Thibault Viennet

Project title

Cracking the code of FoxO3 transcription regulation by phosphorylation

What is your project about?

One of the most important processes in biology is transcription, or the conversion of DNA into RNA. Select DNA genes shall be turned on only in specific cell types and at certain time points, meaning that transcription is a tightly regulated process. Proteins called transcription factors serve as master regulators of transcription, they bind to DNA in specific sites, recruit the transscription machinery and allow the expression of genes into messenger RNA. FoxO3 is a critical transcription factor that keeps cells in check and protects against aging and cancer. Dysregulated FoxO3 can result in disease. My project aims at understanding how FoxO3 is regulated by phosphorylation, which is a small chemical modification that impacts protein structure, dynamic behaviour and interactions.

How did you become interested in your particular field of research?

I came to structural biology thanks to circumstances in my studies. At the time, I was a chemical engineering student and wanted to specialize in pharmaceutical engineering, but that elective was discontinued, and I was allowed to choose a Master’s degree at the University instead. I chose bioanalytical chemistry and became absolutely fascinated by how we can visualize the structure and dynamics of proteins and understand their biological functions at the atomic level. I did my Master’s thesis work in structural biology of a Hepatitis C protein and my scientific journey continued on from there.

What are the scientific challenges and perspectives in your project?

The big challenge in investigating transcription factor regulation for structural biologists like myself is that the interesting parts, the ‘brains’ of proteins that contain most of the phosphorylation sites, are not actually structured. They do not adopt a single, stable, 3D structure but rather a whole array of interconverting conformations. This means that most analytical techniques we usually use (X-ray crystallography and cryo-electron microscopy) fall short. However, we can use Nuclear Magnetic Resonance or NMR. NMR is a technique related to MRI, where we analyse how samples inside powerful magnets respond to radiofrequencies, and this gives us atomic-level information about the conformation and dynamics of proteins.

What is your estimate of the impact, which your project may have to society in the long term?

With the lifespan increasing, our societies are facing a major challenge in helping people stay healthy as long as possible. Aging-related disorders such as neurodegeneration and some cancers constitute ever increasing health burdens. Understanding the biological processes by which our organisms protect us from aging, and why they are more efficient in some individuals, holds great promise for developing treatment options for aging-related disorders.

Moreover, targeting transcription factors with drug design has been extremely challenging so far, it is considered a holy grail of drug discovery, any advances on that journey will have a great impact on pharmacological research.

Which impact do you expect the Sapere Aude programme will have on your career as a researcher?

The Sapere Aude: DFF Research Leader Grant is an invaluable chance to kick start my own research group. I will now be able to recruit a team of postdoc and PhD student to work on understanding FoxO3 transcription in aging. We will together establish methods and procedures to study protein phosphorylation on the structural level. This is an exciting prospect, and I am confident it will also form the base for future endeavours in addressing the mysteries of biological regulation. I am grateful to have the opportunity to prove myself as a research leader.

Background and personal life

I grew up in a small village in the middle of France, among beautiful volcano landscapes. My studies and scientific career then took me to Lille, Lyon, Düsseldorf and Boston. Every move brought up a new environment and new encounters with people who helped me grow as a person and as a scientist. Now I live in Aarhus with my partner. We enjoy cooking, specifically Vietnamese recipes, and traveling whenever we can to discover new parts of the world with a curiosity for new foods and cultures that is not so dissimilar from my own scientific curiosity.