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Hi Akanksha, can you tell me a bit about yourself, your research and your path to Oxford?
I am a BBSRC Discovery Fellow, and my research is focused on understanding the molecular pathways involved in sleep and circadian rhythms. After completing my PhD in Genetics from the University of Leicester, I moved to the University of Southampton as a Research Fellow for three years, followed by four years at the Medical Research Council, Harwell as a Senior Post-doc. I'm now based in Aarti Jagannath’s lab at SCNi. My research focus is basically understanding the molecular mechanisms which are involved in daily time keeping, which seems to be central to our overall health and fitness.
Can you explain what you mean by daily time keeping?
Daily time keeping also known as circadian rhythm is the internal biological clock that aligns our behaviour and physiology with the environment, such as the sleep/wake cycle, and it is synchronised by environmental light. Our brain receives the light input, processes it and sends this ‘time-of-day’ information to other organs, such as the heart and liver, to set in motion a range of daily processes around the body. Research has showed us that there's a particular time of the day that is well suited for particular activities such as exercise and eating. Performing these activities at the right time of day is highly beneficial for overall well-being and fitness.
You may think sleep and dance are two completely independent things, but they have so much in common. I’m interested in how we can use the power of art to understand the biological mechanism.
What inspired you to focus on sleep and rhythms as your area of research?
It was a bit of serendipity. I was given an opportunity to do research as part of my doctoral research on epigenetics –something that is not encoded in our gene, but rather looking at the environment and how it impacts a gene. I was astonished how epigenetic mechanism drives seasonal rhythms, in a highly regulated fashion. For example, insects such as fruit flies have a well-established seasonal rhythm - they overwinter and enter a state of hibernation called diapause, and then during summer they actively thrive and reproduce.
I then went on to study the importance of gene regulatory mechanisms in daily rhythms, or circadian rhythms. That's even more interesting because now things are not happening in a particular season, but in a 24 hour cycle. What happens to this change when someone is predisposed to certain diseases such as type 2 diabetes or dementia? All this coming together made me interested to understand how we can leverage what we already know about the circadian system and how they are connected with other diseases like Alzheimer's and Parkinson's. How can we get the two together and improve the quality of life of the patients who are either facing these diseases or identify diagnostic markers.
How did dance come into your science?
I’ve had a passion for dance since high school and coming from the cultural city of Jaipur in India, I was very interested in folk dance. When I started my PhD and learned more about biological clocks, I subconsciously started making this connection - it's like a dance happening within our body. There are ups and downs, and it has to be well synchronised - the brain has to talk to the heart and the liver and this whole synchrony gives it this beautiful output.
Another very strong connection is how light sets the circadian clock in motion, similarly musical beat or rhythm sets the dance in motion. You may think sleep and dance are two completely independent things, but they have so much in common. I’m interested in how we can use the power of art to understand the biological mechanism. I think it's a whole new concept of interdisciplinary science, the marrying of two fields together in understanding how our body responds.
How else do you think your passion for dance has helped your neuroscience work?
Often during research, we are presented with a result or an observation, and I think my understanding of dance helps me often to understand my research that how dynamic these concepts could be and there could be multiple regulators and we have to factor everything in like in dance. It's not just the music, it could be the environment, the costume, the props. All these are kind of regulators which would contribute to the final performance.
It's all dependent on these multiple factors, so sometimes it does help to for me to see my scientific observation with a different lens that I take from my passion of art or dance, and then to see whether I can understand it in a better way.
Have you got any hope for the future to further combine them?
This year I participated in an outreach event run by TORCH (The Oxford Research Centre in the Humanities) on the theme of sleep and dance, where I could share my passion and experience in both fields. I'm very interested in this interdisciplinary field of science which is bringing together different concepts, and not just understanding but helping. For example, music could be a very important tool for use in palliative care in Alzheimer's or Parkinson's. We have these different streams that don't quite talk to each other, but I think that with digital transformation, AI, and people now getting involved on a global platform, it's an excellent opportunity to combine our knowledge to learn and benefit for human welfare.
...when you knock out this one gene, you're not just messing with the core clock circuitry, but you're also messing with the downstream rhythmic genes...From basic to advanced processes, everything is impacted.
Returning to your scientific research, you recently published a paper in eLife, can you tell us more?
We have this molecular clock which is encoded and that is made-up of a certain set of clock genes and clock-controlled genes that go up and down during the day. I am interested in the factors that regulate this highly regulated wave of gene expression. My previous lab (Dr Patrick M Nolan) in MRC Harwell found out that there is this massive zinc finger protein ZFHX3 and if you have a mutation in this protein, basically what happens is the clock runs faster. Normally the clock runs at a pace of around 24 hours that coincides with the length of the day. There were two questions I wanted to answer.
1. What happens if I completely wipe out this gene? Can I see the clock still functioning?
2. If the clock is functioning, is it functioning at the same pace, and if not, what's happening at the molecular level?
We used an inducible mutant mouse model to wipe out this gene in adult mice and study if the clock is functioning.
What did you discover?
Firstly, we saw a change in patterns of activity at the behaviour level: mice are nocturnal, they sleep in the light phase, but in the animals where we have knocked out this gene, they seem to be active towards the end of the light phase.
Secondly, at the molecular level, most of the clock genes seems to be rhythmic, but showing an advancement in their peak expression in mutants. This supported what we discovered in the behaviour level.
Thirdly, what was really interesting is that apart from the clock genes, there are other genes known as clock-controlled genes. These constitute about 30% of total expressed genes, and 55% of these genes tend to be impacted when you wipe out the ZFHX3 protein, which is a very pronounced effect. This shows that when you knock out this one gene, you're not just messing with the core clock circuitry, but you're also messing with the downstream rhythmic genes, which would now influence everything from cell cycle to neuropeptide signalling. From basic to advanced processes, everything is impacted.
This is the first time we have shown how this particular gene that encodes a transcription factor is now interacting with these DNA binding histone proteins and regulating the genes.
What's the impact of this study in your field?
We have identified a clock modulator - a gene which is highly expressed in suprachiasmatic nucleus (SCN), which is where the clock centre is and that is regulating the pace of the clock. In the past, some genome wide association studies have shown that this gene is indeed related to other disorders and diseases such as spinocerebellar ataxia. This gives us an opportunity to test whether there is a connection between circadian misalignment and these diseases via this particular gene.
Read the full paper: Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus, in eLife
Discover more about the Sleep and the Rhythms of Life project from TORCH (The Oxford Research Centre in the Humanities).