Tapscott, Stephen JSmith, Andrew A2024-02-122024-02-122023Smith_washington_0250E_26271.pdfhttp://hdl.handle.net/1773/51224Thesis (Ph.D.)--University of Washington, 2023DUX4 is a pioneer transcription factor that drives zygotic gene activation (ZGA) in the early embryo. DUX4 is also the causative gene of facioscapulohumeral dystrophy (FSHD). Recently, DUX4 has been credited for driving the totipotent program in naïve embryonic stem cells, and for driving immune evasive properties in an assortment of cancers. Thus, DUX4 has its fingers in a lot of pots, but its mode of expression in these different contexts is not well understood and there hasn’t been a thorough study of DUX4 expression across different tissue types in development. The mouse ortholog of DUX4, mouse Dux, largely mirrors the function of its human counterpart and, in these chapters, I discover mouse Dux expression in the adult male germline as well as in the trophoblast giant cells (TGC) of the developing placenta, which I propose is driving maternal immune tolerance during embryo implantation. I then define the transient nature of DUX4 expression in rare cells across an assortment of human cancers and show how DNA-damaging agents can promote this DUX4+ state, which then leads to an immune evasive phenotype. The expression of DUX4 in the context of FSHD is relatively well-defined, but these rules don’t appear to apply to DUX4 expression in development and cancer. I show that DUX4 RNA transcripts are fundamentally different in development and cancer from those driving DUX4 in FSHD. Even though these transcripts all end up driving expression of the same DUX4 protein, this indicates different molecular mechanisms may be activating transcription of DUX4 in a developmental context. Furthermore, I demonstrate that DUX4 can drive transcription of itself. Although other master regulator genes have been reported to autoregulate, this is novel for DUX4. I hope these findings aid the field in its pursuit of understanding the modes and consequences of DUX4 expression in wanted and unwanted contexts.application/pdfen-USnoneCancerDevelopmentDUX4PlacentaRNA splicingTotipotentMolecular biologyGeneticsCellular biologyMolecular and cellular biologyThesis