A conversation with Dr Raffaella Nativio by Dr Mike Morten
Dr Mike Morten joined the UK DRI in 2020 and is a Research Associate in the lab of Dr Yu Ye. His research focuses on super-resolution imaging, cell stress, proteasomes and neurodegeneration.
Dr Raffaella Nativio is a Lecturer in the Department of Brain Sciences and group leader at UK DRI Imperial. Dr Nativio's research investigates epigenetic mechanisms involved in healthy aging and age-related neurodegeneration.
Mike: Hi Raffaella, to start off I wondered if you could tell me how did you first get interested in science and how did that transform into studying epigenetics?
Raffaella: Hi Mike. Both my parents are science teachers, and it is possible that this sparked my interest in the natural sciences, although I also liked philosophy. In high school I got fascinated by genetics, especially the combinatorial aspect of it revealed by Mendel’s studies on genetic traits (dominant and recessive) in the pea plant. The jump from genetics to epigenetics came pretty quickly, as epigenetics explains phenotypes beyond gene combination. In my undergraduate studies I really enjoyed reading about the mechanisms of transcription and DNA replication which are linked to chromatin regulation, and during a firsthand experience in the lab of Dr Giuseppe Macino in Rome that studied quelling in N. crassa, I decided that I really wanted to work on epigenetics and chromatin mechanisms. And yes, I went onto studying epigenetic regulation in different biological systems in both my graduate and postgraduate studies – I am very happy with my choices so far!
Mike: From my understanding, as a non-expert, epigenetics concerns of looking at DNA and its surrounding environment. Is there a better way you could describe it?
Raffaella: A simplified definition of epigenetics is a change in phenotype without a change in genotype. This involves how DNA responds to the environment inside and outside the cell in which it exists. Examples of epigenetics include the process through which totipotent stem cells become other cell types, such as skin cells (keratinocytes) or brain cells (neurons) but also the development of an entire organism from a single fertilized egg. There are so many aspects of epigenetic regulation that are fascinating and so many more to be discovered! Because the way epigenetics integrates external stimuli, such as environment, diet and lifestyle, into the DNA, there is an increasing interest for the role of epigenetics in complex systems, such as aging and age-related disorders like cancer and neurodegeneration.
Mike: So it is a big research area! What are the areas you are interested in?
Raffaella: We are interested in studying the role that epigenetics play in aging brain and age-related neurodegeneration. I started working on this topic during my postdoctoral training in the laboratory of Dr Shelley Berger at the University of Pennsylvania – a wonderfully multidisciplinary lab, fostering links between epigenetics and different aspects of biology.
Additionally, because of my training in molecular biology, I am still very interested in the basic mechanisms of epigenetic regulation, and particularly those involving gene transcription regulation by enhancers, which are DNA elements that modulate the expression of a gene at a distance through looping mechanisms. Given that enhancers have been implicated in aging and neurodegeneration, I hope that we can identify some basic aspects of their regulation while studying their involvement in aging and neurodegeneration.
Mike: Could you tell a bit about your research?
Raffaella: Yes, let me start by explaining the rationale of my work. Aging is the top risk factor for neurodegeneration and mechanisms involved in aging could be involved in neurodegeneration. At the same time, it has been shown that epigenetics impacts aging and lifespan in lower organisms, such as yeast, fly and worms. Therefore, given the link between aging and neurodegeneration, and between aging and epigenetics, the hypothesis that epigenetics is involved in aging and neurodegeneration in humans was very plausible to us. With this in mind, together with my former colleagues and close collaborators at University of Pennsylvania, we went onto performing a series of studies comparing the epigenome of Alzheimer’s affected brains to healthy aging, starting by asking whether Alzheimer’s is an acceleration of aging. We used ChIP-seq to identify regions of the genome that are enriched with a particular histone modification called H4K16ac (acetylation of lysine 16 on histone H4). Histones are proteins that wrap the DNA around to keep it organized in the nucleus, and their modifications, such as acetylation, regulate gene expression. Our comparative analyses revealed changes of H4K16ac in Alzheimer’s that went opposite to those in healthy aging, thus indicating that the epigenome of Alzheimer’s is different from healthy aging and that changes in H4K16ac during aging could protect against neurodegeneration. In a second study, we integrated several types of omics data, including mass spectromety, ChIP-seq for several other histone modifications, and RNA-seq from the same set of samples. In this study we identified that two other histone modifications (H3K27ac, H3K9ac) were specifically enriched in AD and were associated with genes linked to disease pathways. These studies now provide the foundations for our future research.
Mike: And you have used some pretty impressive techniques including ChIP-seq and RNA-seq in your previous papers, are there any strategies you are excited about using in the future?
