Featured scientist profiles

July 2023: Dr Clara Lopes Novo

This month, Imperial Stem Cell and Regenerative Medicine Network (ISRMN) interviewed Dr Clara Lopes Novo, a Project Research Scientist at the Francis Crick Institute, Honorary Research Fellow at Imperial College London and ISRMN member.

Interviewee: Dr Clara Lopes Novo
Interviewer: Priyanka Peres (priyanka.peres22@imperial.ac.uk)

Priyanka: Good afternoon Dr Novo, thank you so much for meeting with me. I am very excited to discuss your research with you - it is a fascinating exploration of what drives genomic instability in the genome and epigenome, and you've chosen stem cells as your main model of study, which is particularly interesting to us. Before we discuss that, what got you started in science and what has been your journey so far?

Dr Novo: You’re welcome, and yes, it's a funny story. Why science? Ever since I was born, I have always been very curious about science and biology in particular. When I was 11, I went to an exhibition in the Atomium building in Brussels. There, they had a molecule of DNA stretching from one wall to another, which was labelled as “the code of life”. I was amazed and I even asked my biology teacher for further reading about DNA. From that moment I decided I wanted to be a scientist and study genetics.

Priyanka: That's so exciting. It's so interesting how our experiences as children continue to motivate us in the future.

Dr Novo: Yes, especially that phrase: “This molecule encodes the meaning of life”, in all organisms, in everything, every life has a code. I thought that was amazing.

Priyanka: Did that mean you studied biology as an undergraduate?

Dr Novo: Yes. I did biology with a heavy focus on genetics. Although I did study other subjects within biology, genetics has been my focus since undergrad, and my PhD was in human molecular genetics as well. So yes, this has been my area of research since the beginning.

Priyanka: And how did you find yourself here, studying genomic instability?

Dr Novo: That again, is a funny story. So I study junk DNA: the repetitive, noncoding sections of the genome. Although we now know it is expressed, at the time, ‘junk DNA’ was seen as non-functional. The reason I got interested in this area was one of the first courses I had in
university. The lecturer was talking about telomeres and she said “This is part of junk DNA but it's also important for cancer and ageing”. I was baffled - how could something be “junk” DNA and yet important for ageing, cancer and more? So I got really interested in telomeres and that's what I first studied in my postdoc. During that time, I wrote a review about the 3D organisation of the nucleus and telomeres specifically. That was the first time that I shifted my perspective of genetics from 2D to 3D. We tend to think of DNA as a linear molecule but it's not, it has a complex 3D structure. I realised that that's what I am interested in - the three-dimensional nucleus and its impact on embryonic development and stem cells.

Priyanka: Why is it that you chose stem cells specifically, to study 3D organisation?

Dr Novo: Well, during early embryonic development, in the pre-implantation embryo, the chromatin is very plastic, as these cells can develop into any cell type - the 3D organisation hasn't been defined yet. Then, cells start exiting pluripotency and priming for different cell fates and each cell type has a very defined 3D organisation. So before that point, there is a small window of development. If you want to understand what regulates how the genome is organised in 3D, this is the developmental window that you need to study.

Priyanka: That's very interesting. Within this field, what are you currently working on?

Dr Novo: So I have continued to study junk DNA or heterochromatin - telomeres and pericentromeres. These are regions of the genome that are normally very compact and have silencing epigenetic marks. Except in stem cells - where they are still compact and heterochromatic. My work aims to understand why: why pluripotent stem cells require these regions or why they can tolerate these regions being less heterochromatic. We found that if we force compaction and increase heterochromatin in these regions in embryonic stem cells it leads to genetic instability. Based on this, we believe there is a need for less compaction in these regions in pluripotent embryonic stem cells. There seems to be a need to maintain this junk DNA, this heterochromatin, in a more relaxed manner. Currently, I am studying the role of telomeres and pericentromeres in relation to genomic instability in mouse embryonic stem cells.

Priyanka: And what is your prediction of the role that they might have?

Dr Novo: Given that these regions are very heterochromatic and their neighbouring genes are often silenced, my hypothesis is that by allowing these regions to be less heterochromatic in stem cells, they don’t silence nearby genes as strongly. Then, once the cells exit pluripotency and these regions become more heterochromatic, it creates ‘heterochromatin hubs’ where any genes in the vicinity by 3D structure (through genome looping or other structures) are silenced and repressed.

Priyanka: So it would be a kind of mass silencing of genes that control pluripotency?

Dr Novo: Exactly, just by the folding of the genome, which would increase gene silencing in these hubs. Genome folding also happens differently in the different cell types. And so you have different sets of genes potentially being silenced by these heterochromatin hubs.

Priyanka: What do you envision as the impact of this work in the future?

Dr Novo: There are actually two main points for this. One of them is that all these rearrangements of the 3D organisation - the compaction and the heterochromatinization of junk DNA - happen normally during embryonic development, but the reverse happens during tumorigenesis. Most tumours have relaxed junk DNA and less heterochromatin. Telomeres are also elongated to grant immortality to cancer cells and overall, the 3D organisation of the cell type of origin is lost in the tumour-derived cells. This represents a loss of 3D memory in the cell. So we hope that by understanding the processes that naturally occur during embryonic development, we may actually understand how these processes can be deregulated and contribute to tumorigenesis.

The other potential future impact of this work comes from the link to genetic instability. Early compaction of these regions often leads to aneuploidy in the cell. Aneuploidies are the most common defect observed in spontaneously aborted embryos, which are not able to implant in the uterine wall. We don’t fully understand this process: stem cells do have relaxed DNA repair pathways that allow them to continue dividing but clearly some process is still checking for genetic or chromosomal defects such as aneuploidy. We believe that understanding the epigenetic regulation of heterochromatin and genetic stability in the embryo could provide invaluable biomarkers for IVF treatments. We could potentially identify which embryos look like they have a more promising 3D organisation of their genome. So this research has potential for an impact on reproductive biology as well. However, there is still a lot to learn about what regulates the stability of the genome in preimplantation embryos. We also know that in ageing women, the processes that maintain the 3D organisation of the
genome and the epigenetics - the positions of heterochromatin marks - start decreasing efficiency. In an ageing population such as ours that starts having children at a later age, I think research into reproductive biology will become increasingly important.

Priyanka: Fascinating, thank you for explaining that. What would you say has been the most challenging aspect of this work for you?

Dr Novo: I would say - the dogmas in the field. So, for example, heterochromatin was thought to be very compact and very static in 3D, but new insights from pre-implantation mouse embryos have shown that it is actually quite mobile and a lot more flexible than we anticipated for many years. A big challenge has been to get the scientific community to understand that.

Priyanka: On the other hand, what's been the most rewarding or exciting part of it for you?

Dr Novo:
Very similar - it's through challenges that we move forward, after all. The most rewarding has been to speak with people and watch them change their minds or consider a new perspective, based on our data, especially our live imaging of heterochromatin.

Priyanka: Thank you so much. This has been incredibly interesting and all the best to you with
all of your work. Thank you so much for speaking with me and the ISRMN