The epigenetic code
Virtually all the cells in our bodies contain the same DNA. This is the same DNA we were given when we started life as the fusion of an egg and sperm, with half our DNA coming from mum and half from dad. But we have hundreds of different types of cells - from blood to bone, liver to lung and everything in between. So how does this huge diversity arise if all these different cells have the same DNA?
To get some answers I spoke to Professor Tony Kouzarides from the Gurdon Institute at the University of Cambridge.
Tony - Well, the first thing to say that differences come down to different parts of our DNA being turned on and off - in other words, different genes in different types of cells. What we now know is that there's a crucial part of a cell that allows this turning on and off which is a set of proteins called histones around which the DNA is wrapped up. So the DNA is not naked. It's actually occupied and entangled in a set of proteins that control its activity.
Kat - So, it's like a massive load of string actually being organised and wrapped up.
Tony - Yes, DNA is very, very long in each of our cells and has to be put into a very small area. It's about 2 metres long. Each DNA in our cell is 2 metres long.
Kat - And a cell is absolutely tiny.
Tony - It's really, really tiny. And the only way to actually fit the DNA in is to compact it around these proteins. Now because it's very, very dense in these cells, one of the ways in which it has to be controlled is to unwind it and allow a gene to be available to be turned on and off. So, it's like being camouflaged in this compact structure.
Kat - It has to be unwound so that you can read it, so you can actually do something with the gene.
Tony - And use it, that's right. So, genes have to be used and they have to be unwound to be used.
Kat - So, what do we know so far about how DNA is packaged up and some of these signals that are put on it to tell a cell whether to use it or not use it?
Tony - Because it is packaged, there are signals that allow it to be unpackaged and these signals can be coming from the outside that could be environmental, that could be cellular, and they end up by being small, very tiny changes in these protein called histones, and on the DNA ,which allow the unwinding. But also, allow the machinery to come and tell the gene to turn on and off. So there's machines, cellular machines that come and use DNA and make products or turn off products and these are signalled to by these very small changes in histones.
Kat - I've seen images of these and you sort of have the DNA as a string wrapped around these balls of histones, and it's almost like you have little chemical flags on the surface that say, "Here we are, come and use this one. Don't use that one." Do we now really know a lot about the identity of these flags and how they work?
Tony - Well, we know quite a lot about the identity. There's many different types of marks as we call them on chromatin which is the structure - this histone/DNA structure is called chromatin. And what we know a lot about is the enzymes that put on these marks, the different changes on the histones. These are very interesting enzymes because they control many biological processes. In fact, almost all biological processes that involve the regulation of DNA deal with these enzymes, or the other way to look at it, these enzymes control all the biological processes that DNA is involved in.
Kat - So a gene is not going to get switched on without these enzymes, and it's not going to get switched off without these enzymes too.
Tony - Yes, these are crucial enzymes and now, we're discovering that these enzymes are involved not only in the normal way that a cell works, but actually, are misregulated in any disease. Primarily, the one we know of cancer.
Kat - So, what sort of changes do we see in these histone marks in cancer cells?
Tony - Because there's so many of these little changes, we can categorise them and catalogue them, and we can start to understand how they change. But really, that's just cataloguing. What we now are looking for is the genes that change when these enzymes that have put these little tiny marks on are damaged in cancer cells. So, the important thing is the genes that have changed rather than which marks are where.
Kat - You can almost embark on some kind of grand cataloguing thing and say, "This changes, this changes, this changes..." But if it's not actually changing the patterns of which genes are on and off, then it's not making a difference.
Tony - Exactly, and the way we know that the genes are important because now, there are small tiny molecules that can affect these enzymes. So, these are pharmaceutically relevant inhibitors for example of enzymatic activity, you kill the enzyme by adding this small thing to the cell, small chemical, and then you can see that a very small number of changes in genes that come on and off. So then you know that those genes are important in cancer and they are driving the cancer itself.
Kat - And presumably then these molecules, these chemicals that you have that can change these patterns, could they potentially be useful for treating cancer?
Tony - Well in fact, that's the whole point of developing these molecules, because pharmaceutical companies now realise that this area is very exciting with respect to pharmacological intervention against cancer. And therefore, they're developing these small molecules to treat patients and we as a lab are collaborating with these companies to work out exactly how these small molecules work to inhibit cancer.
Kat - We first discovered the structure of DNA in 1953 when Watson and Crick figured out that it was a double helix. What happened after that? How long did it take to really figure out this level of regulation of DNA and how it's controlled?
Tony - For some time, it's been known that the DNA is packaged into the cell in this way by wrapping around histones. But really, the modern era of regulation came when the first enzymes were discovered that put down these little marks that change genes, and this was in 1996. It's a very new field and it's progressing very rapidly because a lot of scientists are realising that all the work that they've been doing in the past may relate to how chromatin and histones change, and this is called epigenetics.
Kat - What do you think the potential is for epigenetic-changing drugs in the future for treating cancer and treating other diseases?
Tony - I think it's a major untapped source of targets for many, many diseases, and it's really the tip of the iceberg with what we know at the moment. It's a bit like saying, 'genes control everything'. Well actually, they don't. Our environment controls a lot of what our genes do and this is the missing link - how is it that external events can actually control what our genes do and how our genes can be misregulated in disease. That comes all down to epigenetics.
Kat - That was Professor Tony Kouzarides from the Gurdon Institute at the University of Cambridge.