15 January 2026
Meet Fabio Marcuccio, Postdoctoral Fellow at the Legnini Group (Genomics Research Centre, Functional Genomics Programme), who has been awarded a prestigious Marie Skłodowska-Curie Actions Postdoctoral Fellowship for the project “Regulation of mRNA homeostasis by poly(A) binding proteins”. The €193,643.28 grant will support a 24-month research programme aimed at uncovering how cells keep messenger RNA (mRNA) levels stable despite constant changes in their environment.
By combining genetic engineering, advanced imaging, molecular and biophysical approaches, and mathematical modelling, the project will investigate whether poly(A) binding proteins act as an internal “sensor” that allows cells to measure and fine-tune mRNA production and removal. This fundamental work seeks to resolve a long-standing question in gene regulation, with potential long-term implications for understanding disease mechanisms and RNA-based therapies, including mRNA vaccines.
Fabio, can you explain the project’s main objective?
Messenger RNA (mRNA) is a molecule central to all life forms. mRNA acts like a set of instructions that tells the cell how to make the proteins it needs to survive and do its job. For this to work, cells must always keep the amount of mRNA at the right levels. What is surprising is how cells can manage this balance, even when conditions change. If more mRNA is produced, cells will also remove it faster, while if less is made, they slow down its removal. This mechanism is called mRNA buffering. It is a vital mechanism, but we still don’t understand how cells are able to coordinate this mRNA production and removal to ensure that the right levels are maintained.
My project aims to find out whether cells use an internal “sensor” to monitor mRNA levels and keep them constant. This sensor would work much like a thermostat in a house, which measures temperature and adjusts heating or cooling to keep it steady. We have identified promising sensor candidates, the poly(A) binding proteins. These proteins attach to every mRNA molecule, and we believe they may allow cells to measure how much mRNA is present and adjust its production or removal accordingly.
To test this hypothesis, I will genetically engineer cells to alter the abundance of these proteins. I will then combine advanced imaging with other molecular and biophysical approaches to measure the changes in mRNA production and removal when the abundance of these proteins is altered. I will then use the data from these experiments to build mathematical models to describe how this system works, allowing us to confirm our hypothesis or to generate new predictions.
What are the main steps in the project’s development?
The RNAhome project is divided in three main work packages:
- first, the generation of cellular models with different abundance of “sensor” proteins;
- second, the use of advanced microscopy and biophysical methods to measure how RNA production and removal change at varying abundance of these “sensors”;
- third, the development of a mathematical model to describe this dynamic system.
I expect to obtain the first results during the first year of the fellowship, once the cellular models are established and the initial imaging experiments are completed. These early findings will provide important insights, which will then be validated and expanded using complementary techniques during the second year. In the final phases of the project, mathematical modelling will bring together all the measured parameters, helping us to interpret the data and build a coherent description of this complex and dynamic system.
Who are your collaborators on this project?
No project can be performed by yourself, and the highly multidisciplinary nature of RNAhome will strongly rely on collaborations. Collaborations within the Legnini group, my host research group, will be essential to the success of this project. The group brings together researchers with diverse expertise, and the project will strongly benefit from this collaborative environment, where ideas, skills and knowledge are continuously shared and developed. The project will also rely strongly on collaborations within different HT groups and facilities. The National Facility for Data Handling and Analysis will help me develop the pipelines required for microscopy image analysis. The Biophysics Unit will provide technical expertise to perform the experiments required to extract important kinetic parameters for my model, and the National Facility for Genome Engineering and Disease Modelling will provide the required cellular models.
What impact do you hope to achieve with this project?
