Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity

Takako I. Jones; Guo-Liang Chew; Pamela Barraza-Flores; Spencer Schreier; Monique Ramirez; Ryan D. Wuebbles; Dean J. Burkin; Robert K. Bradley; Peter L. Jones

To begin to identify the mechanisms and pathways disrupted by DUX4-fl expression in murine skeletal muscle, RNA-seq analysis was performed on gastrocnemius muscles isolated from control, moderate (MD9), and severe (SD9) model mice, and analyzed for mRNA expression levels (Table S1 ). Genes with significant differential expression (>2-fold) from the ACTA1-MCM controls were identified (Table S2 ). The ACTA1-MCM/+ and FLExD/+ single transgenic mice only showed 3 genes differentially expressed (2 upregulated and 1 downregulated) between the mice ( Figure 6A and Table S2 ), which is consistent with our previous qRT-PCR studies showing no significant differences in expression of DUX4-fl or several prominent DUX4-FL targets between these mice [41] . In contrast, the transcriptomes for both the moderate and severe models were significantly different from the ACTA1-MCM controls when analyzing genes significantly misregulated >2-fold ( Figure 6B , C, and Table S2 ). The However, when these DUX4-induced genes (>2-fold) from murine skeletal muscle were compared with differential gene expression profiles from human FSHD patient muscle biopsies [24] there was very little overlap, with only 127 upregulated genes and 10 downregulated genes being the same (Table S3 ). This is not surprising since human DUX4 expressed in cultured mouse cells induces a gene set that only partially overlaps with DUX4 expression in cultured . CC-BY-NC 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/471094 doi: bioRxiv preprint human cells [70, 71] , and many functional DUX4 binding sites in the human genome are within poorly conserved retroelements [72] .