Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells.
Facioscapulohumeral dystrophy (FSHD) is caused by the mis-expression of the double-homeodomain transcription factor DUX4 in skeletal muscle cells. Many different cell culture models have been developed to study the pathophysiology of FSHD, frequently based on endogenous expression of DUX4 in FSHD cells or by mis-expression of DUX4 in control human muscle cells. Although results generated using each model are generally consistent, differences have also been reported, making it unclear which model(s) faithfully recapitulate DUX4 and FSHD biology. In this study, we systematically compared RNA-seq data generated from three different models of FSHD—lentiviral-based DUX4 expression in myoblasts, doxycycline-inducible DUX4 in myoblasts, and differentiated human FSHD myocytes expressing endogenous DUX4—and show that the DUX4-associated gene expression signatures of each dataset are highly correlated (Pearson’s correlation coefficient, r ∼ 0.75-0.85). The few robust differences were attributable to different states of cell differentiation and other differences in experimental design. Our study describes a model system for inducible DUX4 expression that enables reproducible and synchronized experiments and validates the fidelity and FSHD relevance of multiple distinct models of DUX4 expression.
Division of Human Biology; Division of Public Health Sciences; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Sujatha
S
Jagannathan
Molecular and Cellular Biology Program.
Sean C
SC
Shadle
Medical Scientist Training Program, University of Washington, Seattle, WA, USA.
Rebecca
R
Resnick
Division of Human Biology.
Lauren
L
Snider
Department of Neurology, University of Rochester, Rochester, NY, USA.
Rabi N
RN
Tawil
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Silvère M
SM
van der Maarel
Division of Public Health Sciences; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Robert K
RK
Bradley
Division of Human Biology.
Stephen J
SJ
Tapscott
D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D059467:Transcriptome
C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins