7.7 Altered expression on piRNAs and long noncoding RNAs in cancer

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Epigenetic Control of Gene Expression

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The University of Melbourne

Epigenetic Control of Gene Expression

397 ratings

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

From the lesson

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

Meet the Instructors

Dr. Marnie Blewitt
Head, Molecular Medicine Laboratory
Walter and Eliza Hall Institute of Medical Research

Okay, so we've spoken about aberrant DNA methylation, aberrant histone

modifications and even histone mutations, mutations and histone variants, and a

little bit about nuclear architecture. And now, we come to consider the

noncoding RNAs, this extra arm of the epigenetic machinery.

So, noncoding RNAs, exist in many classes, as you remember we've spoken

about previously microRNAs are indeed globally misexpressed in cancer, but

we don't really consider them to have an epigenetic role because they

are involved in post transcriptional silencing.

They don't alter the epigenome, itself.

As opposed to piRNAs and long noncoding RNAs, which indeed do alter the

epigenome. So we're going to be thinking about,

first of all, very briefly, about piRNAs, and then about the long noncoding RNA

HOTAIR. Just like with histone variants, or

histone modifications and nuclear architecture, we don't yet know a huge

amount about the role of noncoding RNAs in cancer.

But we have some, some preliminary findings which are quite interesting.

So, just to remind you about piRNAs because it's been several weeks since

we've talked about them. piRNAs are expressed from transposons and

they tend to be expressed in a bidirectional manner.

They are processed and then they can either result in post-transcriptional

gene silencing like micro RNAs can, or in some cases, they can be imported back

into the nucleus. And they can result in RNA-directed DNA

methylation, and this is when they're having an epigenetic effect.

So it's interesting that we know that piRNA expression is deregulated in cancer

in general. So, what we want to think about is what's

the role of piRNAs, normally, they're silencing repeats.

So, do we find aberrant expression of piRNAs because they repeat, tend to be

hypomethylated and often active, or is it because there's a relationship between

piRNAs, and stem cell biology and cancer. So, many people think that cancer may

have some sort of a stem cell origin or at least that cancer cells have a bit of

a stem cell like behavior. That is they're very good at renewing

themselves and they're don't exhaust prematurely, so they can continue to

divide. So, we know piRNAs are expressed in stem

cells and they have an important role in stem cells like they do in the germline.

So, we don't yet know much about how this works.

But it's certainly possible that the, the deregulated piRNA expression has

something to do with those the altered repetitive elements or the stem cell

behavior of cancer. That's really all we know about piRNAs

and cancer at the moment, unfortunately. We know just a little bit more about the

long noncoding RNAs. Again, like piRNAs, they're globally

deregulated, but what's the consequence of this global deregulation?

In most cases, we don't really know what the consequence is, it's just been found

that they might be overexpressed or underexpressed in a particular type of

cancer. Although, in some cases, we know that

this has a particular prognostic outcome. So, it may be associated with poor or

favourable prognosis. So, just like I mentioned at the

beginning of this, this week, if we don't yet know the molecular mechanism by which

something acts, but we still know it has some sort of consequence for the patient.

In other words, it's associated with a good prognosis or

associated with a poor prognosis, that can still be quite a useful piece of

information, while we can go back and try and find out what's happening at the

mechanistic level. The example I would like to give you

where we know something about the molecular mechanism with the long

noncoding RNA that is overexpressed in some cancers is for HOTAIR.

So HOTAIR, I mentioned when we spoke about the long noncoding RNAs in Week 2.

HOTAIR air is a long noncoding RNA that it acts in trans and so, it's quite

unusual in that sense. It appears to act as a scaffold, because

it binds to both PRC2, which you'll remember lays down H3K27 methylation, and

to LSD1, and LSD1 demethylates H3K4 methylation.

So, what you see here is PRC2 is laying down an inactive mark and LSD1 is

removing an active mark. So HOTAIR can bring these two complexes

together, and therefore, really consolidate silencing at the target

genes. So normally, HOTAIR is expressed from the

HOXC cluster, but then it acts on the HOXD cluster.

This is why it's acting in trans. Okay?

