7.11 Extension lecture: Aging - Part 2 - Week 7 - Cancer Epigenetics

Okay, so now in the second lecture, we want to think about the specific changes

that we see occurring with epigenome with age,

at least those that we can summarize and believe do occur relatively consistently.

So in terms of DNA methylation, we know other CpG islands, normally in

a young cell you would find that the CpG islands in general were unmethylated.

Whereas you would find methylation spread throughout the genes, so

between the axons and in the intergenic regions.

And particularly in the repetitive elements.

And this is really important, as we've discussed before,

to be able to maintain the silence of these repetitive elements.

And therefore to maintain genetic integrity.

But in an old cell, what we find is that, more commonly, we find

these CpG islands become hypermethylated, as shown by the colored in lollipops.

And the other regions become hypomethylated.

That is we have specific regions of hypermethylation here, and

in general, regions of hypomethylation throughout the rest of the genome.

So what's particularly striking with this is that this is exactly the same as what

occurs in cancer.

So in cancer, we see regions that are hypomethylated the CpG islands.

But genome-wide, particularly that repeats in the intergenic regions,

are hypomethylated.

So this is strikingly similar to cancer.

What I'd like to talk a little bit more about is about the genes that actually

show their CpG islands to be hypermethylated in both aging and cancer.

Because what's quite interesting is that these genes are enriched for those

that were marked by H3K27 trimethylation mediated by polycomb repressive complex 2,

or PRC2, in embryonic stem cells and in adult stem cells.

And this class of genes is actually a really interesting class of genes to

think about.

So here I've got some pictures of the nucleosomes in the same fashion, as I've

shown you before in normal embryonic stem cells and normal adult stem cells.

So that means tissue resident stem cells, such as the blood stem cells, or

the epithelium stem cells, or other neural stem cells indeed we now know exist.

Then, we find at some genes you find a combination of marks, and

these are called bivalent genes.

They're bivalent because they have two particular epigenetic marks that you

wouldn't normally find together.

The first is K3K27 trimethylation,

laid down by polycomb repressive complex 2, or PRC2.

And we know that this is normally a repressive epigenetic mark.

But secondly, at these bivalent genes you also have H3K4 methylation.

And this is normally laid down by MLL, or mixed-lineage leukemia complex.

And this is normally an activating epigenetic mark.

So finding these two marks at the same genes was

particularly unexpected when it was first identified back in 2006.

Not only do these genes, these bivalent genes,

have these two epigenetic marks, along with that they have RNA polymerase II.

This is required for transcription, but it's paused at the promoter.

It's not yet actually transcribing through the locus.

So these genes are repressed.

They're not being expressed.

But they have no DNA methylation and particularly, they have these active and

repressive histone modifications.

And so the term poised is what has been used throughout the literature pervasively

to describe these genes.

They're ready to go.

They're about to be either activated or silenced.

They're ready to go, but not yet active, or really strictly silent.

What then happens is, through differentiation, they can become either

rapidly inactive through loss of that active modification, H3K4 modification,

or rapidly active through loss of the inactive H3K27 modification.

And so what's thought is that by having these bivalent marks,

these double marks here as shown by the histone modifications that I'm showing

you here on the histone tails, that they can either be rapidly activated or

rapidly repressed upon differentiation signals.

And we know that when these differentiation signals come through to

stem cells, either embryonic or adult stem cells, they need to rapidly respond and

differentiate.

In the adult because often this is a response to wound healing.

And in the embryo because this is a very rapid period

of development that happens shortly after implantation.

So what we know is that these genes that have a bivalent domain in their

promoter tend to be important genes that are involved in development.

They're known as developmental regulators, and that's particularly

because they tend to be transcription factors that really define a lineage.

So you want them to come on in one lineage, but

be switched off in the others.

So for example, MYOG or myogenin would be switched on in the muscle lineage but

would not be required in any other cell lineages.

So what we then know happens in cancer is that these same genes that were

bivalently marked, so had the bivalent domain in embryonic stem cells,

then in cancer and in aging are found to be hypermethylated.

So now they don't have these active and repressive histone marks.

But instead of DNA methylation,

as I'm showing you here right at the cytosine level.

So because DNA methylation we think of as being a more stable

epigenetic mark in general, this means that they're no longer poised for

activation, but they're more stably repressed.

Now obviously, through the action of the demethylated enzymes, the TET enzymes,

they could be demethylated.

But in general, these genes are found to be

switched off in a fairly stable way in aging and in cancer.

So we don't yet really understand why these genes that were bivalent in stem

cells tend to become methylated in aging and in cancer.

But it's a really fascinating area for the future.

