Proteogenomic Discovery of Novel Disease-Activity Markers in FSHD Muscle

Investigators: Giorgio Tasca PhD, Lorenzo Calviello PhD, Sujatha Jagannathan PhD

Category: Research - Basic

FSHD is caused by the abnormal activation of a gene called DUX4 in muscle. This gene turns on many other genes that damage the muscle, but we still do not fully understand how it causes disease. New scientific methods have shown that our DNA contains many “hidden” or previously unknown messages. They are parts of the genome that were not recognised as significant contributors to biology and disease. It turns out that these hidden messages can produce small proteins that are usually difficult to detect. Together, they contribute to the so-called “dark proteome”, the ensemble of undetected proteins in our cells.

Our early research suggests that DUX4 may specifically switch on many of these hidden messages in FSHD muscle. Some of them appear to make previously unknown proteins, which might play an important role in how the disease works. They may even be involved in causing inflammation in muscle or could help us identify which muscles are becoming more affected.

In this project, we will study muscle biopsies from people with FSHD using advanced technologies that can detect both RNA (the messages the cell makes) and proteins, even the very small or non-canonical ones. We will create a map of these hidden proteins in FSHD, and study how they could alert the immune system and contribute to inflammation. Finally, we will switch off some of the most promising new candidates in the laboratory to see whether they affect the harmful actions of DUX4.

This work is important because it opens a new area of FSHD research. By uncovering these hidden molecules, we will identify new markers that show how active the disease is and find new targets for treatments. This project may help reveal aspects of FSHD biology that have been invisible until now.