So it seems to act like a molecular scaffold acting in trans, but potentially

has some sequence specificity because it's still acting on a HOX cluster.

What we know about in cancer is that HOTAIR is overexpressed in breast cancer,

and it's particularly associated with metastasis.

In this case, what seems to happen is, if you overexpress HOTAIR in vitro, then it

will re-target PRC2, they didn't test LSD1 unfortunately, but it re-targets PRC2.

What ends up happening is that the gene expression in those cells changes and it

looks more like when HOTAIR is normally expressed when it would, would happen in

embryonic development. So HOTAIR is being expressed in breast,

but it's creating a gene expression signature of more like an embryonic type

of cell, an embryonic fibroblast in this case.

So this suggests that it's not just HOXD which is it a target for HOTAIR, in this

instance of breast cancer, but rather other genes, because what you see is that

metastasis suppressor genes tend to be silenced.

And this might, might be why you have an association with increased metastasis

when you have increased HOTAIR expression.

So potentially, HOTAIR is binding not just to HOXD, but also these other

regions with which we don't know whether or not there is or is not any particular

identity between this transcript sequence and this region in these, in these genes.

It remains to be determined. So, this is a very interesting finding

with relation to breast cancer, but I guess, oftentimes you'll want to know

does this really hold true more broadly or is it just some weird thing that

happens in one type of cancer? And what's being become clear relatively

recently is actually HOTAIR expression is a poor prognostic indicator because of

this assocation with metastasis, not just in breast cancer but also in esophageal

cancer, colon cancer and liver cancer. And so, this mechanism needs to be

established. How is it that HOTAIR is being targeted

to these other regions in the context of cancer?

So, what can we do with this knowledge for HOTAIR, or indeed, for any other long

noncoding RNA? Well, if we just note that it happens to

be associated with a particular prognostic outcome, but we have no real

measure of why that is, or we don't understand yet the molecular mechanism.

We could still use the expression of long noncoding RNAs, whether they be aberrant

overexpression or aberrant decreased expression diagnostically.

So you can detect long noncoding RNAs in in samples if you need to.

And actually, there's already one that's being used diagnostically, and that is

the expression of PCA3. So, this PCA3 is indicative of prostate

cancer, but you can detect PCA3 in the urine.

And this is really good because it's a non-invasive test, it's not even as

invasive as a blood test. It's certainly not nearly as invasive as

having to have a biopsy taken of the prostate itself.

So this is a useful diagnostic test that uses this long noncoding RNA and here's a

picture of this PCA3 long noncoding RNA. Long noncoding RNAs always have this

quite elaborate secondary structure and it's thought that this is how they might

act as some sort of a molecular scaffold because they have so many binding

surfaces a bit like a protein might. But what about therapeutically?

If we know, HOTAIR appears to have an poor prognostic outcome and maybe

mechanistically because it's re-targeting epigenetic modifier complexes.

What could we do about this at the therapeutic level?

Well, we actually know that you can knock down long noncoding RNAs.

In other words, you can reduce their expression with particular other RNAs.

And so, potentially, these could be used in vivo for therapy if it can be worked

out exactly to deliver it to the right cells or to make sure that we can get it

into the cells effectively. And this is something that's being looked

at by pharmaceutical companies at the moment.

So, now, we've spoken about all the different types of epigenetic

modifications we know about and how they go awry in cancer.

So to summarize what we've said so far then, in terms of DNA

methylation, we see genome-wide hypomethylation.

This is predominantly at the repeat, or at the intergenic intervals.

We see tumour suppressor gene hypermethylation.

In terms of histone modifications, there are particular genome-wide alterations,

you see. But you see also gain of silencing marks

and loss of activation marks at the same CPG islands that are methylated.

We know there are actually long range alterations to epigenetic controls.

There are whole regions, megabase regions, that will be silenced or

activated in the context of cancer. And wee know that there's aberrant

nuclear architecture and altered expression of the long noncoding RNAs.

So altogether, this means that essentially, every level of epigenetic

control that we've spoken about over the past five and half weeks now has gone

wrong in cancer. So in the next lecture, I'd

like to start thinking about, although we don't really have an answer to it yet,

how is it that all of these epigenetic aberrations come about?

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