So now I'd like to think about the other epigenetic changes that occur at the level

of the histones in aging, and what this tells us about the aging process.

So mostly, we don't consider histone acetylation to be an epigenetic mark,

because it's not strictly mitotically heritable.

But there are some really fascinating things that occur to histone acetylation

with aging.

And actually, this is where we might be able to have some sorts of drugs that

might slow down aging.

And so I wanted to bring this up as a really interesting area.

So histone H4 lysine 16 acetylation,

or H4K16 acetylation tends to be decreased in aging cells.

Now this isn't actually uniform.

As I said in the first lecture, many of the studies have conflicting results

in terms of what happens to various epigenetic marks with aging.

But some certainly it's decreased in aging cells, although others are increased.

We know that H4K16 acetylation

is normally involved in higher order chromatin organization.

In other words, looping of the chromosomes together into

three dimensional chromosome architecture within the nucleus.

And it's also involved in the DNA damage response.

We also know that the enzymes that lay down H4K16ac.

So there are several, it's not just one.

But one of the ones that deacetylates H4K16 is know as Sirt1.

So Sirt1 in mammals has homologs in lower organisms,

particularly Sir2, in worms, flies and yeast.

So Sir2, if it's overexpressed in worms, flies and yeast,

actually prolongs the lifespan of worms, flies, and yeast.

So it's going against the normal decrease that you might see in its

epigenetic mark that it lays down.

Unfortunately, the same doesn't happen in mice.

So if you overexpress Sirt1 in mice,

you don't actually get increased mammalian lifespan.

But you do improve some of the aspects of aging.

So in other words, you improve some of the phenotypes of aging,

otherwise the mouse doesn't live any longer.

So while this isn't a perfect target to be able to activate Sirt1 in people to

be able to extend their lifespan,

it's promising that maybe it has some role in aging in people as well.

The second example to think about involves Sirt6, so another family member.

But instead Sirt6 is involved in laying down histone h3 lysine 9 acetylation.

So again, histone h3 lysine 9 acetylation tends to be depleted with aging.

But again, it's a variable, and it really depends on the study.

It's also variable for what happens with H3K9 acetylation in cancer.

So we can't draw a direct correlation between H3K9 acetylation in aging and

in cancer, because what happens to H3K9 acetylation in cancer depends on

the type of cancer that we're talking about.

But normally Sirt6 deacetylates H3K9, and this is important in DNA repair.

So if we have mutants in Sirt6, then you have defective DNA repair.

And of course this can lead to premature aging, and

of course could potentially lead to cancer as well.

But what we're interested in doing thinking about is,

what happens if you have over expression or activation of Sirt6?

Now we know over expression of Sirt6 does result in increased mammalian lifespan,

and this is really exciting.

And the reverse is also true,

if you delete Sirt6 in mice, then this accelerates aging.

So we can say that Sirt6 mediated H3K9 acetylation changes really do have

a fundamental role in aging.

And what's interesting now, and I'll come back to it at the end,

is that there are now drugs that are looking at activating Sirt6 as a way

to mediate the effects of aging and potentially prolong human lifespan.

So the final histone modification to think about in aging,

although we can talk about all the various histone modifications, but the one with at

least the next most information available is histone H4 lysine 20 methylation.

So we know that this can be decreased in aged human fibroblasts.

So this is fibroblasts that are from older patients, but are also aged in vitro.

We know that the H4K methylation is increased in rat kidney

from an elderly rat or in liver samples.

And so, again, we have, as you can see, this kind of conundrum between which of

these studies is most representative of what really occurs in aging.

In many cases, for when we want to know about epigenetic

changes occurring in cancer, people turn to the particular aging syndromes.

These syndromes that occur in people, where they have premature and

very rapid aging.

One of these is in Hutchinson-Gilford Progeria syndrome,

which I'll talk about in the next few slides.

And in this case, we see H4K20 methylation increasing in these patients.

So what is H4K20methylation4 anyway?

Well normally, it's that centromeres, telomeres, and

remember these are constitutive heterochromatin, so

they're always repressed, but also at imprint control regions and repeats.

So imprint control regions and repeats, well, repeats, we know,

are also constitutively silenced, that is silenced all the time.

And imprint control regions have a very special type of epigenetic control.

But in general, H4K20 methylation is a repressive histone modification,

one that's found in regions that are transcriptionally repressed.

So let's think about Hutchinson-Gilford Progeria Syndrome.

So this is one of the premature aging syndromes, there are in fact many of them.

And it's caused by de novo mutations, so

mutations that rather than inheriting them because your parent also had them,

they've occurred fresh in the germ line of one of your parents.

