De-activating chromosomes to prevent cancer

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Published: 21 Jul 2015
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Dr Philip Avner - Head of EMBL Monterotondo, Milan, Italy

Dr Avner talks to ecancertv at IFOM EMBL about his work looking at the epigenetic mechanisms that can lead to cancer and other diseases. His research seeks to understand why chromosome activation takes place and how they may be turned off to prevent their undesirable consequences.

My background is basically as a geneticist and I got very interested in early events in development and during that time started looking at some of the really marked events that occur which are programming the embryo and which are allowing cells to have different phenotypes, to have different characteristics at the level of protein expression, at the level of their behaviour.

Obviously that implies something beyond genetics and that’s called epigenetics, meaning beyond.

The paradigm that we have, or the best known paradigm that we have for that, is something called X inactivation.

X inactivation is the process that occurs in females; so females have two X chromosomes whilst a male has one X chromosome and one Y chromosome.

The Y chromosome has many less genes on it than the X chromosome, something like 30 genes only whilst the X chromosome contains 1,500 odd genes on it.

So the question is now why does a cell that has two X chromosomes behave in the female, behave more or less in the same way as a male cell which has only one X chromosome.

Because if we think about other clinical syndromes that we know like, for example, Down’s Syndrome where the presence of an extra copy of the chromosome, so three copies of chromosome 21, has some very important clinical effects.

So why does having two X chromosomes not have clinical effects for the female as opposed to the male?

The answer to that question is because one of the X chromosomes is going to be totally turned off so that it’s not going to produce any proteins, not going to produce any RNA and therefore essentially both cells have one functional X chromosome, even if in the female there are two chromosomes that are present.

What can you tell us about the activation of chromosomes?

There are two basic processes that are known.

One of them is called imprinted X inactivation and in that process there’s a parental effect that’s superimposed on the decision of X inactivation.

So when you have imprinted X inactivation the X that’s going to be chosen to be inactivated always comes from the father and not from the mother whilst later on in cells that will go on to give the embryo proper and develop into the foetus and then develop into the adult, those cells are going to have what we call random X inactivation because either the paternal X, that’s the one from the father, or the maternal X, the one from the mother, can be chosen in any particular cell at the stage when that inactivation takes place.

What have you been looking at in your lab?

We’ve been looking at the very earliest stages here which involve a class of RNA, so the intermediate between the genes and normally making proteins, but there’s a class of RNA that doesn’t go on to make protein and these are called non-coding RNAs.

We know now that there are short or small non-coding RNAs and there are very long non-coding RNAs.

A lot of our activity has been around a molecule or a non-coding RNA which is called Xist which is a very big molecule, one of the biggest known, and was one of the first non-coding RNAs to be discovered early in the 1990s but we still don’t really know how it works in detail and we don’t know what parts of the molecule do what.

So we’re looking at the process to see how X inactivation is actually started by the upregulation of this, that’s to say we make more of Xist in the cell, and somehow this leads to an initiation of a very complex process which is going to turn off the X chromosome and turn off this copy of the X chromosome in a very stable way so that it will remain completely turned off, completely transcriptionally silenced, despite going through many thousands of generations of cell division.

How can this be applied to disease?

What we hoped would be one of the things that would come out of our type of research is that some of the findings of how these long non-coding RNAs work would be transferable in some form to the clinic.

So that may be in different ways.

You can imagine, for example, and this has been one of the early hopes, that if somebody is carrying a gene such as, for example, Duchenne muscular dystrophy in a female where they have one copy, they’re carriers for Duchenne muscular dystrophy mutation but they have one X which is also functional, that maybe you could transfer or turn off the gene that’s carrying the mutation and activate the X chromosome that’s carrying the non-mutated copy.

So that’s one idea that if we could move at least in a certain class of carrier females we could do something.

Then obviously this is the hope that if we understand how we can turn off bits of a chromosome or very large bits of a chromosome, a whole chromosome, then maybe we could use that type of mechanism to try and turn off genes in cancer or in other clinical situations and therefore regain control of the cell in some way.

So it’s not the panacea for everything but it’s one other mechanism that will be part of the arsenal, part of our armoury, that could be used eventually in the clinic.

And there are a number of groups that are working on this that way.