Robin Allshire -Spools and strings

Kat - This month I'm reporting back from a fascinating meeting I went to up in Edinburgh, a Wellcome trust Waddington Symposium entitled "Epigenetics in dialogue with the genome".  We're starting to hear the word epigenetics used more and more frequently, but what does it mean, and what's it all about? A lot of the talks at the conference were centred on so-called epigenetic modifications of DNA - chemical tags that are put directly onto DNA, or onto the spool-like histone proteins that package it up, which are associated with changes in gene activity such as when genes are switched on or off. To find out more about these mysterious marks and how they work, I spoke to one of the organisers of the meeting, Robin Allshire from the University of Edinburgh.

Robin - Our DNA is not just a naked string. The best analogy I can come up with is you wrap it twice around a spool, there's a gap, it gets wrapped around it again, wrapped around it again a bit like beads on a string. You can have these chemical adaptations that cause it to close up or to open up. The debate is whether those adaptations, these additions of chemical groups onto the spools themselves are instructive. In other words, do they force the DNA to shut down? Are they just weak signals of some sort that are helping repression but are not the main driving force? So, in my point of view, what we really want to find out is whether these adaptations or marks, if you want to call them, on the spools actually can carry information through cell division.

Kat - So, let's go into a little bit more detail then. So, we've got their DNA. It's this long string of letters, of bases. It's wrapped around these spools. Tell me a bit more about them and the kind of marks that we can find on them.

Robin - So, these spools are made up of proteins and there are 8 individual proteins that makes up a spool, two of each type, and they're called histones. Those histones form a blob, basically, that the DNA wraps around. But they have these extensions that hang outside.

Kat - You're waving your hands around, like kind of octopus tentacles.

Robin - That's what they're like! That's the way I imagine them in my head. So, you can have adaptations that clamp those tentacles down onto the DNA. They maybe hug neighbouring spools so they're more tightly locked and you're going to have adaptations that cause them to wave around like crazy so that it says, "Come and get me and turn me on."

Kat - So, everything kind of loosens up and that the gene can be read.

Robin - Yeah, exactly.

Kat - So, it's all about kind of combinations of these marks, the tails, how open and close it is, and then all these molecules that are recognising them and locking them down. It all seems complicated.

Robin - So for example, you can generalise to some extent with respect to one of the type of chemical marks which is acetylation. In general, acetylation promotes gene expression. I like to think that it sorts of oils of these tentacles and loosens them off. But again, it can bring in various machinery that opens up then the spools, allowing the DNA to be read.

Kat - What do we know about how these marks can be propagated as cells divide or even as organisms divide and reproduce because it seems to be quite a controversial area? What do we know and what do we not yet know?

Robin - These are chemical marks on the histones are very frequently, referred to as epigenetic modifications. The word 'epigenetic' means many different things to different people. A strict definition is the propagation of a state without the presence of the inducer that enabled that state. So, the question becomes whether these marks can actually be copied during the process of cell division so that both daughter cells have an exact copy of the marks.

Kat - So, if a skin cell divides, it makes 2 cells and they know that they're meant to be skin cells.

Robin - Yeah, exactly. So the question is, can the more actually be recognised, so as the cell goes through division, you have to deposit or assemble, make new spools on the new DNA, and can you copy the marks from the pre-existing spools that were there so that they take on the same state?

Kat - And can you? This is the big question, isn't it?

Robin - So, this is the big question. So recently, what we've been able to do in a model organism, fission yeast, we have tested this in a very simple way where we artificially bring the enzymes - so that's the proteins with an activity that puts a certain chemical mark which is called lysine9 methylation on a specific part of one of the histones in the spool - what we were doing is we artificially bring it somewhere and then we're able to get rid of it. Then when we get rid of it, the question is, can it be copied? In normal cells - so wild type cells - it cannot be copied. But then we ask, "Can we make it be copied?" what we did was we took away an opposing activity that removes that mark. When we take it away, now we see that it can be copied. Not only is it copied for one cell to two daughter cells, we can see it being copied for many cell divisions and we're going to also see it go through the process of meiosis.

Kat - That's kind of yeast babies?

Robin - Yes, yeast babies.

Kat - Well, it sounds to me like there's a lot of molecules that are putting these marks on, taking them off. There's this balance between the copying and the removing, all these kind of things. It feels like a very complicated field. Where do you think the really big questions are, the things that really need to be sorted out?

Robin - Well, so one of the things that people are trying to figure out is, whether these modifications are instructive in the sense of responding to environmental differences or pressures for example in a plant temperature or geographical location. In us, in people, you could say whether you've got high fat diet or a low fat diet. That's a very active and hot area at the moment where people are trying to see, is there an underlying contribution of these type of events  - for example, there's lots of studies that show that diet can influence traits in children but then the question becomes is that just because they were developing in the womb of a mother who had a bad diet or smoking too much, or whatever, so environmental effects. So, the real test is whether it can be transmitted via the father through his sperm because of his bad habits. What we found at this meeting actually is that there seems to be some interesting things happening in that area and I think that's a big hot topic for the future.

Kat - What's it like to be part of this now?

Robin - It's exciting and there's various controversies that need to be sorted out but that just adds to it - scientists are naturally questioning both in terms of asking how something works but also questioning whether the way we think things work is actually the way they do work. And we're all the time tearing down the models that we create. That makes it exciting because we're still trying to figure out things. It hasn't gone stale. There's a lot of things to find out yet.

Kat - That was Robin Allshire, from the University of Edinburgh.