And it's a mutation that occurs in a gene that encodes lamin A.

It doesn't mean that lamin A is no longer made,

but rather it means that lamin A protein isn't processed properly.

So the lamins are involved in the nuclear lamina, as I'm showing you here.

So you'll remember, back in week two,

we talked about the nuclear lamina as a region where we had chromatin regions

being drawn to the nuclear lamina, mainly for transcriptional repression.

So these patients make the nuclear lamina, they make lamin A, but it's not made in

a normal fashion, and it doesn't actually do its job in the normal fashion.

And so what means is that these patients age extremely rapidly, and they rarely

survive into their teen year, that's really, a horrible, horrible disorder.

So, if you have a look here, here's a picture of one of these patients.

And there are many other pictures that you could find online.

They tend to look like elderly individuals by the time they're just five or six.

And this is a picture here on the right of a nucleus from these patients.

So here's a normal nucleus, with lamin A being labeled with the green color,

and that's nice and beautifully spherical.

And here we can see it just in two dimensions being round.

But in these patients, while they still have lamin A,

being shown in green, you can see this really abnormal nuclear morphology.

So we know that this abnormal nuclear morphology also means they have

disorganized heterochromatin, so in other words,

those regions that should be silenced are all disordered.

They don't have appropriate DNA repair, and

they also have increased genomic instability.

Which of course given the relationship between epigenetic changes and

genetic changes could all be interlinked.

So why is this happening in these patients?

So there are many changes that are occurring,

because of this disruption to the nuclear lamina.

But predominantly we have disrupted heterochromatin, and

that's because heterochromatin does tend to need to bind at

that nuclear lamina region, and this nuclear lamina is no longer normal.

And you have misregulated gene expression.

And so these patients, unfortunately, have very, very large scale changes to

their epigenome, and large scale changes to the genes that are being expressed,

meaning that they have this premature aging.

But the question really remains,

is this normal aging occurring at a much more rapid rate?

So if we want to study normal aging, is studying these patients informative?

Studying these patients is certainly extremely informative, so that we can work

out how to treat these patients and be able to hopefully extend their lifespan.

But is it what happens to the rest of us?

Is it just the same thing that happens to the rest of us, only sped up?

And I think that remains to be seen.

So what I mentioned on some of these slides going through is the commonalities

between the epigenetic changes we see in aging, and those we see in cancer.

In general, we don't yet have a complete set of data on either topic, but

certainly not on aging.

There's a much broader literature on what are the epigenetic changes that occur

in cancer.

So we know some of the changes that occur, but some of these studies have been done

in the aging syndromes, like Hutchinson Progeria syndrome.

Some of them, they differ between tissues, and also between different models.

And so, it's likely that there are going to be variations between all of

these particular scenarios, and

we need to have a much deeper literature to be able to understand what's going on.

So having said that, there is still a high degree of correlation between the changes

that occur in aging and those that occur in cancer.

So there's variability, there are going to be things that change specific with

some type of cancers and not others, but in general, there is a lot of commonality.

And so this leads to the suspicion that maybe the aging related changes

are actually a forerunner to malignancy.

So you have the epigenetic changes that occur normally with cancer and

perhaps this then predisposes us to be able to get cancer with age.

And so these underlying epigenetic changes may be the actual instigating events for

cancer, and then if you get one hit on top of that, for example,

another problem with, DNA damage or overexpression of an oncogene.

This will then tip us over the edge to lead to tumor genesis.

And again, these sorts of studies are going to be really interesting to look at

for the future.

So I mentioned at the end of the last lecture

about some of the ideas about how this epigenetic variation occurs with age.

And I think the most predominant idea is that there's some drift.

We have some stochastic epigenetic errors that occur, and

these are maintained over time.

And so as you get older, you've had more and

more stochastic epigenetic changes occur.

And therefore, you've drifted further and further away from normal, if you like.

But that might be drifting in a different direction between the cells that are found

even within one tissue and, certainly, between you and another individual.

What's quite interesting, I think, is to think about how the environment

might influence these epigenetic changes, or might influence epigenetic drift.

So we know now that exposure to chronic inflammation can change epigenetic state.

It can lead to a feedback.

And yet, chronic inflammation is also a feature of aging.

So what's the relationship between these two?

Which comes first, if you like?

We also know other dietary factors that can influence epigenetic state.

So do these dietary factors or your exposure to particular dietary factors

that happen over your lifespan alter your epigenetic state and

alter this drift that's occurring?

So as I mentioned earlier, there are greater differences between old twins and

young twins, even in the case of genetic identity.

So this state does tend to lead supports the idea that, really,

what's happening with aging is an accumulation of epigenetic errors

that are potentially influenced by the environment over our lifespan.

