The Festival of Genomics and Biodata is just around the corner, and we’ve had the opportunity to sit down with some of our expert speakers to get a sneak peek into what they’ll be discussing, and why they think you should come along to the event.
In today’s interview, we speak to Aarti Jagannath (Associate Professor, University of Oxford) about the importance of sleep and circadian rhythms in health and wellbeing.
Register for the Festival of Genomics and Biodata here.
Please note transcript has been edited for brevity and clarity.
FLG: Hi everybody. Today, we’re joined by Aarti Jagannath, who will be joining us in January at the upcoming Festival of Genomics and Biodata. Aarti is going to be giving us a really exciting talk, and we’ve got some time with her today to get a little bit of sneak peek into what she’s going to be discussing. So Aarti, could you kick us off with an introduction to yourself and your career?
Aarti: Thanks, Lyndsey. I’m Aarti Jagannath. I’m an Associate Professor at the Nuffield Department of Clinical Neurosciences at Oxford. I entered the field of genomics as a graduate student, where I was studying how genes could be switched on and off using RNA interference. From there on, I branched into circadian rhythms, where the opportunity arose to understand how genes link up behaviour and environmental signals through a genetic control mechanism, and that is where my lab focuses at the moment. We’re studying circadian rhythms and sleep from the perspective of how the environment, through genes, can ultimately control behaviour. Do you want some more background on my career so far?
FLG: If you’d like to give us some that would be great!
Aarti: I grew up in India, and my undergraduate degree was in India, after which I came to Oxford to do a DPhil on RNA interference, as I mentioned earlier. And from there on, I developed an interest in circadian rhythms, and I worked with Russell Foster here at the University of Oxford. About seven years ago I was awarded a fellowship from BBSRC to set up my own research lab working at this interface between sleep and circadian rhythms, and genes and control mechanisms.
FLG: It sounds like a really interesting topic, but what sparked your interest in sleep and circadian rhythms?
Aarti: It was at the time – which was about 10-12 years ago – a field that was just coming of age. In terms of, we had a good understanding of what the circadian clock was, and this fact that there was a set of genes that oscillated to then control behaviour was known, and that, in itself, was a really fascinating finding. But for me, the opportunity lay in trying to understand how these genes are actually sensing the environment and set to the right time. Because we all have an internal clock, but that internal clock has to report the correct time, and for this, the genes that underlie the clock have to be sensitive to environmental input. That opportunity was there to try and understand what this system was and how it shaped up.
More broadly, the clock and sleep are two such fundamental processes for health and well-being, but also in terms of biology, they’re such a good opportunity to try and understand how it is that genes can control really precise and highly quantifiable behaviors. So, the timing that the clock establishes is something that’s very discrete, very quantifiable, as is sleep. To have that system to play with, to understand exactly how genes control behaviour, was a really interesting place in which to be, to do research.
FLG: It sounds like sleep is a lot more complex than perhaps we give it credit for! Your research investigates the gene regulatory landscape that controls the timing of sleep and circadian rhythms. Could you give us an overview of the key findings from some of your recent work?
Aarti: How sleep and circadian rhythms are timed is really a function of how light information gets from the environment to the clock genes. That happens by light being sensed through the retina, and then the retina timing the expression of clock genes within a discrete part of the brain called the suprachiasmatic nucleus. My lab’s work has really focused on what light does in the suprachiasmatic nucleus, and what signaling pathways and gene regulatory pathways ultimately are influenced by light. I’ll explain three areas of work that are our focus at the moment.
One is understanding the role of this kinase family that light regulates, so the kinase can then feedback both onto clock gene regulation, as well as multiple other synaptic units. Therefore controlling the neuron, both at the level of gene transcription, but also at the level of synapses and firing. This kinase family can really set the scene as to how light is perceived, and what sleep and circadian rhythms can then do within that landscape and within that framework. That’s one key area of research, which is this kinase family called the salt inducible kinase family.
Another is trying to understand the regulatory processes that light switches on, and then trying to find ways in which we can mimic that process. One recent [discovery in my] lab is that targeting adenosine signaling, which is essentially the same pathway that caffeine works on, switches on the clock gene transcriptional pathway in a manner that light also does. So, by targeting that system, essentially by providing the system with mimics of things like caffeine, what you can do is move the clock around. Essentially move the hands of the clock. That’s another area that we’re really excited about, and that has a lot of translational potential, obviously.
And finally, an area that I will talk in more detail about at the Festival itself is to do with the gene regulatory landscape, in the sense that the clock is essentially a gene regulatory mechanism that establishes a 24 hour oscillation. But other environmental cues, such as light, stress, your sleep state, all of these, switch on their own gene regulatory pathways that then converge at the level of chromatin. What we’re doing is profiling that chromatin architecture and trying to find the functional relevance of what those changes mean. Which factors interact? What is the molecular level at which, say, light and the 24-hour oscillatory system interact? What does that look like in terms of transcription factors, in terms of how chromatin is structured? How does this differ in different parts of the brain? And how do other factors like, say, stress or meal timing, how do they feed in? Does whether you’re male or female have an influence? We’re getting really fascinating insights about all of that by profiling chromatin architecture alongside functional readouts, and that is something I will talk more about at the Festival.