Raffaella: Thank you. Both ChIP-seq and RNA-seq are straightforward to perform, unless the type of sample is challenging to work with. What is impressive about these techniques is that by being coupled with high-throughput sequencing, they provide a complete screenshot of a particular event happening in the cell, such as of all the expressed genes in the case of RNA-seq. These methods are highly quantitative and therefore can be used to measure differences between biological conditions such as those of disease versus control. Some other impressive techniques based on high-throughput sequencing are those like HiC, which allow to detect DNA elements, such as enhancers and promoters, that are arranged closely together in the nuclear space despite being far apart in the linear DNA sequence. Given that enhancers are implicated in neurodegeneration, it is important to know the chromatin architecture of the nucleus, so to assign each enhancer to their target gene. This will further improve our understanding of the gene pathways involved in aging and neurodegeneration. Other techniques and systems that we plan on using are gene editing tools such as CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) cell culture models to test hypotheses generated by the analyses of genome sequencing data in tissue.
Mike: What do you hope to find out using these methods?
Raffaella: Based on our previous findings, indicating that different histone modifications are differently associated with healthy aging and Alzheimer’s, we now aim to investigate the epigenetic mechanisms that trigger the onset or progression of neurodegeneration during the course of aging. We are also interested in how the epigenome of different cell types of the brain, such as neurons and glia, modulate environmental, metabolic and genetic risk, which will help us to understand the contribution of the environment and the genotype to neurodegeneration.
Mike: So you are mapping out the entire genome rather than looking at specific targets?
Raffaella: Yes, the systems that we are studying are complex and there is a lot we don’t know and that we have to discover ourselves. Our findings so far point to a set of dysregulated systems, such as the involvement of multiple types of histone modifications, their modulators, and their target genes. Most, if not all age-related diseases are multifactorial and cannot be explained by a single dysregulated gene. In contrast, we know that the early onset of Alzheimer’s is due to a set of well-defined genetic mutations, and therefore it is possible that the mechanisms that lead to late vs early onset Alzheimer’s are different.
Mike: And what does that mean in terms of trying to understand dementia or finding new therapies?
Raffaella: Epigenetic modulation is plastic and reversible, and drugs that modulate the activity of chromatin factors could potentially be used to modulate neurodegeneration-related processes. For example, we would like to potentiate the pathways that protect from disease while inhibiting those that promote it. At the cell type-specific level, we would like to improve neuronal resilience while modulating microglia activation. Some epigenetic drugs have been used for cancer treatment, and studies in mouse models of neurodegeneration have shown some effects on memory using generic histone deacetylase inhibitors. However, I believe that we need very targeted epigenetic drugs, which could be cell-type and pathway-specific.
Mike: Are there any other diseases or important research avenues relevant to the epigenetic markers you are studying?
Raffaella: Epigenetics has been extensively studied in the context of cancer, where mutations have been found in genes that code for epigenetic factors, or where widespread epigenetic changes were observed that were connected to cancer progression. The application of epigenetics, and even more of epigenomics, to the study of the brain has only recently started, thanks to the increasing availability of tissue samples for research and the recent advancements in technologies for epigenomic studies using low input material. These advancements have opened up new possibilities for exploring the epigenome in the context of aging and age-related neurodegeneration. In the future, we will compare the epigenome across multiple types of age-related neurodegenerative diseases and compare those with healthy aging to identify shared or disease-specific epigenetic pathways that could become the targets of therapeutical interventions.
Mike: Switching gears a little but… What experiment/research project are you most proud of or have enjoyed the most?
Raffaella: Several of the projects I carried out were either technically challenging or required involved downstream analyses, such as the integration of multi-omics data. My PhD project involved the use of the 3C technology to investigate the chromatin conformation at an imprinted locus. Given the complex nature of imprinted loci, where regulatory elements can act differently depending on whether they are on the maternal or paternal allele, we had to devise strategies to identify differences based on the parental origin of the allele. The project was successful, and we also identified a new role for cohesin in chromosome conformation - so I was quite happy of the outcomes of my PhD work. And in my recent studies, I was particularly proud of pioneering the epigenetic comparison between Alzheimer’s and normal aging. The findings of these studies are at the basis of the work that I have been setting up at Imperial, so I am very pleased by how those studies turned out.
Mike: It’s nice to hear you mention some of your colleagues. What memories do you have any of mentors or teachers that stand out?
Raffaella: Looking back, I am very grateful for all the wonderful people I met during my years of scientific training. My lab mates of the early days trained me in using molecular biology techniques. With my peers I had great scientific discussions, friendship, and fun in the lab. I also had amazing collaborators, who with their expertise and kindness have done everything from helping to make our projects scientifically solid to giving great career advice. I am particularly fortunate for having had mentors who made important contributions to the field of epigenetics! Through them I got great projects, direction, scientific discussions, career advice and support for scientific independence. They taught me not only about science, but also about other aspects that are important to run a lab, such as the importance of having an ambitious vision, of good communication, and of fostering a culture of care and respect for each other in the lab. It has been great to enjoy their support on my path to scientific independence at Imperial College and UK DRI.
Mike: Finally, does the UK have better coffee than the US?
Raffaella: I am not sure as I don’t drink coffee, but what I can say is that the tea I drink in the UK is pretty strong and gives me a good boost to start my day at Imperial! ;)