But other than this drift that occurs, are there other concerted

changes that occur in the epigenetic factors themselves?

We know that in cancer, which has many similar features to aging,

that there are changes to the epigenetic regulators themselves.

So with aging, is it all stochastic, or

do we also have changes to the epigenetic factors themselves?

Well, there are some, and maybe there'll be more revealed with time.

But at the moment, what we know is DNMT1, the maintenance methyltransferase, and

DNMT3A, which is involved in de novo methylation, decrease with aging.

And this would suggest how we tend to get demethylation with time.

However, we also get hypermethylation at some CpG islands.

And we know that DNMT3B tends to increase in some cell types.

And in particular, this is found in senescent cells.

Now remember, I said senescent cells increase with aging, but

senescence itself is not aging.

So again, we don't really know whether this occurs in normal aging or

whether it just happens in senescence.

But potentially,

this could explain some of the differences that we see occurring in DNA methylation.

In general, in aged cells we think there are fewer changes to epigenetic modifiers,

or at least fewer than we've identified so

far compared with what we see in frank cancers,

where we have lots of mutations or changes in the expression of epigenetic modifiers.

But really, this remains to be examined with future experiments.

So I think one of the most interesting things to think about is does this

knowledge about some of the epigenetic changes that occur with age,

does this suggest any treatment for aging?

Because, obviously, most of us would like to find the fountain of youth.

We'd like to work out how can we prevent aging?

How can we extend our productive lifespan, not just necessarily extend our lifespan,

but keep us being hundred year olds?

That's probably not the best thing.

But rather, extend the period of our lives, where we feel productive and

healthy and well.

So because we already have drugs that hit the epigenetic machinery because

of the large amount of work that's gone into looking to target these

in cancer chemotherapy, one idea is that we might be able to use these,

not just as anticancer drugs, but also potentially to prevent aging.

So obviously, this would require that we use these drugs in roughly normal people.

And this is scary in many, many cases.

Because we know if we alter the epigenome, perhaps if this doesn't occur

in a very regulated way, it might cause actually more harm than good.

But potentially over time,

these epigenetic inhibitors might be able to be directed to particular sites

in the DNA, where we know are commonly methylated in aging, for example.

Probably, the drugs that are being furthest ahead with regards to

aging are those that try to activate SIRT6 and maybe also other SIRTs.

And you remember SIRT6,

if you overexpressed it, extended the lifespan in mammals.

And so what they're trying to do now is be able to activate the function

of SIRT6 to promote its activity, and therefore, prolong lifespan.

So it'd be interesting to see if these chemicals that are around that can do this

now actually come into the clinic and used in common when they're used.

But I imagine what will end up being likely is that these sorts of drugs will

still be used with other anti-aging treatments that are already around and

already actually receive a lot of press and a lot of coverage.

So the one that many people have heard about is caloric restriction.

So what's being shown first of all in worms, I think,

was that if you decrease the calorie intake, then you can extend your lifespan.

And this is true, it seems, in other models as well, model systems as well,

such as mice.

And so there are actually patients, people out there, not patients necessarily,

people out there that deliberately restrict the number of calories they take

in because this does appear to extend your lifespan.

Those of us that really like chocolate don't really like this answer,

I don't like it.

I would prefer to eat as much chocolate as I like.

And so there are clearly other mechanisms as well that are being under

investigation.

For example, anti-inflammatory drugs.

So many patients are on aspirin all the time.

This thins the blood a little bit, as well as being anti-inflammatory.

And we know chronic inflammation happens with age.

And if you can reduce that, you may reduce some of the signs of aging.

And also, because there's a potential interrelationship between

chronic inflammation and epigenetic changes,

maybe there'll be some other beneficial side effects.

And aspirin, other than being rather troublesome for

the stomach unless it's enteric-coated, doesn't seem to have severe side effects.

But there are also many labs in

many places around the world that are looking for stem cell therapy.

So can we use stem cells to boost our stem cells again?

This is more, instead of looking at maybe those original

causes of aging that cause the damage when we're thinking about the hallmarks,

this is more looking at the phenotypic level.

Can we restore some stem cells to give back some cells that might be able to help

with wound healing, or help with other aspects that are unrelated to aging?

So I hope this has really piqued your interest in this

field of epigenetics and aging.

There are some reviews that we've given you online so

that you can read about this a little bit more broadly.

And I hope it promotes some active discussion within the discussion forums

because it's something that affects all of us and an area that's a very current and

active area of research.

7.11 Extension lecture: Aging - Part 2

Epigenetic Control of Gene Expression

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