The genetic mutations that cause FSHD all lead to mis-expression of the DUX4 protein, thus potential therapies centre around inhibiting DUX4 activity. The DUX4 protein functions in the nucleus of the cell where it turns on a set of genes that are not compatible with healthy muscle. Our previous work has shown that one end of the protein binds DNA, while the other end of the protein interacts with various cofactors to regulate gene expression. We have recently determined the atomic structure of the DNA binding part of the DUX4 protein, and the current grant focuses on obtaining an atomic resolution structure of the part of the protein that regulates gene expression. Our work has shown the DUX4 interacts with two protein cofactors named p300 and CBP and that this interaction is central to the function of DUX4. We will probe the molecular structure of this part of DUX4 and determine how it interacts with p300 and CBP. This molecular detail will be valuable for designing and developing small molecule inhibitors of DUX4 function that could be developed into therapies for FSHD.