FSHD Muscular Dystrophy Provides a Molecular Understanding of the Repetitive (epi) Genome

Facio-Scapulo-Humeral muscular dystrophy (FSHD) is one of the most important hereditary diseases affecting the skeletal muscle and has a strong epigenetic component (ie not associated with changes in the DNA sequence). Unlike the majority of hereditary diseases, FSHD is not caused by a genetic defect in a gene encoding for a protein. Instead, the disease is associated to the reduction of the number of copies of DNA, called D4Z4, which are repeated many times towards the end of the long arm of chromosome 4. Despite years of intensive research the pathogenesis of FSHD remains largely unknown. For this reason, there is no treatment or cure for the disease. The objective of this research project is to understand the molecular mechanism of FSHD. We recently identified DBE-T, a non protein-coding RNA that is produced preferentially in FSHD patients. Although our results indicate that DBE-T is required to trigger the cascade of events leading to FSHD, its mechanism of action is poorly understood. With this project, we aim to characterize the activity of DBE-T and evaluate its relevance as a therapeutic target. We strongly believe that, by studying the regulation and mechanism of action of DBE-T, we will be able to develop complementary therapeutic approaches for the treatment of FSHD.