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The overall objective of this study is to identify, characterize, and ultimately inhibit DUX4 protein modifications that may contribute to its toxic properties in FSHD muscle. Although the FSHD field has largely accepted the model that DUX4 plays a key role in FSHD, we do not yet understand how the DUX4 protein is regulated. Thus, delineating how DUX4 protein function is regulated is an important unmet need in the field, especially for therapeutic design. The DUX4 gene encodes a transcription factor protein that operates by turning on other genes, some of which may be toxic to muscle. I hypothesized that reversible chemical changes on the DUX4 protein (called post-translational modification [PTM]) may be a control switch that regulates the DUX4 function of DUX4 protein. PTMs play key roles in how a protein binds to other molecules, where it goes inside a cell, and how stable the protein is. My primary goal was to first identify whether DUX4 had PTMs (it does), and then to map them on the protein, and determine their contribution to DUX4 toxicity. I then set out to identify enzymes responsible for adding or removing these modifications, with the rationale that these would then become drug targets. By accomplishing these goals, I hope to establish a framework for a DUX4-targeted drug therapy designed to disrupt PTMs and prevent DUX4 toxicity to muscle.