you've got silencing of MLH1 by DNA methylation.
This is something we're going to talk
about a lot next week in cancer epigenetics.
So, they have this hypermethylation, but no detectable mutation.
And this is called a germline or constitutional epimutation, because this
DNA methylation is found in all of the tissues of its somatic, or all of the
somatic cells of these patients. Okay.
So, it's soma wide or constitutional. So, but just like MLH1 or Lynch syndrome
when it's caused by genetic mutation, the interesting thing is MLH1 epimutations
still run in families. So, if it's an epimutation, why should it
run in families? It's this potentially a case of
transgenerational epigenetic inheritance. So, there are three reports that I'm
going to bring up in this discussion. The first of these that came out looked
at two separate families. So, they had, they looked at the
father in one case. And here I'm just showing the two
alleles of MLH1. So, one allele was methylated and the
other was unmethylated, and he suffered from Lynch Syndrome.
They then looked at the methylation of MLH1 in two of his offspring that had not
yet developed Lynch syndrome. They tried looking in this case and,
or couldn't get sample when they didn't know.
But they knew that in this case that there was an unmethylated allele,
and the person also didn't suffer from Lynch syndrome.
In the second family they had a female, and she had this methylated allele of MLH1.
And again in both of her offspring, in
this case they could study both of the offspring.
They found that there was no methylation being passed on.
But because they couldn't really study the oocytes in this case.
They couldn't say, let's ask whether or not this is possibly, has the potential
to be transgenerationally inherited. Despite the fact that none of the
offspring showed this MLH1 hypermethylation, they still thought
there was a possibility that there might be some
potential for transgenerational inheritance based on the fact that you
just haven't looked at very many children, because these people, we don't
have as many children as mice I guess if you like.
but we can't study the oocytes. Really can't access oocytes, certainly
not in older women when there really aren't any left.
But, they could study the sperm of this man.
So, he consented to provide a sperm sample.
And what they found was that if they looked at this MLH1 gene and about 1% of
cases, they could find methylation. So, although they never saw that the
methylation was certainly passed to the children, this raised the
possibility that they might be some failure of clearing of the epigenetic
marks at this MLH1 gene. And therefore, the potential for
transgenerational epigenetic inheritance by the sperm.
So, as you can imagine, this was a very very high profile paper, and attracted a
lot of attention. Because this was really the first time
when they had some molecular evidence for the potential of transgenerational
epigenetic inheritance in people. The next study was a larger pedigree that
they looked at. And here we're just starting out with
this female. And this female had Lynch syndrome, which
is why she's coloured in black. And she also had methylation of MLH1 on
one of her two alleles. She hadn't inherited this methylation
from her parents, because the allele came from her father.
That black allele. But he had an unmethylated version and
never suffered from Lynch syndrome. She had four children in total from two
separate fathers. And when you looked the methylation in
all four of these children, one of these males, all the children were males, had
methylation of the MLH1. And therefore there was some hereditary basis.
So, it had been passed on it
would look like in one case at least. And so, methylation was causing him to be
this carrier at the moment, which is why he's got a black dot in the middle of him.
But he hasn't yet suffered from Lynch
syndrome from the time of publication. But of course it's possible given that he
has hypermethylation of this mismatch repair gene.
has hypermethylation of this mismatch repair gene.
that methylation, or does it remain? In this case, what they did was they
actually performed a slightly higher purity sperm preparation.
So, you'd think the sperm's quite pure, but actually there's quite a few other
things that come along with sperm. And so, you need to make sure that you
are only looking at the mature sperm, those that can swim, for example.
So, when they perform a better sperm preparation by actually testing that the
sperm can swim before they isolate them, and also they can pair to a good set of controls.
So, they looked not only at MLH1 locus in
terms of DNA methylation of the sperm from this male, but also looked at imprint
control region of a gene that is known to paternally methylated.
So, in other words its subject to paternal imprinting and it should be
methylated in a 100% of sperm cells, and then one that should be unmethylated.
So, that would be a maternally one.