FLG: It sounds like it’s going to be a really exciting talk at the Festival, and it sounds like you’re doing some great work. And you mentioned there the translational potential of some of this work, which is obviously really important given the health consequences that a disrupted circadian rhythm could have. Could you give us any insights into the potential long term consequences of chronic sleep disruption and circadian rhythm disruption on brain function, and health in general?
Aarti: Sleep and circadian rhythm disruption can have really deleterious consequences. One important thing to keep in mind is we evolved with a fairly robust circadian and sleep system. We evolved tilling the fields and relying on the external light-dark cycle for all of our behavior. So, we are highly, highly rhythmic creatures that really follow the sun. But in the last 50 years or so, we’ve completely dismantled that. We live indoors, for example. Right now I’m talking about the importance of natural light in an office that’s entirely artificially lit, and so we’ve controlled our environments in a way that suits our 24/7 lifestyles. That, in turn, can have hugely disruptive consequences on the sleep and circadian rhythm biology, because that biology relies on light as a timing queue, so this disruption has now become really widespread in society as a result.
We know now what the consequences of something like this are, because this is really a new problem that we’re facing. Links have been found with pretty much every aspect of physiology; the clock controls cell division, so naturally, circadian disruption causes cancer, and we know now of very strong links on that side. Shift work is now a classified carcinogen, for example. We know that sleep and circadian disruption can precipitate various neurodegenerative conditions. And it’s always a bidirectional relationship, where people with neurodegenerative disorders also have bad sleep and circadian disruption, and they sort of feed into each other with this feedback loop. The same is true for many psychiatric diseases, schizophrenia, bipolar disorder, all of these present with significant sleep and circadian disruption, and the disruption can also trigger episodes in themselves. We know that there’s a cause and effect going on over there. Metabolic conditions as well, diabetes and weight gain and things. The biology that underlies this is all controlled by the clock, because we evolved as rhythmic creatures that received meals at certain times and processed them during the day, but took on rest and recuperation at night. Now, we’ve messed that up. Our clocks evolved to deal with certain levels of blood glucose and metabolites coming in at certain points of day, but since we no longer do that, that throws the system into disarray. So, we know that weight gain and diabetes are also consequences of sleep and circadian disruption.
FLG: Sounds like some of the pitfalls of modern life really can contribute to this.
Aarti: Absolutely. Yeah.
FLG: And how do you see your findings being applied in clinical settings to address those problems?
Aarti: I suppose there are a few different ways. An understanding of the biology that arises from our research, I think that in itself is very powerful in being able to provide the right advice. Modifying lifestyle can have a hugely beneficial effect, restricting evening light, timing exercise, timing meals, all of these things can help a lot clinically. How best to do that, and how to do that in a way that relies on evidence, comes from research like ours. That’s at the most basic and fundamental level.
In terms of specific targets, in terms of specific areas that we can then act on with, say, small molecule drugs, the knowledge for those pathways comes from our research. For example, by understanding the mechanisms by which light regulates clock gene expression, we know that targeting adenosine receptors is a smart way of getting into that system. There are small molecule drugs against adenosine receptors that can then be trialed in the clinic, and that’s something we want to do going forward. This is true for multiple areas in which we’re studying how clock regulation occurs, various kinases, for example, how they can be targeted. And in terms of gene regulatory networks, understanding which elements are the key nodes in those networks will tell us how we can intervene to reach those nodes.
FLG: Sounds really interesting. Onto a bit of a more technical question – your work focuses on a multi-omics approach. What would you say is the benefit of using multi-omics over just a singular omic?
Aarti: That’s a really good question. For us, it’s been really exciting to be able to see what comes out of looking at multiple different omics readouts. When you look at gene regulatory pathways, understanding chromatin architecture changes gives you the very top level of insight, but then understanding how that changes gene expression or how methylation patterns feed in, and how that then changes how the cell functions, is what really gives you an understanding of the functional relevance of those changes. For us – especially in terms of the clock – integrating all of these to then look at how clock gene expression and therefore clock targets behave is something we can only get from a multi-omic approach.
FLG: It sounds like it’s really important to have those different layers. And it does sound like there’s quite a complex interplay going on here, between circadian rhythms and a lot of physiological processes. What are the main challenges you face trying to study those interactions at a molecular level?
Aarti: One of the biggest challenges is that we use mouse models. And the master clock – which is really the area that we’re interested in, because that is the area that receives environmental information, collates all of it, and sends it to the rest of the body, saying, ‘this is your time cue,’ – that area of the brain is tiny. And so, for us, every technique that we thought about, we’ve had to spend a long time adapting to a really small brain region. It’s given us some really fascinating insights, but to us, that’s a big challenge in terms of technically, how we can get there? For example, with relevance to genomics, getting enough material for any single cell work or enough clean material that is just [from] that brain region to look at chromatin accessibility or the proteome. We’ve had to spend quite a long time adapting our protocols, trying to fit them so we get clean data from that brain nucleus. That is one challenge. The second is that a lot of the work that we do has to be a systems level approach, which means we need to rely on a human or an animal readout, not cell lines. So, the pace at which some of these things can happen is also probably slower than it would be in other fields, like, say, cancer, where you can do quite a lot with cell lines.
