MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy. MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy

We identified MATR3 as the first direct endogenous inhibitor of DUX4. We found that MATR3 directly binds to DUX4 DNA-binding domain and blocks DUX4-mediated gene expression. As a result, MATR3 administration rescues cell viability and myogenic differentiation of FSHD muscle cells, while it does not affect healthy muscle cells. Notably, we characterized a short MATR3 fragment that is necessary and sufficient to directly block DUX4-induced toxicity to the same extent of the full-length protein. Overall design: Examination of the transcriptomic differences due to MATR3 overexpression in muscle cells from FSHD muscular dystrophy patients.