Peter Jones - DNA methylation
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 tackled the wonderful world of epigenetics in last month's podcast, exploring some of the ways in which genes get turned on and off during development and disease, and now it's time to turn our attention to one of these marks in particular: DNA methylation.
As has become increasingly clear over the past few decades, there's more to life than the four chemicals letters, or bases - known as A, C, T and G - that make up DNA. These letters can be modified in certain ways, primarily by the addition of a small chemical tag known as a methyl group to the letter C. This modification is known as DNA methylation, and it's thought to play an important role in controlling how our genome gets used during normal development, life and disease.
To get the low-down on the mysteries of methylation I spoke to one of the leading experts in the field - Professor Peter Jones from the Van Andel Institute in Michigan.
Peter - The presence of 5-methylcytosine, in other words, covalently modified extra base in DNA, was really found I think more than 60 years ago. But exactly 40 years ago in 1975, there were two papers that appeared - one by Robin Holliday who was here in England and one by Arthur Riggs who was in Southern California, postulating that these chemical marks on DNA could have information coding properties. In other words, they could specify which genes would be used and which ones would not be used. And very importantly, in these prophetic papers, they proposed a mechanism for inheritance. So, the idea was that as you know, you inherit your genes and then methylation patterns put on the DNA during development which tells cells what they should do and what not to do. Just like the genes could be replicated, the methylation pattern can also be copied and replicated. So, these two papers really stimulated the field. I got involved in the field completely by chance. I was working with a drug which was developed in Prague, in Czechoslovakia in the late '70s. We found that this drug could change the differentiated state of cells very markedly.
Kat - So, it would make them forget what they were meant to be doing.
Peter - Well actually, better than that. You know, telling them to do something else. They didn't only forget what they were but they did something else. Actually, they were non-descript cells growing in a culture dish and we could change them into beating muscle and fat and cartilage. So, we'd had no idea how this could possibly be. It was very unusual. But then when we looked into it in more detail, we discovered these papers that I just told you about and we're able to figure out that the way these drugs worked is they worked as erasers. They got into the DNA, they removed the methylation from the DNA because they inhibited that process, and then the cells went ahead and did their thing, and put in new methylation patterns and became either muscle, fat or cartilage. And so, these experiments and those of Adrian Bird and others were really important in showing two things. First of all, that the patterns could be inherited and secondly, that they could be changed. And if you changed them, it had major impact on the cells.
Kat - One of the ways I really like thinking about DNA methylation, it's almost like a kind of post-it notes in the recipe book that kind of cells remember somehow that they're going to use these genes and not use that gene, and they need to keep remembering to do that. Where have we come from those early discoveries that there were these kind of marks on DNA and they could be taken off, and that cells could then do new things?
Peter - Well, those were really hypotheses and they turned out to be essentially correct. So, I think what we've done in the last few years was figure out how the patterns are copied. We've worked out how these patterns are really important in telling cells apart from each other. We have found much to our surprise that these patterns are fundamentally altered in human cancer and in fact can be used to silence genes which are important in the development of cancer. So that in fact, cancer can develop because its methylation patterns are altered. And so, it's been a really interesting few years. Also, more recently, the drug that I just told you about - 5 azacytidine - is now being used in patients to treat cancer. And so, we've gone the full loop from an idea in 1975 to 30, 40 years later actually having drugs in the clinic which can be used to treat cancer in people. So, it's a very exciting time.
Kat - What do you think are still some of the - I guess, the known unknowns, the questions that you still really want to answer?
Peter - I think the questions are still very, very substantial. We don't know the very, very fine detail of exactly how cells can put these patterns on in a precise manner. We don't know exactly how the cells can recognise the patterns. We know they're altered, we know they're there, we know they're useful, we know they're deranged in cancer, but we don't know all the real details of exactly how these patterns are applied.
Kat - With DNA methylation, it's a mark that's put onto DNA. It could be copied as cells divide. What do we know about the possibility that it could be even passed on say, from parent to child because this is a really exciting but quite weird area, I guess?
Peter - Yes, it is exciting and I would also say it's not at all clear the extent to which that really happens. I think that there is a lot of interest in that area, particularly with the public. The public likes to hear about things like that, you know. But I think the evidence at the moment is in my opinion, unconvincing. We have a long way to go to be sure whether in fact that can happen because what happens is, when cells get through the germ line, when they make the sperm or eggs, the methylation patterns are essentially erased. They reset, they rejigged in such a way that you can make a human being. As part of that process, most of the changes that might have occurred earlier on are actually erased. But there are people that believe that this can happen and I would say the jury is still out.
Kat - The other things that we sometimes see in the paper, we hear the word epigenetics, we hear about maybe DNA methylation and it might be possible to change it, for example, influence it through what you eat or drink. What's the evidence on that? Can I pimp my genome through my diet?
Peter - That's a very good question as to where the diet influences the epigenome. So yes, there are experiments which seem to show that. There have been experiments done in pregnant mice for example which show that if you alter the diet of the mother, you could change methylation patterns and influence various properties of the mice. But the generality remains very, very unclear. And so, there's a long way to go, again, very controversial area. Some people believe in it, others don't.
Kat - So I guess, if a good scientist, we have to do the experiments and get the data.
Peter - Yes, I would absolutely agree that that's necessary.
Kat - How do you feel about working in this field that's taking our understanding on how genes works so much further than the four letters of DNA into this sometimes seemingly, almost magical world of taking the genome that's in all our cells and then using it in so many different ways?
Peter - Well, I found it extremely exciting, the fact that we can now begin to understand to a certain extent how this works. But yes, it's very, very exciting and then to understand its ramifications, not only in normal human development but also in abnormal development and in late onset diseases which is what I think we now need to look at. Is there a role for changing DNA methylation patterns in the genesis of those diseases? We don't know, but we're beginning to look.
Kat - That was the Van Andel Institute's Peter Jones, and we'll be hearing from one of the scientists he mentioned - Adrian Bird - later on.