With this fellowship, I aim to elucidate a key mechanism regulating gene expression, a problem that has remained unresolved for decades, and whose solution will open countless new research avenues and advance our understanding of disease mechanisms with invaluable therapeutic implications such as mRNA vaccines, which rely on a deep understanding of mRNA stability to ensure their efficacy and safety.RNAhome is a fundamental research project, and its impact on human health will not be immediate. However, history shows that the major breakthroughs often originate from basic, curiosity-driven science. The COVID-19 pandemic clearly demonstrated how decades of fundamental research enabled the rapid development of mRNA vaccines when an urgent global challenge emerged. For many years, scientists studied RNA simply to understand how cells function, how genetic information is copied, modified, and translated into proteins. This foundational knowledge has already proven essential for revolutionary RNA-based technologies. In the same way, RNAhome aims to uncover principles of RNA regulation that could lay the groundwork for future advancements in RNA therapeutics and help improve existing treatments. While the outcomes may not be predictable, it is precisely this curiosity-driven research that often leads to the most transformative innovations.
How does this advance RNA research?
As part of the Functional Genomics Programme of the Genomics Research Centre, we are interested in one big question: how is RNA metabolism regulated within a cell? RNA is constantly produced, modified, transported, and removed, and the rates of these processes determine RNA stability. Understanding the key factors that determine this stability is central to understanding gene regulation. RNAhome will advance this field by uncovering critical aspects of this regulation, meaning how RNA production in the nucleus and removal in the cytoplasm are coordinated. By understanding how these processes are coupled, the project will add a new layer of control of gene regulation and show how cells maintain the right balance of RNA to function properly.
Are you excited about this fellowship?
I am very excited about this fellowship because, for the first time in my career, I will manage my own research budget, which represents a first small step toward becoming an independent scientist. Even more exciting is that a significant part of the fellowship will support my personal training, allowing me to attend conferences, workshops, and other learning opportunities. I have always believed that learning something new every day is the best aspect of this job, and this fellowship boosts that experience by focusing on my personal growth, skills development, and the chance to shape my own research journey. After all, who wouldn’t be excited to get paid for learning something new every day?
What are the main challenges, and how do you plan to overcome them?
Working on ambitious projects is never a straight line from start to finish. It is a winding path full of challenges, unexpected results, and changing hypotheses. The best way to face this is to embrace the journey and enjoy the process. My plan is to work hard, do my best, and draw on the expertise of my colleagues, collaborators, and the fantastic facilities within the institute. With so many instruments and sharp minds around me, I hope to turn obstacles into opportunities for learning, and make this an exciting and rewarding part of the fellowship.
How does this project build on your previous work?
This research builds on a long-standing interest in understanding RNA dynamics at the single-cell level. The field has advanced tremendously in the last decades; however, many fundamental questions remain unanswered and addressing them requires both new technologies and fresh conceptual ideas.
My earlier work focused on developing new tools, but I wanted to delve deeper into the fundamental science of RNA regulation. This is how I came to work with my current supervisor. The inception of this project was a deeply creative process: during my first months at the institute, I spent hours reading and brainstorming with my supervisor. We would propose ideas, challenge them, demolish them, and rebuild them until we found one that truly excited us both. This collaborative process was inspiring and reinforced my belief that science advances best through open dialogue and shared thinking. As Itai Yanai and Martin Lercher have argued, “it takes two to think”, a principle that I believe should be embraced more often in science and beyond.
What inspired you to pursue this research direction?
I am a biomedical engineer by training. As a student, I have always been fascinated by bio-inspired technologies. Nature’s designs are incredibly functional, yet our attempts to imitate them are generally imperfect. During my PhD, I developed microscopy approaches for single-cell RNA sequencing, which introduced me to the RNA world. I became interested in how cells can change and reprogram their gene expression to adapt to treatment, and I worked on developing technologies to explore this behaviour. Along the way, I realised that many engineering tools and concepts can be applied to tackle fundamental biological questions. For example, the feedback mechanisms that we believe cells use to adjust RNA levels is analogous to a negative feedback voltage regulator in electronics, both conceptually and how it can be analysed mathematically. I also learned that transformative discoveries often come from fundamental, curiosity-driven science. This fellowship will allow me to pursue a fundamental project, and, hopefully, give an engineer the means to survive (and even thrive!) in a biological institute.
Funded by the European Union (Horizon Europe MSCA RNAhome, GA n. 101207176). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Executive Agency. Neither the European Union nor the granting authority can be held responsible for them
