Revealing and Suppressing Long-Range Genomic Contacts that Cause Endogenous DUX4 Activation

Investigator: Mitsuru Sasaki-Honda PhD

Category: Research - Basic

This research project aims to uncover how DUX4, the central player of this disease, becomes activated in patients' muscles. While numerous excellent studies have explained how DUX4 damages muscles once it appears (i.e., downstream events), our understanding of what allows DUX4 to appear (i.e., upstream regulatory mechanism) still remains limited and controversial. Moreover, it is a well known and unaddressed question why DUX4 is not always, or rather rarely, ON when we look at each cell in one muscle cell pool derived from an FSHD individual, where basically all the cells should share the identical genetic FSHD setting. Importantly, such rare DUX4 activation appears sufficient to cause muscle degeneration in FSHD. Using a cell culture system that monitors rare DUX4 activation, I will confirm a new mechanism that switches on DUX4, not through a local "finger" push, but through a long-range "arm" contact. Based on this finding, we will also test a therapeutic concept to block such arm reach by strengthening the original border before the switch. We will also test the combined effect of this approach with blocking the switch itself to enhance DUX4 suppression. Our findings will add a new layer to DUX4 suppression strategies.