Professor Vardhman Rakyan has been pioneering epigenetics research since 1999 when he undertook his PhD on epigenetic inheritance at the University of Sydney under the supervision of Professor Emma Whitelaw. This was followed by a postdoctoral position at the Sanger Institute, UK under the guidance of Dr Stephan Beck, where he developed functional genomics tools for genome-wide DNA methylation analysis. Since 2007, Vardhman has led his own research group at the Queen Mary University of London’s Blizard Institute.
We caught up with Vardhman to find out more about his latest research and to hear his vision for the future of epigenetics research.
What are your current research interests?
Our primary interest is understanding how the environment influences gene function. It is really all about interactions; we don’t just focus on genetics or environmental influences but the interaction between the two. Epigenetics is one facet that we are interested in as we feel it plays a key role in this process. However, the underlying genetics is just as important, as evidenced by how the environment can have an effect on one individual but no effect on another.
What particular environments do you study?
We do a lot of work with mouse models where we study developmental programming. We expose pregnant females to poor in utero diet and examine the effect that this has on the phenotype of the offspring in later life. In these experiments, we see that epigenetic marks are changing in response to that environment and that these key changes occur early in development in utero. This hypothesis is nothing new and has been validated by many independent studies.
Our recent interest is looking at the role of genetics in this process. We have found that the mice with different genetic make-up respond differently to receiving a poor diet. In one of the phenotypes we study in mouse, weening weight, we have identified genetic variation in the ribosomal DNA (rDNA) to be particularly important. What’s fascinating is that rDNA exists in many copies in mammalian genomes and each copy can be genetically different. We’ve found that mice with rDNA copies that have an adenine at a particular site in the promoter region will respond to the environment; however, those with a cytosine at the same site will not respond. We believe that during the environmental challenge, the adenine variant promoters attract more methylation, leading to silencing of the gene, whereas those with a cytosine at that position do not attract methylation and thereby show no alteration in phenotype in response to in utero insult.
What technique do you employ to specifically analyse rDNA?
We started off using reduced representation bisulfite sequencing (RRBS) and whole genome sequencing but then, as a result of this work, we were able to use targeted bisulfite PCR. What we can’t tell using this technique though is which specific rDNA copy we are looking at as we are analysing 100s of copies in aggregate. Short-read technologies cannot reveal that information as at most we will get a few hundred base pairs and rDNA copies are about 40kb in length. To overcome this, eventually we’d like to move into long-read sequencing for methylation studies.
What first ignited your interest in epigenetics?
It was by accident really, initially I had no burning desire to study epigenetics. During the honours year of my undergraduate degree at the University of Sydney, I worked on signalling receptors for ATP but knew I wanted to move into molecular biology and genetics. There were only 2 such labs in Biochemistry Department where I planned to do my PhD, and one of them was full; however, they suggested talking to Professor Emma Whitelaw who ran the other lab. She was a highly acclaimed with the epigenetic field and accepted me to do a PhD. However, the real turning point for me came in the mid 90’s when I first heard about the human genome project. Then, in 2003, the opportunity arose to work in epigenomics with Dr Stephan Beck at the Sanger Institute, which was incredibly exciting.
While epigenetics is central to my group’s research, I don’t always refer to myself as an epigeneticist. While it’s good to have an identity, you don’t need to be pigeon-holed. Our main aim is to understand gene:environment interactions and whatever molecular mechanisms are involved.
What do you think are the outstanding challenges associated with studying DNA modifications and epigenetics, and how are you approaching them?
There a number of challenges we try to address, covering both ‘research’ and ‘technology’. The main research challenge for us and other groups in the field is proving that any epigenetic change identified is causative of the phenotype. As for technological challenges, I think many of these will be addressed though long read platforms.
Single-cell work is also very intriguing but the costs are too high – at least for the work we do, which involves many individual samples. In our research, we look at an aggregate of all the copies of rDNA within all the cells so it is essentially averaged over 2 levels. The ideal technology would allow us to look at all copies individually on a per cell basis. This isn’t going to happen over the next couple of years, even though the technology is developing really quickly. However, it’s not just about the speed of technological development, it is about when it becomes affordable, that’s when it will kick off. Recently there have been several excellent papers that show what single-cell technology can do but, for truly meaningful insight into how gene:environment interactions happen in mammals and what that means at the population level, it is unaffordable.
What excites you most about the future of epigenetics?
From a technology perspective, the holy grail would be getting all of the genetic and epigenetic information from a single method. Research wise, the key is linking epigenetic changes to phenotype. We are at an early stage of defining this and we need to maintain momentum in order to retain interest in the field.
Is data analysis challenging? How do you handle data analysis?
There are many computational challenges, which are evolving in step with changes in experimental methodology. However, data analysis is generally becoming easier as some standards have now been established with accepted protocols but new challenges come up every day. I’m not a computational biologist but my work does require a lot of computational analysis and input. Traditionally, we’ve had computational biologists in the lab and we collaborate with others externally to ensure we have the access to the required expertise.
Recent research has suggested that 5hmC could be an effective biomarker for many diseases. What do you think the future will hold for epigenetic biomarkers?
The evidence suggests that 5hmC may turn out to be the most useful biomarker in many contexts. The big advantage of DNA methylation is that it is modifiable by the environment. It is also highly stable, so stored samples are a whole lot easier to analyse than by other techniques such as gene expression. I believe that, in time, DNA methylation based biomarkers will be used together with other assays as part of an integrated suite of diagnostic tools. If you integrate your genetics with methylation, changes in gene expression, microRNAs and circulating nucleic acids, you’ll get a more accurate picture of your health status – so I see it as one part of a larger suite of biomarkers. Integration is where we are heading. I can dream of a time when we have a wearable device that can sample your blood and monitor many things including DNA methylation.
I may be biased but I think our recent work on rDNA, which was published in Science is a very nice paper!
In the field of epigenetics, there have been quite a few interesting publications on the mouse epigenetic ageing clock that showed you can modify the clock to slow it down and speed it up using dietary and other interventions. Using the environment to change the rate of ageing is incredibly exciting.
There was a recent paper in Cell that showed ribosomes can bind lots of different proteins. This excites us as it may be linked to our findings that genetic variation within rDNA attracts different levels of epigenetic variation, which could ultimately influence protein production.
Finally, there has been a number of papers on non-mammalian organisms examining the transmission of environmental stresses from one generation to the next. They are getting a handle on the mechanisms involved, so for me, it is only a matter of time before we can sort out what is happening in mammals.
What advice would you give any young researchers entering the field of epigenetics today?
Firstly, I would say to always be open to new technologies. An old but true cliché is that the questions remain the same, it’s just our abilities to answer them that changes. Don’t get stuck using a method because you’ve done it in the past.
Secondly, at least early in your career, try to get into something that will help you address mechanisms. It’s easy to look on the surface, so experience of working on mechanistic biology will always hold you in good stead. Go for the interesting and hard questions not necessarily the easy ones.
Are you presenting your work at any conferences this year?
I have presented at a number of conferences this year including Barcelona, Sweden, the US and Switzerland. In September, I will be presenting our aging work at the ESVCN congress (20-23 September). This latest research shows that the rate of CpG methylation change correlates with lifespan across the mammalian species studies, including human, mouse, naked mole rat, whales, macaque, and dogs.
Where can we find out more about your research?
If people would like to find out more information about our group or to contact me, they can visit our page on the Blizard Institute website. The QMUL Epigenetics Hub also provides further information on the 7 epigenetics labs within Queen Mary University of London.
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