Conservation and Innovation in the DUX4-family Gene Network

Abstract

Facioscapulohumeral dystrophy (FSHD) is caused by the mis-expression of the DUX4 transcription factor in skeletal muscle. Animal models of FSHD have been hampered by incomplete knowledge of the conservation of the DUX4 transcriptional program in other species besides humans. We demonstrate that both mouse Dux and human DUX4 activate repetitive elements and genes associated with cleavage-stage embryos when expressed in muscle cells of their respective species. Specifically, mouse DUX activated the transcription of MERV-L retrotransposons and genes such as Gm4340 (a.k.a. Gm6763), Slc34a2, Tcstv1/3, Tdpoz 3/4, Usp17la-e and Zfp352, all of which are characteristic of mouse two-cell embryos. Human DUX4 activated transcription of orthologs of mouse DUX-induced genes, including orthologs of genes characteristic of mouse two-cell embryos. Despite functional conservation, we found that the binding motifs of mouse DUX and human DUX4 have diverged. To better understand the extent of conservation or divergence between these factors and to assess current mouse models of FSHD, we expressed human DUX4 in mouse muscle cells. In this context, human DUX4 maintained modest activation of early embryo genes driven by conventional promoters, but did not activate MERV-L-promoted genes. These and additional findings indicate that the ancestral DUX4-factor regulated a cleavage-stage embryo program driven by conventional promoters, whereas divergence of the DUX4/Dux homeodomains correlates with their retrotransposon specificity. These results provide insight into how species balance conservation of a core developmental program with innovation at retrotransposon promoters and provide a basis for developing crucial animal models of FSHD.