So, one that's maternally imprinted should be unmethylated in all sperm cells
And what they found was that there was no
difference between the MLH1 locus and this maternally imprinted, imprint
control region that should be unmethylated.
So, if there's no difference, this would suggest that there's no carrier of
methylation through spermatogenesis, through primordial germ cell
development in this male. So, in this case, there was really no
argument for transgenerational epigenetic inheritance because you couldn't find it
in the gametes. And this conflicted with the previous data.
However, as I've said, this set of
studies were performed with more controls and with a better sample preparation.
And so, in this case, it would appear that there wasn't any argument for
transgenerational epigenetic inheritance through the gametes.
Another very exciting finding, but also very controversial because it conflicted
with the earlier data. So, the final work that has come out now
that I'll talk about follows a much larger pedigree where it's unusual,
because what they found was that if you look at this founder mother who has
methylation on the black allele. She passed on this methylation to all of
her children in this generation. Two of which have gone on to have Lynch
syndrome hence they're coloured black. The other three are carriers, and indeed
whenever this black allele is inherited in their children the methylation is also inherited.
So, this 100% penetrance.
Rather than in the last pedigree, which I'll go back to, where you can see out of
three, only one. Now, in this pedigree you can see
everybody inherited the methylation in this generation.
That's all five children in this generation inherited the methylation, and
the two that inherited the right allele in this generation also
inherited the methylation. It's 100% penetrant.
What they actually found was, of course this looks like it could be
transgenerational epigenetic inheritance. But when they went back to form the
genetic studies to test whether or not there may be some underlying genetic
difference, which results in this establishment of the the DNA methylation
being or occurring differently in this case.
They found that there was indeed a mutation in the five prime untranslated region
So, there was a snip, a single
nucleotide polymorphism. So, there was one base different between
this allele and other alleles. And it appears to be this allele, when
they go on to test it, which results in expression of MLH1, and then is
associated with DNA methylation. So, this is an example where it would
appear to be transgenerational epigenetic inheritance that certainly constitutional
MLH1 epimutation. However, it's caused by a genetic
difference rather than by some stochastic epigenetic establishment of it's effects.
So, the summary for this week then is that we know that there are environmental
factors that can alter epigenetic makeup.
There appear to be these at least when we have the very controlled studies in mice
or in rats. There are sensitive periods when if
you're exposed to these environmental factors, and these are predominantly
during the establishment of epigenetic marks rather than the maintenance of
epigenetic marks. We know that at least in mice some of
these epigenetic marks can be transmitted transgenerationally.
And so, this means that any environmental effect which alters epigenetic state at
least has the potential that it could alter subsequent generations as well.
However, the human evidence to show that this happens is still lacking.
We still don't have any case of transgenerational epigenetic inheritance
via the gametes in humans. Finally, that last example should have
pointed, should have been able to show you that we really have to consider
the contribution of genetic effects. So, is there an underlying genetic basis
for the epigenetic difference. Especially in the cases when environmental factors
for example, smoking are known to cause mutations in and of themselves.
So, we come back to these three questions again to end the week.
If we know that these environmental factors seem to be able to alter
epigenetic state, although we don't always know how, what proportion of the
genome is sensitive to the environment? So, are there only very restricted number
of alleles like the unusual agouti viable yellow allele that they're actually
sensitive in this way? Or are there many large number of
alleles that are sensitive spread throughout the genome?
What proportion of the population, so, how many of us are actually genetically
sensitive to altered environment? Many of us may actually have the right
underlying genetics to have any sort of sensitivity to these altered methyl
donors, for example, or BPA. The jury is still out, we still don't
know what the answer is for that. And we certainly don't know what
proportion of any environmentally induced epigenetic events are mitotically
heritable, and therefore really have the potential to cause a phenotype, or
miotically heritable, and therefore have the potential to show transgenerational
epigenetic occurrence. There's a lot we still don't understand,
but it's been a very active area of research, and an area that we're very
interested to work out. Because it has such a fundamental bearing
on human health. Next week, we're going to think about
cancer epigenetics and how epigenetic control goes awry in the instance of malignancy.
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