FLG: You mentioned earlier about how the circadian clock can pick up cues from the external environment. Can you explain some of the molecular mechanisms that are involved in that process, and how do they help synchronize the internal time with those external cues?
Aarti: The way light input works is that the only area in mammals that receives light information is the eyes, and so the eyes collect light information, as they do for the visual system. But there is another class of photosensitive cells within the retina that are separate from the visual system that then send the information on how much light there is, and how long this light is being seen, to the master clock. So, that’s a direct synaptic connection through glutamate receptors, and that then triggers cyclic AMP calcium-related signaling pathways within the cells of this master clock, within the neurons of the master clock, which then ultimately converge on clock genes. The clock genes that we’re talking about are called period, and their partners are called cryptochrome. And the way the clock functions is that period and cryptochrome oscillate with a 24-hour expression, and that oscillation of period and cryptochrome is driven by two transcription factors called clock and bmal. period and cryptochrome feedback onto clock and bmal through a negative feedback loop, and that loop takes about 24 hours, and that is what sets the 24-hour oscillation. Light, by controlling the levels of period directly through the pathway we just talked about, then makes sure that the oscillation is aligned with the outside light-dark cycle. That is why light at night has a detrimental effect, because your clock then is responding to that light by switching on the clock genes at a time when it really shouldn’t be.
FLG: And you did touch on this. But in your opinion, what are the most significant environmental factors that influence the circadian rhythm, and how can we go about aligning our behaviours with those natural cycles to improve our health?
Aarti: Light is the most important time cue to the circadian clock. In terms of behaviours, seeking natural light during the day, preferably in the mornings every day, is something that’s incredibly powerful, and probably some of the strongest signals that you can give the clock. For me personally, it’s very difficult to actually put in practice what you say, but having got a dog and being the one that’s the designated walker in the mornings, I can see has made a big difference to my own sleep circadian health. Then the two other factors that have a big influence are mealtimes and exercise. Each person is different, so one size doesn’t fit all and everyone doesn’t necessarily have the same clock to respond in the same way to exercise at set times. Nevertheless, keeping those as far as possible within a routine and keeping that routine to what would be the natural day is more likely to have a beneficial impact on aligning your clocks with the natural world.
FLG: That sounds like really good advice, and it does make sense. You’re really touching on what you said earlier, modern life, artificial light, working schedules can all make that really difficult, and I imagine must make it quite difficult in your research as well?
Aarti: Absolutely, yes.
FLG: Now, reflecting on your career, what would you say has been the most exciting or groundbreaking moment for you?
Aarti: I guess the most exciting times were the ones that actually got me hooked into science in the first place. One example is where, as I was saying, we were studying this kinase pathway that regulates how light is perceived by the clock, or how strong that light signal is. Our hypothesis was that if you switch off this kinase, the amount by which light will shift your clock genes will greatly increase. And for me, as a young scientist, we first did that experiment and then saw that we’d essentially cured jet lag in mice, and we could see the mice re-train their clock to a shift in the light-dark cycle. For example, we simulated a flight east to Thailand after switching off this kinase using RNA interference, and we saw that the mice instantly jumped to the new time zone. That was really exciting. It was really lovely to see, because it was literally that bridge for me, from environmental light through to an actual gene that we could then manipulate, and that that was really exciting. So, for me, that’s been groundbreaking, and since then, it’s been many incremental steps that are all very exciting.
FLG: That does sound really exciting. I suppose, seeing that direct correlation between your research and things that happen in real life, it puts it in perspective. It does sound really, really great. And as I mentioned earlier, you’re speaking at The Festival of Genomics and Biodata in January, what are you looking forward to about the event, and why would you encourage people to come along?
Aarti: For me personally, it’s an opportunity to interact with people who work in this area but are not from my field. I’m coming to this as a behavioral neuroscientist and not as a geneticist, not as somebody who works on genomics. To interact with people who use genomics in this way to answer their own research questions, which are completely different to me, is the most exciting draw, because I think this is going to be hugely enriching for me to understand how people apply the technology there is, and how far you can take it to answer outstanding questions in biology. For people to attend, in general, I would say that this is such an exciting place to be at the moment, because we know what genome sequences are, but how they behave, how they interact, where does the specificity come from, why do we have so much dark DNA over there, and what are these 3D interactions actually doing to me? This is a whole wide world of research now that’s just opening up. Any young scientist interested in taking the next new thing on, the next big thing on, I think would find the Festival a great place to be.
FLG: Thank you very much. We’re really looking forward to having you with us in January and we’re really excited to hear your talk. Thank you again for taking the time to speak with us today.
Aarti: Thank you. And yeah, I’m looking forward to it.
Register for the Festival of Genomics and Biodata here.
